CN1980904A - CETP inhibitors - Google Patents
CETP inhibitors Download PDFInfo
- Publication number
- CN1980904A CN1980904A CNA2005800226187A CN200580022618A CN1980904A CN 1980904 A CN1980904 A CN 1980904A CN A2005800226187 A CNA2005800226187 A CN A2005800226187A CN 200580022618 A CN200580022618 A CN 200580022618A CN 1980904 A CN1980904 A CN 1980904A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- optional
- halogen
- compound
- phenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Compounds having the structures of Formula I, including pharmaceutically acceptable salts of the compounds, are CETP inhibitors, and are useful for raising HDL-cholesterol, reducing LDL-cholesterol, and for treating or preventing atherosclerosis: In the compounds of Formula I, B or R<SUP>2</SUP> is a phenyl group which has an ortho aryl, heterocyclic, benzoheterocyclic or benzocycloalky substituent, and one other position on the 5-membered ring has an aromatic, heterocyclic, cycloalkyl, benzoheterocyclic or benzocycloalky substituent connected directly to the ring or attached to the ring through a -CH<SUB>2</SUB>-.
Description
Invention field
The present invention relates to suppress cholesteryl ester transfer protein (CETP) and therefore can be used for treating a compounds atherosis with prevention of arterial.
Background of invention
Atherosclerosis and clinical effectiveness thereof, coronary heart disease (CHD), apoplexy and peripheral vascular disease cause quite huge burden to developed country health management system arranged.Only in the U.S., have 13,000,000 patients to be suffered from CHD by diagnosis approximately, the patient who dies from CHD every year surpasses 500,000.In addition, estimate that this spends in continues to spread along with obesity and diabetes are epiphytotics and increases in 1/4th following centuries.
For a long time, have realized that in Mammals that the variation that circulation lipoprotein distributes is relevant with the danger of atherosclerosis and CHD.HMG-CoA reductase inhibitor, particularly statins successfully reduce coronary artery events clinically and are based on minimizing cyclic low-density lipoprotein cholesterol (LDL-C), and the LDL-C level directly relates to the atherosclerosis danger of increase.Recently, epidemiological study shows, high density lipoprotein cholesterol (HDL-C) level and atherosclerosis retrocorrelation, and the conclusion that draws is that low Serum HDL-C level is relevant with the CHD danger of increase.
The metabolism control of lipoprotein levels is to involve the complexity of multiple factor and dynamic process.A human important metabolism control is cholesteryl ester transfer protein (CETP), a kind of plasma glycoprotein, its catalysis cholesteryl ester from HDL to the transfer of the lipoprotein that contains apoB (particularly to VLDL) (referring to Hesler, C.B. wait the people, (1987) Purification andcharacterization of human plasma cholesteryl ester transfer protein., J.Biol.Chem.262 (5), 2275-2282)).Under physiological condition, clean reaction is that wherein CETP carries triglyceride level to HDL and the allos exchange (heteroexchange) from HDL transportation cholesteryl ester to apoB lipoprotein from apoB lipoprotein.
In the mankind, CETP works in the transportation of counter-rotating cholesterol, and by this Umklapp process, cholesterol is returned liver from peripheral tissues.What is interesting is, many animals do not have CETP, comprise have high HDL level and known to coronary heart disease resistive those, for example rodent is (referring to Guyard-Dangremont, V. wait the people, (1998) Phospholipid andcholesteryl ester transfer activities in plasma from 14 vertebratespecies.Relation to atherogenesis susceptibility, Comp.Biochem.Physiol.B Biochem.Mol.Biol.120 (3), 517-525).The many epidemiological studies of the active natural variation of CETP have been carried out relating to for the effect of coronary heart disease danger, comprise that research to the known people's null mutation of minority is (referring to Hirano, K.-I., Yamashita, S. and Matsuzawa, Y., (2000) Pros and cons of inhibiting cholesteryl estertransfer protein, Curr.Opin.Lipidol.11 (6), 589-596).These researchs clearly illustrate that retrocorrelation between blood plasma HDL-C concentration and the CETP activity is (referring to Inazu, A. wait the people, (2000) Cholesteryl ester transfer protein and atherosclerosis, Curr.Opin.Lipidol.11 (4), 389-396), the hypothesis that obtains is: to reduce simultaneously that the LDL level suppresses the mankind the pharmacology of CETP lipid transfer activity be useful by increasing the HDL-C level.
Although by the great therapeutics progress of statins such as Simvastatin (ZOCOR ) representative, statins has only realized that in atherosclerosis with in the treatment of the atheromatosis incident that takes place subsequently and the prevention about 1/3rd danger reduces.At present, has only seldom pharmacological treatment can be used for advantageously the raising cyclical level of HDL-C.Some statins and some fibrates provide the optimum of HDL-C to increase.Being provided for of having good grounds clinically raise HDL-C the nicotinic acid of effective treatment be subjected to the puzzlement of patient's compliance issues, part is because side effect such as flush.The medicine of HDL cholesterol levels of raising safely and effectively can adapt to needs of medical treatment great but that be met not yet so far, and it provides the pharmacological treatment means that can significantly improve the circulation lipid profile by the mechanism of replenishing mutually with existing treatment.
There are several drugmakers studying or just in clinical trial, testing the compound of the new classification that suppresses CETP.There is not the listing of CETP inhibitor at present.Need new compound so that can find safety and effective one or more medicinal compounds.New compound described herein is very effective CETP inhibitor.Compound with similar structures can be referring to WO2003/032981.
Summary of the invention
Compound with formula I structure comprises the pharmacologically acceptable salt of this compound, is the CETP inhibitor with purposes as described below:
In the compound of formula I:
Y is selected from-C (=O)-and-(CRR
1)-;
X is selected from-O-,-NH-,-N (C
1-C
5Alkyl)-and-(CRR
6)-;
Z is selected from-C (=O)-,-S (O)
2-and-C (=N-R
9)-, be R wherein
9Be selected from H ,-CN and-C
1-C
5Alkyl, described alkyl is optional to be replaced by 1-11 halogen;
Each R be independently selected from H ,-C
1-C
5Alkyl and halogen, wherein-C
1-C
5Alkyl is optional to be replaced by 1-11 halogen;
B is selected from A
1And A
2, A wherein
1Have following structure:
R
1And R
6Be independently selected from respectively H ,-C
1-C
5Alkyl, halogen and-(C (R)
2)
nA
2, wherein-C
1-C
5Alkyl is optional to be replaced by 1-11 halogen;
R
2Be selected from H ,-C
1-C
5Alkyl, halogen, A
1With-(C (R)
2)
nA
2, wherein-C
1-C
5Alkyl is optional to be replaced by 1-11 halogen;
Wherein B and R
2In the middle of have one to be A
1And B, R
1, R
2And R
6In the middle of have one to be A
2Or-(C (R)
2)
nA
2This pattern I compound comprises a group A
1With a group A
2A
3Be selected from:
(a) be selected from the aromatic ring of phenyl and naphthyl;
(b) with the optional non-aromatics cycloalkyl ring condensed benzyl ring of 5-7 unit that comprises 1-2 two keys;
(c) 5-6 unit heterocycle, described heterocycle have 1-4 be independently selected from N, S, O and-N (O)-heteroatoms, and optional 1-3 two keys and the carbonyl of comprising; A wherein
3Be connected with A
3The tie point of benzyl ring be carbon atom; With
(d) comprise benzheterocycle with the heterocyclic fused benzyl ring of 5-6 unit, described heterocycle has 1-2 heteroatoms that is independently selected from O, N and S, and optionally has 1-2 two key (except two keys of fused phenyl ring), wherein A
3Be connected with A
3The tie point of benzyl ring be carbon atom;
A
2Be selected from:
(a) be selected from the aromatic ring of phenyl and naphthyl;
(b) with the optional non-aromatics cycloalkyl ring condensed benzyl ring of 5-7 unit that comprises 1-2 two keys;
(c) 5-6 unit heterocycle, described heterocycle have 1-4 be independently selected from N, S, O and-N (O)-heteroatoms, and optional 1-3 two keys and the carbonyl of comprising;
(d) comprise benzheterocycle with the heterocyclic fused benzyl ring of 5-6 unit, described heterocycle has 1-2 heteroatoms that is independently selected from O, N and S, and optionally has 1-2 two keys (except two keys of fused phenyl ring); With
(e) optional have 1-3 two keys-C
3-C
8Cycloalkyl ring;
A wherein
3And A
2Optional respectively by the individual R that is independently selected from of 1-5
aSubstituting group replace;
Each R
aBe independently selected from-C
1-C
6Alkyl ,-C
2-C
6Alkenyl ,-C
2-C
8Alkynyl, optional have 1-3 two keys-C
3-C
8Cycloalkyl ,-OC
1-C
6Alkyl ,-OC
2-C
6Alkenyl ,-OC
2-C
6Alkynyl, optional have 1-3 two keys-OC
3-C
8Cycloalkyl ,-C (=O) C
1-C
6Alkyl ,-C (=O) C
3-C
8Cycloalkyl ,-C (=O) H ,-CO
2H ,-CO
2C
1-C
6Alkyl ,-C (=O) SC
1-C
6Alkyl ,-OH ,-NR
3R
4,-C (=O) NR
3R
4,-NR
3C (=O) OC
1-C
6Alkyl ,-NR
3C (=O) NR
3R
4,-S (O)
xC
1-C
6Alkyl ,-S (O)
yNR
3R
4,-NR
3S (O)
yNR
3R
4, halogen ,-CN ,-NO
2With 5-6 unit heterocycle, described heterocycle has 1-4 heteroatoms that is independently selected from N, S and O, and described heterocycle is also optional to be comprised carbonyl and optionally comprise 1-3 two keys, wherein said be connected with R
aThe tie point of ring be carbon atom, wherein said heterocycle optional by 1-5 be independently selected from halogen ,-C
1-C
3Alkyl and-OC
1-C
3The substituting group of alkyl replaces, wherein-and C
1-C
3Alkyl and-OC
1-C
3Alkyl is optional to be replaced by 1-7 halogen; Wherein for R wherein
aBe selected from-C
1-C
6Alkyl ,-C
2-C
6Alkenyl ,-C
2-C
6Alkynyl, optional have 1-3 two keys-C
3-C
8Cycloalkyl ,-OC
1-C
6Alkyl ,-OC
2-C
6Alkenyl ,-OC
2-C
6Alkynyl, optional have 1-3 two keys-OC
3-C
8Cycloalkyl ,-C (=O) C
1-C
6Alkyl ,-C (=O) C
3-C
8Cycloalkyl ,-CO
2C
1-C
6Alkyl ,-C (=O) SC
1-C
6Alkyl ,-NR
3C (=O) OC
1-C
6Alkyl and-S (O)
xC
1-C
6The compound of alkyl, R
aOptional replaced, and optionally be independently selected from following substituting group replacement by 1-3 by 1-15 halogen: (a)-OH, (b)-CN, (c)-NR
3R
4, (d) optional have 1-3 two keys and optional by 1-15 halogen replacement-C
3-C
8Cycloalkyl (e) is optionally replaced by 1-9 halogen and optionally is independently selected from-OC by 1-2 is individual
1-C
2The substituting group of alkyl and phenyl replaces-OC
1-C
4Alkyl, (f) optional have 1-3 two keys and optional by 1-15 halogen replacement-OC
3-C
8Cycloalkyl, (g)-CO
2H, (h)-C (=O) CH
3, (i) optional by 1-9 halogen replacement-CO
2C
1-C
4Alkyl and (j) optional by 1-3 be independently selected from halogen ,-CH
3,-CF
3,-OCH
3With-OCF
3The phenyl that replaces of group;
Condition is: when B is A
1, X and Y are-CH
2-, Z is-C (=O)-, and R
2Be to have substituent R in the 4-position
aPhenyl, R wherein
aBe to choose substituted as mentioned above-OC wantonly
1-C
6During alkyl, then at R
2On do not have other R
aSubstituting group, wherein R
aBe selected from-OH ,-OC
1-C
6Alkyl ,-OC
2-C
6Alkenyl ,-OC
2-C
6Alkynyl and optional have 1-3 two keys-OC
3-C
8Cycloalkyl, all these groups are optional to be substituted as mentioned above,
N is 0 or 1;
P is the integer of 0-4;
X is 0,1 or 2;
Y is 1 or 2;
R
3And R
4Be independently selected from respectively H ,-C
1-C
5Alkyl ,-C (=O) C
1-C
5Alkyl and-S (O)
yC
1-C
5Alkyl, wherein in all cases ,-C
1-C
5Alkyl is optional to be replaced by 1-11 halogen; And
R
5Be selected from H ,-OH ,-C
1-C
5Alkyl and halogen, wherein-C
1-C
5Alkyl is optional to be replaced by 1-11 halogen.
In formula I compound and compound subsequently, except as otherwise noted, alkyl, alkenyl and alkynyl can be straight or brancheds.
Detailed Description Of The Invention
A lot of The compounds of this invention have with following formula Ia, or its pharmacologically acceptable salt:
A lot of The compounds of this invention have with following formula Ib, or its pharmacologically acceptable salt:
A lot of other The compounds of this invention have with following formula Ic, or its pharmacologically acceptable salt:
Other The compounds of this invention has with following formula Id, or its pharmacologically acceptable salt:
In one group of formula I compound,
Each R
aBe independently selected from-C
1-C
6Alkyl ,-C
2-C
6Alkenyl ,-C
2-C
6Alkynyl, optional have 1-3 two keys-C
3-C
8Cycloalkyl ,-OC
1-C
6Alkyl ,-OC
2-C
6Alkenyl ,-OC
2-C
6Alkynyl, optional have 1-3 two keys-OC
3-C
8Cycloalkyl ,-C (=O) C
1-C
6Alkyl ,-C (=O) C
3-C
8Cycloalkyl ,-C (=O) H ,-CO
2H ,-CO
2C
1-C
6Alkyl ,-C (=O) SC
1-C
6Alkyl ,-NR
3R
4,-C (=O) NR
3R
4,-NR
3C (=O) OC
1-C
6Alkyl ,-NR
3C (=O) NR
3R
4,-S (O)
xC
1-C
6Alkyl ,-S (O)
yNR
3R
4,-NR
3S (O)
yNR
3R
4, halogen ,-CN ,-NO
2With 5-6 unit heterocycle, described heterocycle has 1-4 heteroatoms that is independently selected from N, S and O, also optional carbonyl and the optional individual two keys of 1-3 that comprise of comprising of described heterocycle, wherein said heterocycle is a carbon atom with the tie point of the ring that is connected, wherein said heterocycle optional by 1-5 be independently selected from halogen ,-C
1-C
3Alkyl and-OC
1-C
3The substituting group of alkyl replaces, wherein-and C
1-C
3Alkyl and-OC
1-C
3Alkyl is optional to be replaced by 1-7 halogen; Wherein for R wherein
aBe selected from-C
1-C
6Alkyl ,-C
2-C
6Alkenyl ,-C
2-C
6Alkynyl, optional have 1-3 two keys-C
3-C
8Cycloalkyl ,-OC
1-C
6Alkyl ,-OC
2-C
6Alkenyl ,-OC
2-C
6Alkynyl, optional have 1-3 two keys-OC
3-C
8Cycloalkyl ,-C (=O) C
1-C
6Alkyl ,-C (=O) C
3-C
8Cycloalkyl ,-CO
2C
1-C
6Alkyl ,-C (=O) SC
1-C
6Alkyl ,-NR
3C (=O) OC
1-C
6Alkyl and-S (O)
xC
1-C
6The compound of alkyl, R
aOptional replaced, and optionally be independently selected from following substituting group replacement by 1-3 by 1-15 halogen: (a)-OH, (b)-CN, (c)-NR
3R
4, (d) optional have 1-3 two keys and optional by 1-15 halogen replacement-C
3-C
8Cycloalkyl (e) is optionally replaced by 1-9 halogen and optionally is independently selected from-OC by 1-2 is individual
1-C
2The substituting group of alkyl replaces-OC
1-C
4Alkyl, (f) optional have 1-3 two keys and optional by 1-15 halogen replacement-OC
3-C
8Cycloalkyl, (g)-CO
2H, (h)-C (=O) CH
3And (i) optional by 1-9 halogen replacement-CO
2C
1-C
4Alkyl,
Condition is: when B is A
1, X and Y are-CH
2-, Z is-C (=O)-, and R
2Be to have substituent R in the 4-position
aPhenyl, R wherein
aBe to choose wantonly by 1-11 halogen to replace-OC
1-C
6During alkyl, then at R
2On do not have other R
aSubstituting group, wherein R
aBe selected from-OH ,-OC
1-C
6Alkyl ,-OC
2-C
6Alkenyl ,-OC
2-C
6Alkynyl and optional have 1-3 two keys-OC
3-C
8Cycloalkyl, all these groups are optional to be substituted as mentioned above.
In formula I, Ia, Ib, Ic and Id compound and pharmacologically acceptable salt thereof,
A
3Be phenyl, described phenyl is optional by 1-4 substituent R
aReplace, wherein R
aBe independently selected from-C
1-C
5Alkyl ,-OC
1-C
3Alkyl ,-CO
2C
1-C
3Alkyl ,-CO
2H, halogen ,-NR
3R
4,-C (=O) C
1-C
3Alkyl ,-C (=O) H ,-C (=O) NR
3R
4,-SC
1-C
3Alkyl ,-C
2-C
3Alkenyl ,-CN ,-NO
2With 1,2,4- di azoly, wherein all that occur-C
1-C
3Alkyl and-C
1-C
5Alkyl is optional to be replaced by 1-6 substituting group that is independently selected from 1-5 halogen and one-OH group; And-C
2-C
3Alkenyl is optional to be replaced by 1-3 halogen.
In formula I, Ia, Ib, Ic and Id compound and pharmacologically acceptable salt thereof,
A
2Be selected from phenyl, cyclohexyl and 5-6 unit heterocycle, described heterocycle have 1-2 be independently selected from N, S, O and-N (O)-heteroatoms, and optionally comprise 1-3 two key, wherein A
2Optional by individual following substituting group the replacement :-C that is independently selected from of 1-2
1-C
4Alkyl ,-OC
1-C
3Alkyl ,-NO
2,-CN ,-S (O)
xC
1-C
3Alkyl ,-NHS (O)
2C
1-C
3Alkyl ,-NR
3R
4,-NR
3C (=O) R
4,-C
2-C
3Alkenyl ,-C (=O) NR
3R
4, halogen and pyridyl, wherein in all cases, C
1-C
3Alkyl, C
1-C
4Alkyl and C
2-C
3Alkenyl is optional to be replaced by 1-3 halogen, and condition is, for formula Ia compound, when B is A
1, X and Y are-CH
2-, Z is-C (=O)-, and R
2When being phenyl, then at R
2On be selected from optional substituted-OC
1-C
3The R of alkyl
aThe number of group is 0 or 1.
In formula I, Ia, Ib, Ic and Id compound and pharmacologically acceptable salt thereof, R
3And R
4Be independently selected from respectively H and-C
1-C
3Alkyl.
In formula I, Ia, Ib, Ic and Id compound and pharmacologically acceptable salt thereof, p is 0-2.
At a subgroup formula I compound, comprise in its pharmacologically acceptable salt,
A
1Be
R wherein
7And R
8Be independently selected from respectively H, halogen ,-NR
3R
4,-C
1-C
3Alkyl ,-OC
1-C
3Alkyl ,-CN ,-NO
2And pyridyl, wherein in all cases, C
1-C
3Alkyl is optional to be replaced by 1-3 halogen.
In a subgroup formula I compound, A
2Be selected from phenyl, pyridyl and cyclohexyl, wherein A
2Choose wantonly by 1-2 and be independently selected from-C
1-C
4Alkyl ,-OC
1-C
4Alkyl ,-NO
2The substituting group of ,-CN and halogen replaces, wherein the C in all use
1-C
4Alkyl is optional to be replaced by 1-3 halogen, and condition is, for formula I compound, when B is A
1, X and Y are-CH
2-, Z is-C (=O)-, and R
2When being phenyl, then at R
2On be selected from optional by 1-3 halogen replacement-OC
1-C
4The R of alkyl
aThe number of group is 0 or 1.
In other subgroup, A
2Optional by 1-2 be independently selected from halogen ,-C
1-C
4Alkyl and-substituting group of CN replaces, wherein-C
1-C
4Alkyl is optional to be replaced by 1-3 halogen.
In aforesaid a lot of embodiment of the present invention, comprise in its pharmacologically acceptable salt A
1Be
R wherein
7Be selected from H, halogen ,-NR
3R
4,-C
1-C
3Alkyl ,-OC
1-C
3Alkyl ,-CN ,-NO
2And pyridyl, wherein in all cases, C
1-C
3Alkyl is optional to be replaced by 1-3 halogen; And
R
8Be selected from H, halogen ,-CH
3,-CF
3,-OCH
3With-OCF
3
In a lot of preferred embodiments of the present invention, A
3Be phenyl, described phenyl is independently selected from following substituting group by 1-3 and replaces: C
1-C
4Alkyl, OC
1-C
4Alkyl ,-CN, Cl, F ,-C (=O) CH
3,-CH=CH
2,-CO
2H ,-CO
2CH
3,-S-CH
3,-S (O) CH
3,-S (O)
2CH
3With-C (=O) NR
3R
4, C wherein
1-C
4Alkyl and-OC
1-C
4Alkyl is optional to be replaced by 1-5 F substituting group, and optional by a group-OH replacement.
In other embodiments, A
3Be phenyl, described phenyl is optional to be independently selected from following substituting group replacement by 1-3: Cl, F ,-C
1-C
4Alkyl and-OC
1-C
4Alkyl, wherein-C
1-C
4Alkyl and-OC
1-C
4Alkyl is optional to be replaced by 1-5 F.
The preferred value of Y is-(CRR
1)-.
In certain embodiments, R and R
6Be independently selected from respectively H and-C
1-C
5Alkyl, wherein-C
1-C
5Alkyl is optional to be replaced by 1-11 halogen.In the group of these embodiments, R
1Be selected from H ,-C
1-C
5Alkyl and-(C (R)
2)
nA
2, wherein-C
1-C
5Alkyl is optional to be replaced by 1-11 halogen.In these schemes, B and R
2In the middle of have one to be A
1And B, R
1And R
2In the middle of have one to be A
2Or-(C (R)
2)
nA
2This pattern I compound comprises a group A
1With a group A
2
In the subgroup of compound, A
3Be selected from:
(a) be selected from the aromatic ring of phenyl and naphthyl;
(b) 5-6 unit heterocycle, described heterocycle have 1-4 be independently selected from N, S, O and-N (O)-heteroatoms, and optional 1-3 two keys and carbonyl, the wherein A of comprising
3Be connected with A
3The tie point of benzyl ring be carbon atom; With
(c) comprise benzheterocycle with the heterocyclic fused benzyl ring of 5-6 unit, described heterocycle have 1-2 be independently selected from O, N and-S (O)
x-heteroatoms, and optional have 1-2 two key, wherein A
3Be connected with A
3The tie point of benzyl ring be carbon atom.
In the subgroup of compound, A
2Be selected from:
(a) be selected from the aromatic ring of phenyl and naphthyl;
(b) 5-6 unit heterocycle, described heterocycle have 1-4 be independently selected from N, S, O and-N (O)-heteroatoms, and optional 1-3 two keys and the carbonyl of comprising;
(c) comprise benzheterocycle with the heterocyclic fused benzyl ring of 5-6 unit, described heterocycle has 1-2 heteroatoms that is independently selected from O, N and S, and optionally has 1-2 two keys; With
(d) optional have 1-3 two keys-C
3-C
8Cycloalkyl ring.
A in the above
3And A
2Subgroup in, A
3And A
2Optional by the individual R that is independently selected from of 1-4
aSubstituting group replace.
R
aSubgroup comprise and be independently selected from following substituting group :-C
1-C
6Alkyl ,-C
2-C
6Alkenyl, optional have 1-3 two keys-C
3-C
8Cycloalkyl ,-OC
1-C
6Alkyl ,-C (=O) C
1-C
6Alkyl ,-C (=O) H ,-CO
2H ,-CO
2C
1-C
6Alkyl ,-OH ,-NR
3R
4,-NR
3C (=O) OC
1-C
6Alkyl ,-S (O)
xC
1-C
6Alkyl, halogen ,-CN ,-NO
2With 5-6 unit heterocycle, described heterocycle has 1-4 heteroatoms that is independently selected from N, S and O, and described heterocycle is also optional to be comprised carbonyl and optionally comprise 1-3 two keys, wherein said heterocycle be connected with R
aThe tie point of ring be carbon former in, wherein said heterocycle optional by 1-5 be independently selected from halogen ,-C
1-C
3Alkyl and-OC
1-C
3The substituting group of alkyl replaces, wherein-and C
1-C
3Alkyl and-OC
1-C
3Alkyl is optional to be replaced by 1-7 halogen;
Wherein for R wherein
aBe independently selected from-C
1-C
6Alkyl ,-C
2-C
6Alkenyl, optional have 1-3 two keys-C
3-C
8Cycloalkyl ,-O) C
1-C
6Alkyl ,-C (=O) C
1-C
6Alkyl ,-CO
2C
1-C
6Alkyl ,-NR
3C (=O) OC
1-C
6Alkyl and-S (O)
xC
1-C
6The compound of alkyl, R
aOptional replaced, and optionally be selected from following substituting group replacement by 1 by 1-15 halogen: (a)-OH, (b)-NR
3R
4, (c) optionally replaced by 1-9 halogen and optionally be independently selected from-OC by 1-2 is individual
1-C
2The substituting group of alkyl and phenyl replaces-OC
1-C
4Alkyl and (d) phenyl, described phenyl optional by 1-3 be independently selected from halogen ,-CH
3,-CF
3,-OCH
3With-OCF
3Group replace;
Condition is: when B is A
1, X and Y are-CH
2-, Z is-C (=O)-, and R
2Be to have substituent R in the 4-position
aPhenyl, R wherein
aBe to choose substituted as mentioned above-OC wantonly
1-C
6During alkyl, then at R
2On do not have other R
aSubstituting group, wherein R
aBe selected from-OH or optional substituted as mentioned above-OC
1-C
6Alkyl.
In the subgroup of compound, n is the integer of 0-2.In other subgroup, n is 1 or 2.
In subgroup independently, R
3And R
4Be independently selected from respectively H and-C
1-C
5Alkyl, wherein in all cases ,-C
1-C
5Alkyl is optional to be replaced by 1-11 halogen.At other independently in the subgroup, R
3And R
4Be independently selected from respectively H and-C
1-C
3Alkyl, perhaps be selected from H and-C
1-C
2Alkyl.
In the subgroup of formula I, Z is selected from-C (=O)-,-S (O)
2-and-C (=N-R
9)-, be R wherein
9Be selected from H ,-CN and CH
3The preferred value of Z is-C (=O)-.
In subgroup independently, R
5Be selected from H ,-OH and-C
1-C
5Alkyl, wherein-C
1-C
5Alkyl is optional to be replaced by 1-11 halogen.In other subgroup, R
5Be selected from H and-C
1-C
3Alkyl, perhaps be selected from H and-C
1-C
2Alkyl.
In some subgroup, each R is independently selected from H and C
1-C
3Alkyl.In other group, R is selected from H and C
1-C
2Alkyl.R is H or CH in other group
3
In some subgroup, R
6Be selected from H and-C
1-C
3Alkyl, wherein C
1-C
3Alkyl is optional to be replaced by 1-5 halogen.In other subgroup, R
6Be selected from H and C
1-C
2Alkyl.In other group, R
6Be H or CH
3
In some subgroup, R
1Be selected from H ,-C
1-C
3Alkyl and-(C (R)
2)
nA
2, wherein-C
1-C
3Alkyl is optional to be replaced by 1-5 halogen; And R
2Be selected from H ,-C
1-C
3Alkyl, A
1With-(C (R)
2)
nA
2, wherein-C
1-C
3Alkyl is optional to be replaced by 1-5 halogen, and R
6Be H or alkyl.In these schemes, B and R
2In the middle of have one to be A
1And B, R
1And R
2In the middle of have one to be A
2Or-(C (R)
2)
nA
2This pattern I compound comprises a group A
1With a group A
2
In the subgroup of compound, A
3Be selected from:
(a) phenyl;
(b) 5-6 unit heterocycle, described heterocycle have 1-2 be independently selected from N, S, O and-N (O)-heteroatoms, A wherein
3Be connected with A
3The tie point of benzyl ring be carbon atom; With
(c) comprise benzheterocycle with 5 yuan of aromatic heterocycle condensed benzyl rings, described heterocycle have 1-2 be independently selected from O, N and-S (O)
x-heteroatoms, A wherein
3Be connected with A
3The tie point of benzyl ring be carbon atom.
In subgroup, A
2Be selected from:
(a) phenyl;
(b) 5-6 unit heterocycle, described heterocycle have 1-4 be independently selected from N, S, O and-N (O)-heteroatoms, and optionally comprise 1-3 two keys;
(c) comprise benzheterocycle with 5 yuan of heterocyclic fused benzyl rings, described heterocycle has 1-2 heteroatoms that is independently selected from O, N and S; With
(d)-C
5-C
6Cycloalkyl ring.
In a lot of compounds, A
3And A
2Optional respectively by the individual R that is independently selected from of 1-4
aSubstituting group replace.In each subgroup, A
3Optional by 1-3 substituent R
aReplace, perhaps by 2-3 substituent R
aReplace.In each subgroup, A
2Optional by 1-3 substituent R
aReplace, perhaps by 1-2 substituent R
aReplace.R
2Often by 2 substituent R
aReplace, perhaps by 2-3 substituent R
aReplace.
In a lot of compounds, A
3Be selected from phenyl, thienyl, imidazolyl, pyrryl, pyrazolyl, pyridyl, N-oxidation-pyridyl, thiazolyl, pyridazinyl, pyrimidyl, pyrazinyl, benzothienyl, benzothienyl-S-oxide compound and benzothienyl-S-dioxide.
In a lot of compounds, A
2Be selected from phenyl, thienyl, imidazolyl, thiazolyl, pyrryl, pyrazolyl, 1,2,4-triazolyl, tetrazyl, benzodioxole base, pyridyl, N-oxidation-pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, cyclopentyl, cyclohexyl and THP trtrahydropyranyl.
In some subgroup, R
aBe selected from-C
1-C
4Alkyl ,-C
2-C
4Alkenyl, cyclopropyl ,-OC
1-C
2Alkyl ,-C (=O) C
1-C
2Alkyl ,-C (=O) H ,-CO
2C
1-C
4Alkyl ,-OH ,-NR
3R
4,-NR
3C (=O) OC
1-C
4Alkyl ,-S (O)
xC
1-C
2Alkyl, halogen ,-CN ,-NO
2With 5-6 unit heterocycle, described heterocycle has 1-2 heteroatoms that is independently selected from N, S and O, wherein said heterocycle be connected with R
aThe tie point of ring be carbon atom, wherein said heterocycle is optional to be replaced by 1-5 substituting group that is independently selected from halogen;
Wherein for R wherein
aBe selected from-C
1-C
4Alkyl ,-C
2-C
4Alkenyl ,-OC
1-C
2Alkyl ,-C (=O) C
1-C
2Alkyl ,-CO
2C
1-C
4Alkyl ,-NR
3C (=O) OC
1-C
4Alkyl and-S (O)
xC
1-C
2The compound of alkyl, R
aAlkyl optional replaced by 1-5 halogen, and optionally be selected from following substituting group replacement by one: (a)-OH, (b)-NR
3R
4, (C) optionally replaced by 1-3 fluorine atom, and optional by a phenyl replacement-OCH
3And (d) phenyl, described phenyl optional by 1-3 be independently selected from halogen ,-CH
3,-CF
3,-OCH
3With-OCF
3Group replace;
Condition is: when B is A
1, X and Y are-CH
2-, Z is-C (=O)-, and R
2Be to have substituent R in the 4-position
aPhenyl, R wherein
aBe to choose substituted as mentioned above-OC wantonly
1-C
2During alkyl, then at R
2On do not have other R
aSubstituting group, wherein R
aBe selected from-OH or optional substituted as mentioned above-OC
1-C
2Alkyl.
In preferred group, X is selected from-O-,-NH-and-N (C
1-C
3Alkyl)-.X can also be selected from-O-,-NH-and-N (CH
3).In highly preferred group, X is O.
In a lot of groups, Z is-C (=O)-.
The compound of a preferred subgroup has formula Ie, comprises its pharmacologically acceptable salt
In formula Ie compound, X is selected from-O-,-NH-,-N (C
1-C
5Alkyl)-and-(CH
2)-;
Z is selected from-C (=O)-,-S (O)
2-and-C (=N-R
9)-, be R wherein
9Be selected from H ,-CN and optional by the C of 1-11 halogen replacement
1-C
5Alkyl.
Each R be independently selected from H and-CH
3
B is selected from A
1And A
2, A wherein
1Have following structure:
R
1Be selected from H ,-C
1-C
5Alkyl and-(C (R)
2)
nA
2, wherein-C
1-C
5Alkyl is optional to be replaced by 1-11 halogen;
R
2Be selected from H ,-C
1-C
5Alkyl, A
1With-(C (R)
2)
nA
2, wherein-C
1-C
5Alkyl is optional to be replaced by 1-11 halogen;
Wherein B and R
2In the middle of have one to be A
1And B, R
1And R
2In the middle of have one to be A
2Or-(C (R)
2)
nA
2This pattern I compound comprises a group A
1With a group A
2
A
2Be selected from phenyl, cyclohexyl and pyridyl, wherein A
2Optional by 1-2 be independently selected from halogen ,-C
1-C
4Alkyl and-substituting group of CN replaces, wherein-C
1-C
4Alkyl is optional to be replaced by 1-3 halogen;
Each R
aBe independently selected from-C
1-C
3Alkyl and halogen, wherein-C
1-C
3Alkyl is optional to be replaced by 1-3 halogen;
Each R
bBe independently selected from Cl, F ,-C
1-C
4Alkyl and-OC
1-C
4Alkyl, wherein-C
1-C
4Alkyl and-OC
1-C
4Alkyl is optional to be replaced by 1-5 F;
N is 0 or 1;
P is the integer of 0-2; And
Q is the integer of 0-3.
Group with compound of formula Ie comprises formula If, Ig and Ih compound and pharmacologically acceptable salt thereof:
In formula If, Ig and Ih compound, R
1And R
2Be independently selected from respectively H and-C
1-C
5Alkyl, wherein-C
1-C
5Alkyl is optional to be replaced by 1-11 halogen.Other group as defined above.
In the subgroup of above-claimed cpd, A
2Can be selected from phenyl, cyclohexyl and pyridyl, wherein A
2Optional by 1-2 be independently selected from halogen ,-CH
3,-CF
3Replace with the substituting group of-CN.
In the subgroup of above-claimed cpd, each R
aBe independently selected from-CF
3And Cl.
In the subgroup of above-claimed cpd, each R
bBe independently selected from-C
1-C
3Alkyl ,-OCH
3And F.
In the subgroup of above-claimed cpd, R
1And R
2Be independently selected from respectively H and-C
1-C
2Alkyl.
In the subgroup of above-claimed cpd, X is selected from-O-, NH-,-N (CH
3)-and-CH
2-.
In the subgroup of above-claimed cpd, Z is selected from-C (=O)-,-S (O)
2-and-C (=N-CN)-.
In the subgroup of above-claimed cpd, p is 1.
In the subgroup of above-claimed cpd, q is 2 or 3.
The subgroup of compound defined above comprises compound and the pharmacologically acceptable salt thereof with formula Ii:
In formula Ii, R
7Be selected from Cl and-CF
3
R
cBe selected from halogen ,-CH
3,-CF
3With-CN; And t is the integer of 0-2.Other group as defined above.
The subgroup of compound defined above comprises compound and the pharmacologically acceptable salt thereof with formula Ij:
In formula Ij, R
7Be selected from Cl and-CF
3
R
cBe selected from halogen ,-CH
3,-CF
3With-CN; And
T is the integer of 0-2.Other group as defined above.
Definition
" Ac " is ethanoyl, i.e. CH
3C (=O)-.
Unless otherwise defined, " alkyl " is meant the saturated carbon chains that can be straight or branched or its combination.Other group such as alkoxyl group and alkyloyl with prefix " alkane " also can be the carbochain of straight or branched or its combination, unless carbochain has definition in addition.The example of alkyl comprises methyl, ethyl, propyl group, sec.-propyl, butyl, sec-butyl and the tertiary butyl, amyl group, hexyl, heptyl, octyl group, nonyl etc.
" alkylidene group " is meant to have difunctionality but not the alkyl of single functionality.For example, methyl is an alkyl, and methylene radical (CH
2-) be corresponding alkylidene group.
" thiazolinyl " is meant the carbochain that comprises at least one carbon-to-carbon double bond, and it can be straight or branched or its combination.The example of thiazolinyl comprises vinyl, allyl group, pseudoallyl, pentenyl, hexenyl, heptenyl, 1-propenyl, crotyl, 2-methyl-2-butene base etc.
" alkynyl " is meant the carbochain that comprises at least one carbon-to-carbon triple bond, and it can be straight or branched or its combination.The example of alkynyl comprises ethynyl, propargyl, 3-methyl-1-pentene alkynyl, 2-heptyne base etc.
Except as otherwise noted, " cycloalkyl " is meant the saturated carbon ring with 3 to 8 carbon atoms.This term also comprises the cycloalkyl ring that condenses in aryl.The example of cycloalkyl comprises cyclopropyl, cyclopentyl, cyclohexyl, suberyl etc." cycloalkenyl group " is meant the non-aromatic carbocyclic with one or more pairs of keys.
When substituting group that is used for description scheme or group, " aryl " (with " arylidene ") is meant the compound of monocycle or dicyclo, and wherein said ring is aromatic nucleus and only comprises into ring carbon atom.Term " aryl " also can refer to condense in cycloalkyl or heterocyclic aryl.Preferably " aryl " is phenyl and naphthyl.Generally, phenyl is most preferred aryl.
" EDC " is 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide.
Except as otherwise noted, " heterocyclic radical ", " heterocycle " and " heterocyclic " are meant and comprise 1-4 the first ring of heteroatomic saturated or fractional saturation or fragrant fully 5-6 that is independently selected from N, S and O in rings.
" benzheterocycle " expression condenses first heterocyclic benzyl ring in the heteroatomic 5-6 with 1-2 respectively do for oneself O, N or S, and wherein heterocycle can be saturated or unsaturated.The example comprises indoles, cumarone, 2,3-Dihydrobenzofuranes and quinoline.
" DIPEA " is diisopropylethylamine.
" halogen " comprises fluorine, chlorine, bromine and iodine.
" HOBT " is I-hydroxybenzotriazole.
" IPAC " is isopropyl acetate.
" Me " represents methyl.
" Weinreb amine " is N, O-dimethyl hydroxyl amine.
The term that occurs in the pharmaceutical composition " composition " is intended to comprise the product that contains activeconstituents, constitutes the inert fraction of carrier, and from combination, the complexing of any two or more compositions or the spawn that associates and directly or indirectly obtain, or the spawn that directly or indirectly obtains from the disassociation of one or more compositions, or the spawn that directly or indirectly obtains from other reaction type or other interaction type of one or more compositions.Therefore, pharmaceutical composition of the present invention comprise by with compound of the present invention and pharmaceutically acceptable carrier mixed any composition.
Substituting group " tetrazolium " is meant 2H-tetrazolium-5-base substituting group and tautomer thereof.Optical isomer-diastereomer-geometrical isomer-tautomer
Formula I compound can comprise one or more asymmetric centers, therefore can be used as racemoid, racemic mixture, independent enantiomorph, the mixture of diastereomer and independent diastereomer and exists.When demonstration has the structure of three-dimensional chemical configuration, also separately and the venue comprise other stereochemical structure, for example enantiomorph, diastereomer (when there being diastereomer), and the mixture of enantiomorph and/or diastereomer comprise racemic mixture.
More described herein compounds can comprise olefinic double bond, and unless otherwise indicated, it is intended to comprise E and two kinds of geometrical isomers of Z.
More described herein compounds can be used as tautomer and exist.Example is ketone and enol form thereof, is called the keto-enol tautomerism body.Independent tautomer and composition thereof all is included in the formula I compound.
Compound with formula I of one or more asymmetric centers can be separated into diastereomer, enantiomorph etc. by means commonly known in the art.
Perhaps, enantiomorph and other compound with chiral centre can use optical purity starting raw material and/or reagent with configuration known to synthesize by stereospecific synthesis.
Some biphenyl herein and biaryl compound are observed the mixture into atropisomer (rotational isomer) in NMR spectrum.Independent atropisomer and composition thereof all is included in the scope of compound of the present invention.
Salt
Term " pharmacologically acceptable salt " is meant from the pharmaceutically useful nontoxic alkali or the salt of acid preparation, comprises from the salt of mineral alkali or organic bases and mineral acid or organic acid preparation.The salt that derives from mineral alkali comprises salt of aluminium, ammonium, calcium, copper, iron (III), iron (II), lithium, magnesium, manganese (II), potassium, sodium, zinc etc.The salt of preferred especially ammonium, calcium, magnesium, potassium and sodium.The salt of solid form can exist more than a kind of crystalline structure, and also can be the form of hydrate.The salt that derives from pharmaceutically useful non-toxic organic alkali comprises primary amine, secondary amine, tertiary amine, replace amine (comprising naturally occurring replacement amine), cyclammonium and basic ion exchange resin, as arginine, trimethyl-glycine, caffeine, choline, N, N '-dibenzyl-ethylenediamin, diethylamine, 2-diethylaminoethanol, the 2-dimethylaminoethanol, thanomin, quadrol, N-ethylmorpholine, N-ethylpiperidine, glycosamine, glucosamine, Histidine, breathe out amine, Isopropylamine, Methionin, methylglucosamine, morpholine, piperazine, piperidines, versamid 900, PROCAINE HCL, PHARMA GRADE, purine, Theobromine, triethylamine, Trimethylamine 99, the salt of tripropyl amine and tromethane etc. etc.
When compound of the present invention was alkalescence, its salt can be from pharmaceutically useful nontoxic acid such as mineral acid and organic acid preparation.This acid comprises acetate, Phenylsulfonic acid, phenylformic acid, camphorsulfonic acid, citric acid, ethyl sulfonic acid, fumaric acid, glyconic acid, L-glutamic acid, Hydrogen bromide, hydrochloric acid, isethionic acid, lactic acid, toxilic acid, oxysuccinic acid, amygdalic acid, methylsulfonic acid, glactaric acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succsinic acid, sulfuric acid, tartrate, tosic acid etc.Special optimization citric acid, Hydrogen bromide, hydrochloric acid, toxilic acid, phosphoric acid, sulfuric acid and tartrate.
Should be appreciated that as used in this article, the compound of formula I also is intended to comprise pharmacologically acceptable salt.Metabolite-prodrug
Metabolite with therapeutic activity, wherein metabolite itself falls within the scope of the present invention, and also is compound of the present invention.To patient's administration the time or to being converted into the compound of The compounds of this invention after patient's administration, promptly prodrug also is a compound of the present invention.
Purposes
Compound of the present invention is the powerful inhibitor of CETP.Therefore they can be used for treating disease and the illness by the CETP inhibitor for treating.
Provide one aspect of the present invention disease of suppression therapy by can be by CETP or prevention or illness or reduction to the compounds for treating of the present invention of patient's drug treatment significant quantity of needs treatments develop into can be by CETP suppression therapy or the method for the danger of the disease of prevention or illness.The patient behaves or Mammals, and the most frequent is the people." treatment significant quantity " is the amount that effectively obtains the compound of required clinical effectiveness when the treatment specified disease.
But the disease that can use the disease of compounds for treating of the present invention or illness and the application of the invention compound to treat and reduce the danger that develops into disease comprises: atherosclerosis, peripheral vascular disease, unusual lipidemia, Hyperbetalipoproteinemia, high alpha lipoprotein mass formed by blood stasis, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disorder, angina, local asphyxia, myocardial ischemia, apoplexy, myocardial infarction, reperfusion injury, postangioplasty restenosis, hypertension, the diabetic vascular complication, obesity, endotoxemia and metabolism.
Estimate that compound of the present invention is effective especially aspect the ratio of rising HDL-C and/or increase HDL-C and LDL-C.These of HDL-C and LDL-C change for treatment atherosclerosis, minimizing or counter-rotating progression of atherosclerosis, reduction develops into atherosclerotic danger or but prevention of arterial is atherosis favourable.
Administration and dosage range
Can adopt any suitable route of administration, be used for Mammals (particularly people) is provided the compound of the present invention of effective dose.For example, can adopt oral administration, rectal administration, topical, parenterai administration, administration through eye, through lung administration, nose administration etc.Formulation comprises tablet, lozenge, dispersion, suspension, solution, capsule, creme, paste, aerosol etc.Preferably, formula I compound oral administration administration.
The effective dose of the activeconstituents that adopts can be decided according to the situation of the specific compound that uses, administering mode, treatment and the severity of treatment situation.This dosage can easily be determined by those skilled in the art.
When disease that treatment formula I compound is suitable for, usually compound of the present invention is being obtained gratifying result during to about 100 milligrams per daily dose administration for about 0.01 milligram with every kilogram of animal or human, preferably as the single per daily dose or being divided into about two to six times dosed administration every day, or adopt controlled release form.In 70kg adult's situation, total order dosage is generally about 0.5 milligram to about 500 milligrams.For special compounds effective, adult dosage can be low to moderate 0.1mg.Dosage regimen can adjusted within this scope even outside this scope, so that best therapeutic response to be provided.
Oral administration uses tablet to carry out usually.The example of dosage is 0.5mg, 1mg, 2mg, 5mg, 10mg, 25mg, 50mg, 100mg, 250mg and 500mg in the tablet.Other oral dosage form also can have identical dosage (as capsule).
Pharmaceutical composition
Another aspect of the present invention provides the compound that comprises formula I and the pharmaceutical composition of pharmaceutically acceptable carrier.Pharmaceutical composition of the present invention comprises as the compound of the formula I of activeconstituents or pharmacologically acceptable salt, and pharmaceutically acceptable carrier and other optional therapeutic component.Term " pharmacologically acceptable salt " is meant from the pharmaceutically useful nontoxic alkali or the salt of acid preparation, comprises from the salt of mineral alkali or mineral acid and organic bases or organic acid preparation.If the administration prodrug, then pharmaceutical composition also can comprise prodrug, or comprises its pharmacologically acceptable salt.Pharmaceutical composition also can be made up of compound and pharmaceutically acceptable carrier of formula I basically.
Composition comprise be suitable for oral administration, rectal administration, topical, parenterai administration (comprising subcutaneous, intramuscular and intravenously), administration through eye (eye with), through the composition of lung administration (intranasal or mouthful cheek suck) or nose administration, but optimal approach will be decided according to the character of treatment situation and the character of severity and activeconstituents in any given situation.They can exist with unit dosage forms easily and prepare by the known any method of pharmaceutical field.
In actual applications, the formula I compound as activeconstituents can be made up according to conventional pharmaceutical compounding process and pharmaceutical carrier intimate mixing.Carrier can be various ways, decides according to the dosage form that administration is required, as, oral or non-enteron aisle (comprising intravenously).When the composition of preparation oral dosage form, can adopt any pharmaceutical media commonly used, for example, in the situation of oral liquid such as suspension, elixir and solution, make water, glycol, oils, alcohol, seasonings, sanitas, tinting material etc.; Or in the situation of oral solid formulation such as powder, hard capsule and soft capsule and tablet, using carrier such as starch, sugar, Microcrystalline Cellulose, thinner, granulating agent, lubricant, tackiness agent, disintegrating agent etc., solid orally ingestible is than liquid preparation more preferably.
Because tablet and capsule are easy to administration, tablet and capsule are represented best oral dosage unit form, in this case, obviously use solid pharmaceutical carriers.If expectation, tablet can carry out dressing by the moisture or non-water technology of standard.This composition and preparation should comprise at least 0.1% active compound.Certainly, the per-cent of the active compound in these compositions can change and can account for about 2% to about 60% of dose unit weight easily.The amount of active compound is for obtaining the amount of effective dose in the useful composition of this treatment.Active compound also can be used as for example liquid drops or sprays nose administration.
Tablet, pill, capsule etc. can also comprise tackiness agent, as tragacanth gum, gum arabic, W-Gum or gelatin; Vehicle is Lin Suanergai for example; Disintegrating agent is W-Gum, yam starch, Lalgine for example; Lubricant is Magnesium Stearate for example; With sweeting agent for example sucrose, lactose or asccharin.When dosage unit form was capsule, it can also comprise liquid vehicle except that the above-mentioned type material, as fatty oil.
Can exist multiple other material as dressing or be used to change the physical appearance of dose unit.For example, tablet can both carry out dressing with shellac, sugar or its.Syrup or elixir can also comprise sucrose as sweeting agent except that activeconstituents, as methyl p-hydroxybenzoate and propylparaben, dyestuff and seasonings such as the cherry seasonings or the orange seasonings of sanitas.
Formula I compound also can be through parenterai administration.Can suitably be blended in the solution or the suspension of these active compounds of preparation in the water with tensio-active agent such as hydroxypropylcellulose.Preparation dispersion liquid in glycerine that also can be in oils, liquid macrogol and composition thereof.Under common storage and working conditions, these preparations comprise sanitas, to prevent microbial growth.
The pharmaceutical dosage form that is suitable for injecting application comprises aseptic aqueous solution or dispersion liquid and is used for aseptic injectable solution and the sterilized powder of the interim preparation of dispersion liquid.In all situations, formulation must be aseptic, and must have the flowability that reaches the degree of can injecting easily.It must be stable under production and condition of storage and must carry out anticorrosion pollution with preventing microorganism such as bacterium and fungi.Carrier can be solvent or dispersion medium, and it comprises for example water, ethanol, polyvalent alcohol (as glycerine, propylene glycol and liquid macrogol), its suitable mixture, and vegetables oil.
Combination therapy
Compound of the present invention (suc as formula I and Ia-Ij) can with also can be used for treating or improve the disease that formula I compound is suitable for or the other medicines of illness and be used in combination.These other medicines can pass through its normally used approach and amount and simultaneously or in a sequence administration of compound in structural formula I.When the compound of formula I and one or more other medicines use simultaneously, the pharmaceutical composition of preferred unit dosage form, it comprises described other medicines and compound in structural formula I.Yet combination therapy also comprises the compound and the treatment of one or more other medicines according to different timetable administrations with formula I.
When using oral preparations, can be single combined tablet-preparation or other oral dosage form form with drug regimen, perhaps that medicine is packaging together as independent tablet or other oral dosage form.Also considered when being used in combination with one or more other activeconstituentss, compound of the present invention and the comparable independent use of other activeconstituents each the time use with lower dosage.Therefore, pharmaceutical composition of the present invention comprises such composition, that is, it also comprises one or more other activeconstituentss except compound in structural formula I.
Can with the form administration of compound of the present invention (suc as formula I) combination, administration or include but not limited to respectively: other compound that improves patient's lipid profile with the example of other activeconstituents of the form administration of aforementioned pharmaceutical compositions, for example (i) HMG-CoA reductase inhibitor (it typically is statins, comprise lovastatin, Simvastatin, Rosuvastatin, Pravastatin, fluvastatin, atorvastatin, upright his spit of fland of cutting down, itavastatin, pitavastatin and other statins), (ii) bile acid chelating agent (Colestyramine, the dialkyl aminoalkyl derivative of colestipol and crosslinked dextran, Colestid , LoCholest ), (iii) nicotinic acid and related compound, nicotinic alcohol for example, niacinamide and nicotinic acid or its salt, (iv) PPAR alfa agonists, for example gemfibrozil and Fenofibric Acid derivative (shellfish special class), comprise clofibrate, fenofibrate, bezafibrate, Win-35833 and etofibrate, (v) cholesterol absorption inhibitor, for example stanol ester, β-Gu Zaichun, steroline is for example for quinamine; With azetidinone ezetimibe for example, (vi) acyl-CoA: cholesterol acyltransferase (ACAT) inhibitor such as avasimibe and linolexamide, and comprise selectivity ACAT-I and ACAT-2 inhibitor and double inhibitor; (vii) phenol antioxidant, probucol for example, (viii) microsomal triglyceride transfer protein (MTP)/ApoB secretion inhibitor, (ix) antioxidant vitamin, for example vitamins C and E and β-Hu Luobusu, (x) intend the Tiroidina medicine, (xi) LDL (low-density lipoprotein) receptor inducer, (xii) anticoagulant, for example glycoprotein iib/iiia fibrinogen receptor antagonist and acetylsalicylic acid, (xiii) vitamin B12 (also being called Vitral), (xiv) folic acid or its pharmacologically acceptable salt or ester, for example sodium salt and methylglucosamine salt, (xv) FXR and LXR part, comprise inhibitor and agonist, (xvi) promoting agent of raising ABCA1 genetic expression and (xvii) ileal bile acid carrier.
Can use the preferred classes of the treatment compound of the lipid profile that is used for improving the patient (promptly raise HDL-C and reduce LDL-C) to comprise one or both of statins and cholesterol absorption inhibitor with The compounds of this invention.Preferred especially The compounds of this invention and Simvastatin, ezetimibe or with the two the combination of Simvastatin and ezetimibe.Further preferably, the statins of The compounds of this invention and non-Simvastatin, for example lovastatin, Rosuvastatin, Pravastatin, fluvastatin, atorvastatin, the upright combination of cutting down his spit of fland, itavastatin and ZD-4522.
At last, The compounds of this invention can use with the compound that is used for the treatment of other disease such as diabetes, hypertension and obesity and other antiatherogenic compound.Such combination can be used for treating one or more diseases for example diabetes, obesity, atherosclerosis and unusual lipidemia, the disease of perhaps relevant with metabolism syndrome more than one.Such combination can show synergy in these diseases in treatment, can reduce the active ingredient of dosage, and for example dosage can be to be dosage below the therapeutic dose during for independent the use.
Can be used for including but not limited to main antidiabetic compound, comprising with the example of other activeconstituents of The compounds of this invention Combined Preparation:
(a) PPAR gamma agonist and partial agonist comprise glitazone and non-glitazone (as pioglitazone, englitazone, MCC-555, rosiglitazone, balaglitazone, netoglitazone, T-131, LY-300512 and LY-818);
(b) biguanides such as N1,N1-Dimethylbiguanide and phenformin;
(c) Protein Tyrosine Phosphatases-1B (PTP-1B) inhibitor;
(d) DPP IV (DP-IV) inhibitor comprises vildagliptin, sitagliptin and saxagliptin;
(e) Regular Insulin or insulin-mimickers, for example Insulin lispro, Lantus, lente insulin and suction insulin preparation;
(f) sulfonylurea, for example tolbutamide, Glipizide, glimepiride, acetohexamide, chlorpropamide, Glyburide or related substances;
(g) alpha-glucosidase inhibitor (acarbose for example; Adiposine; Camiglibose; Emiglitate; Miglitol; Voglibose; Pradimicin-Q; And salbostatin); (h) PPAR α/γ dual agonists, for example muraglitazar, tesaglitazar, farglitazar and Raveglitazar;
(i) PPAR delta agonists, for example GW501516 and in WO97/28149 those disclosed;
(j) glucagon receptor antagonist;
(k) GLP-1; The GLP-1 derivative; GLP-1 analogue, for example exendins such as exenatide (Byetta); With non-peptidyl GLP-1 receptor stimulant;
(l) GIP-1; With
(m) non-sulfonylurea Regular Insulin succagoga, for example meglitinides (for example nateglinide and rapeglinide).
Can also comprise the anti-obesity compound with other active ingredient that the present invention unites use, comprise 5-HT (thrombotonin) inhibitor, neuropeptide Y 5 (NPY5) inhibitor, melanocyte cortin 4 acceptors (Mc4r) agonist, Cannabined receptor 1 (CB-I) antagonist/counter-rotating agonist, and beta 3 adrenoreceptor agonists.Them are described in more detail in the back in this joint.
These other active ingredients also comprise the active ingredient that is used for the treatment of inflammatory conditions, for example acetylsalicylic acid, non-steroidal antiinflammatory drugs, glucocorticosteroid, azulfidine and selective cyclooxygenase-2 (COX-2) inhibitor comprises L-791456, celecoxib, rofecoxib and Bextra.
Anti-hypertension compound also can be advantageously used in combination therapy with The compounds of this invention.Can comprise (1) Angiotensin II agonist, for example losartan with the example that The compounds of this invention is united the anti-hypertension compound of use; (2) angiotensin-convertion enzyme inhibitor (ACE inhibitor), for example enalapril and captopril; (3) for example nifedipine and diltiazem of calcium channel blocker; (4) endothelin antagonist.
Can comprise with the anti-obesity compound of The compounds of this invention Combined Preparation: (1) tethelin succagoga and tethelin succagoga receptor stimulant/antagonist, for example NN703, hexarelin and MK-0677; (2) Protein-tyrosine-phosphatase-1B (PTP-IB) inhibitor; (3) cannabinoid receptor ligand, for example cannaboid CB
1Receptor antagonist or counter-rotating agonist, for example Rimonabant (Sanofi Synthelabo), AMT-251 and SR-14778 and SR 141716A (Sanofi Synthelabo), SLV-319 (Solvay), BAY 65-2520 (Bayer); (4) anti-obesity serotonergic agent (serotonergic agent), for example Phenfluoramine, dexfenfluramine, phentermine and sibutramine; (5) β 3-adrenoreceptor agonists, for example AD9677/TAK677 (Dainippon/Takeda), CL-316,243, SB 418790, BRL-37344,1-796568, BMS-196085, BRL-35135A, CGP12177A, BTA-243, trecadrine, ZenecaD7114 and SR59119A; (6) pancreas lipase inhibitor, for example orlistat (Xenical ), Triton WR1339, RHC80267, lipstatin, tetrahydrolipstatin, teasaponin and diethyl umbrella shape base phosphoric acid ester (diethylumbelliferyl phosphate); (7) neuropeptide Y 1 antagonist, for example BIBP3226, J-115814, BIBO 3304, LY-357897, CP-671906 and GI-264879A; (8) neuropeptide Y 5 antagonist, for example GW-569180A, GW-594884A, GW-587081X, GW-548118X, FR226928, FR 240662, FR252384,1229U91, GI-264879A, CGP71683A, LY-377897, PD-160170, SR-120562A, SR-120819A and JCF-104; (9) melanin concentrating hormone (MCH) receptor antagonist; 10) melanin concentrating hormone 1 acceptor (MCH1R) antagonist, for example T-226296 (Takeda); (11) melanin concentrating hormone 2 acceptors (MCH2R) agonist/antagonist; (12) orexin-1 receptor antagonist, for example SB-334867-A; (13) melanocyte cortin agonist, for example Melanotan II; (14) other Mc4r (melanocyte cortin 4 acceptors) agonist, for example CHIR86036 (Chiron), ME-10142 and ME-10145 (Melacure), CHIR86036 (Chiron); PT-141 and PT-14 (Palatin); (15) 5HT-2 agonist; (16) 5HT2C (serotonin receptor 2C) agonist, for example BVT933, DPCA37215, WAY161503 and R-1065; (17) galanin antagonist; (18) CCK agonist; (19) CCK-A (pancreozymin-A) agonist, for example AR-R 15849, GI181771, JMV-180, A-71378, A-71623 and SR146131; (20) GLP-I agonist; (21) corticotropin releasing hormone agonist; (22) Histamine Receptors-3 (H3) conditioning agent; (23) Histamine Receptors-3 (H
3) antagonist/counter-rotating agonist, for example hioperamide, N-(4-amyl group) carboxylamine 3-(1 H-imidazol-4 yl) propyl diester, clobenpropit, iodophenpropit, imoproxifan and GT2394 (Gliatech); (24) beta-hydroxysteroid dehydrogenase-1 inhibitor (11 β-HSD-1 inhibitor), for example BVT3498 and BVT 2733, (25) PDE (phosphodiesterase) inhibitor, for example theophylline, pentoxifylline, Zaprinast, Virga, amrinone, milrinone, Cilostamide, rolipram and cilomilast; (26) phosphodiesterase-3B (PDE3B) inhibitor; (27) NE (norepinephrine) transport inhibitors, for example GW 320659, despiramine, Talsupram and nomifensine; (28) ghrelin receptor antagonist; (29) leptin comprises rh-Leptin (PEG-OB, Hoffman La Roche) and reorganization methionyl people leptin (Amgen; (30) leptin derivative; (31) BRS3 (bombesin receptor hypotype 3) agonist, for example [D-Phe6, β-Ala11, Phe13, Nle14] Bn (6-14) and [D-Phe6, Phe13] Bn (6-13) propyl amides; (32) CNTF (cilium neurotrophic factor), for example GI-181771 (Glaxo-SmithKline), SR146131 (SanofiSynthelabo), butabindide, PD170,292 and PD 149164 (Pfizer); (33) CNTF derivative, for example axokine (Regeneron); (34) monoamine re-uptake inhibitor, for example sibutramine; (35) UCP-I (not coupling protein-1,2 or 3) activator, for example Phytanoic acid, 4-[(E)-and 2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl--2-naphthyl)-1-propenyl] phenylformic acid (TTNPB) and vitamin A acid; (36) Triiodothyronine beta-agonists, for example KB-2611 (KaroBioBMS); (37) FAS (fatty acid synthetase) inhibitor, for example Cerulenin and C75; (38) DGAT1 (diacylglycerol acyltransferase 1) inhibitor; (39) DGAT2 (diacylglycerol acyltransferase 2) inhibitor; (40) ACC2 (acetyl-CoA carboxylic acid-2) inhibitor; (41) glucocorticosteroid antagonist; (42) acyl group oestrogenic hormon, for example oleoyl oestrone; (43) dicarboxylic acid transporter inhibitors; (44) peptide YY, PYY 3-36, peptide YY analogue, derivative and fragment, for example BIM-43073D, BIM-43004C, (45) for example NPY3-36, N-ethanoyl [Leu (28,31)] NPY 24-36, TASP-V and ring-(28/32)-Ac-[Lys28-Gru32 of neuropeptide Y 2 (NPY2) receptor stimulant]-(25-36)-pNPY; (46) neuropeptide tyrosine 4 (NPY4) agonist pancreas peptide (PP) for example; (47) for example BIBP3226, J-115814, BIBO 3304, LY-357897, CP-671906 and GI-264879A of neuropeptide Y 1 (NPY1) antagonist; (48) opioid antagonists, for example Nalmefene (Revex ), 3-methoxyl group TREXUPONT, naloxone and TREXUPONT; (49) glucose transport inhibitor; (50) phosphoric acid ester transport inhibitors; (51) 5-HT (thrombotonin) inhibitor; (52) beta blocker; (53) antagonists of neurokinine-1 receptor (NK-I antagonist); (54) clobenzorex; (55) cloforex; (56) MeN-1107; (57) clortermine; (58) cyclexedrine; (59) Dextrofenfluramine; (60) diphemethoxidine, (61) N-N-ethylamphetamine; (62) Phenbutrazate; (63) fenisorex; (64) non-Prey department; (65) Win 11464; (66) McN 1231; (67) furfuryl group methyl amphetamine; (68) Levamfetamine; (69) Levophacetoperane; (70) mefenorex; (71) N-methylephedrone; (72) metamfetamine; (73) pseudonorephedrine; (74) phenpentermine; (75) antapentan; (76) phenmetrazine; (77) picilorex; (78) phytopharm 57; (79) zonisamide; (80) aminorex; (81) amfecloral; (82) amphetamine; (83) Benzphetamine; (84) chlorphentermine.
Use the aforesaid combination treatment of The compounds of this invention also to can be used for treating metabolism syndrome.According to a widely used definition, the patient who suffers from metabolism syndrome is characterised in that to have at least three kinds of symptoms that are selected from following five kinds of symptoms: (1) abdominal obesity; (2) hypertriglyceridemia; (3) low high density lipoprotein cholesterol (HDL); (4) hypertension; (5) fasting glucose raises, if the patient also suffers from diabetes, then it can drop in the characteristic range of diabetes B.In these symptoms each is all at the Third Report of theNational Cholesterol Education Program Expert Panel on Detection that issues recently, Evaluation and Treatment of High Blood Cholesterol in Adults (AdultTreatment Panel III, or ATP III), National Institutes of Health, 2001, definition is clinically arranged among the NIH Publication No.01-3670.The patient who suffers from metabolism syndrome has above-mentioned great vessels of developing into of increase and microvascular complication, comprises the danger of atherosclerosis and coronary heart disease.Aforesaid combination can be improved more than one symptom (for example two kinds of symptoms, three kinds of symptoms, four kinds of symptoms or all five kinds of symptoms) of metabolism syndrome simultaneously.
The CETP test
Adopt BODIPY -CE as cholesteryl ester lipid donor, be used to measure IC according to the method improvement method of describing by people such as Epps
50Value is to differentiate the external long run test of CETP inhibitor compound.Referring to people such as Epps, (1995) Method for measuring theactivities of cholesteryl ester transfer protein (lipid transfer protein), Chem.Phys.Lipids.77,51-63.
The particle that is used to test produces from following source: the synthetic donor HDL particle that comprises DOPC (dioleoyl phosphatidyl choline), BODIPY -CE (Molecular Probes C-3927), triolein (triglyceride level) and apoHDL produces by the described probe sonication of people such as Epps basically; but add non-scattering quencher molecule; be dabcyldicetylamide, to reduce background fluorescence.Dabcyl dicetylamide is by preparing dabcyl n-succinimide and two (hexadecyl) amine in DMF in the presence of the Diisopropylamine catalyzer 95 ℃ of heated overnight.To derive from the natural lipoprotein of human blood as receptosome.By the particle of ultracentrifugation collection density less than 1.063g/ml.These particles comprise VLDL, IDL and LDL.(Pierce, USA) represent by the protein concn of Ce Dinging to test according to BCA for granule density.Before using with particle 4 ℃ of storages.
Test is being carried out in black 96 orifice plates (Cat#-7205) at the bottom of the Dynex Microfluor 2 U types.Preparation comprises half test mixture of CETP, 1 * CETP damping fluid (50mM Tris, pH7.4,100mMNaCl, 1mM EDTA) and receptosome ultimate density, and in each hole of plate the test mixture of adding 100 μ L.The DMSO that contains test compound that adds 3 μ L.Plate is mixed on the plate vibrator, cultivated 1 hour at 25 ℃ then.Preparation comprises second test mixture of donor particle, all the other receptosomes and 1 * CETP damping fluid.Second test mixture that adds 47 μ L in reacting hole is to begin test.Test is carried out under 25 ℃ in the final volume of 150 μ L.The ultimate density of material is: the receptosome (representing by protein content separately) of the donor particle of 5ng/ μ L, 30ng/ μ L, 1X CETP damping fluid, 0.8nM recombinant human CETP (express in Chinese hamster ovary celI and carry out partial purification) and mostly be 2% DMSO when test compound most.Test reads to carry out in the plate device (Molecular Devices Spectramax GeminiXS) at fluorescence, it is 45 minutes kinetics operation that this instrument is set at 25 ℃, under Ex=480nm, Em=511nm, read sample in per 45 seconds, use the edge filter of 495nm, the photomultiplier setting of medium, calibration is opened and 6 readings in every hole.
Data are estimated by obtaining initial rate, for the pseudo-linear portion of curve (normally 0-500 or 1000 seconds), show with relative fluorescence unit/stopwatch.To have inhibitor and not be subjected to the speed of the positive control sample of inhibition (having only DMSO) to compare the per-cent that is inhibited.The inhibition per-cent that is fitted to Sigmoidal 4 parametric equations is used to calculate IC to the logarithmic figure of inhibitor concentration
50
Embodiment
Provide following examples to understand and to understand thoroughly the present invention more completely.Raw material is that make with currently known methods or as follows making.
Embodiment should not regard as and limits the present invention by any way.Scope of the present invention is defined by the claims.The compounds of this invention has the IC that passes through above-mentioned experimental measurement that is less than or equal to 50 μ M
50Value.
Reaction scheme 1
Intermediate 1-2,1-3,1-4,1-5 and the 1-6 that uses among the present invention can buy or preparation shown in reaction scheme 1.To wherein R
aWith p in claims definition, and wherein the halogen 2-halo aniline 1-1 that is preferably the suitable replacement of iodine or bromine at high temperature handles with CuCN in DMF, obtains corresponding 2-cyano-aniline.Perhaps, can prepare nitrile compound (referring to Smith by in the presence of palladium (II) salt or in the presence of some copper or nickel complex, handling 1-1 with KCN and CuI, M.B. and March, J. " March ' s AdvancedOrganic Chemistry ", the 5th edition, John Wiley and Sons, New York, pp.867 (2001) and the reference of wherein quoting).Iodide 1-3 is by preparing (referring to for example: people such as Smith with processing 1-2 such as Isopentyl nitrite, n-amyl nitrite or nitrite tert-butyls in the presence of methylene iodide, J.Org.Chem.55,2543, (1990) and the reference of wherein quoting), reaction is not adopted solvent or is for example carried out in THF or the acetonitrile at solvent.Perhaps, iodide can form diazonium salts by at first using Isopentyl nitrite, n-amyl nitrite, nitrite tert-butyl, Sodium Nitrite or nitrous acid etc., heat subsequently to prepare in the presence of iodine or iodide salt such as cupric iodide, sodium iodide, potassiumiodide, tetrabutylammonium iodide etc.In methylene dichloride, 1-3 is reduced, obtain aldehyde 1-4 with DIBAL.In methyl alcohol or ethanol, use sodium borohydride etc. with aldehyde 1-4 reduction, obtain pure 1-5.For example in methylene dichloride, the ethylene dichloride etc., use carbon tetrabromide and triphenylphosphine to handle 1-5 at solvent, generate bromotoluene 1-6 (referring to Smith, M.B. and March, J. " March ' s Advanced Organic Chemistry ", 5
ThEd., John Wiley and Sons, New York, Pp.518-519 (2001) and the reference of wherein quoting).
Reaction scheme 2
R wherein
a, p and A
3Can shown in reaction scheme 2, make as defined intermediate 2-2 of the present invention and 2-3 in claims.2-cyano group iodobenzene 2-1 can buy or make according to method shown in the reaction scheme 1.Compound 2-2 is by Suzuki or Stille reaction or its modification, adopt iodide 2-1 and the aryl that suitably replaces or the catalytic crosslinking reaction of palladium of heteroaryl boric acid, boric acid ester or trialkyl tin compound to make, this reaction is as people such as Miyaua, Chem.Rev.95,2457 (1995) and the document wherein quoted described, and as Smith, M.B. and March, J. " March ' s Advanced Organic Chemistry ", 5
ThEd., JohnWiley and Sons, New York, pp.868-869 (2001) reaches described in the reference of wherein quoting.In ether, use lithium aluminium hydride with nitrile 2-2 reduction, obtained 2-amino methyl aniline 2-3.Perhaps, can in methyl alcohol, ethanol etc., under nitrogen atmosphere, use palladium on carbon or Raney nickel that nitrile is reduced.Other method that nitrile is reduced into amino methyl can be referring to Smith, M.B. and March, J. " March ' s Advanced Organic Chemistry ", 5
ThEd., JohnWiley and Sons, New York, pp.1204 (2001) and the reference of wherein quoting.
Reaction scheme 3
Wherein R, R
a, p, A
2, A
3Can shown in reaction scheme 3, make as defined The compounds of this invention 3-4 in claims with n.Benzyl amine 3-1 can buy or make according to method shown in the reaction scheme 2.With the alkyl acetate reaction of 3-1, obtain secondary amine 3-2 with the suitable replacement of carrying leavings group in the 2-position.Alkyl acetate can buy or use currently known methods to make.Preferred leavings group can be bromide or iodide, but also can be methanesulfonates, tosylate etc., and solvent can be methylene fluoride, ethylene dichloride, tetrahydrofuran (THF), glycol dimethyl ether etc.For example triethylamine, diisopropylethylamine, N-methylmorpholine wait and carry out this reaction can to adopt or not adopt alkali.Ester functional group reduction with 3-2 obtains amino alcohol 3-3.Preferred reductive agent is LiAlH
4, at solvent for example in ether, tetrahydrofuran (THF), glycol dimethyl ether, the dioxane etc.Can be with other method of ester reductive referring to " March ' sAdvanced Organic Chemistry " 5
ThEd., John Wiley and Sons, New York, pp 1551.For example methylene dichloride, ethylene dichloride, tetrahydrofuran (THF), glycol dimethyl ether etc. and alkali use for example triphosgene (Y=OCCl of phosgene (Y=Cl) or phosgene equivalent for example in triethylamine, diisopropylethylamine, the N-methylmorpholine etc. at solvent
3) or carbonyl-diimidazole (Y=imidazoles) etc. amino alcohol 3-3 cyclization is become oxazolidone 3-4.The enantiomer-pure product can obtain by chiral chromatography.
Reaction scheme 4
Wherein R, R
a, p, A
2, A
3Can shown in reaction scheme 4, make as defined The compounds of this invention 4-3 in claims with n.Benzyl amine 4-1 that suitably replaces and the reacting ethylene oxide that suitably replaces can have been obtained amino alcohol 4-2.Oxyethane can buy or corresponding aldehyde of oil and sulphur in salt make, as " March ' s Advanced OrganicChemistry " 5
ThEd., John Wiley and Sons, New York is described in the pp 1247.Perhaps, this epoxide can be by epoxidation, the halohydrin or 1 of alkene, the cyclization of 2-glycol or " March ' s Advanced Organic Chemistry " 5
ThEd., Jobn Wiley and Sons, New York, other method of describing among the pp 1051 makes.For this reaction, preferred solvent is a Virahol.In addition, this epoxide open loop can be at solvent for example in acetonitrile etc., by means of lewis acid catalyst Yb (OTf) for example
3Wait and carry out.For example methylene dichloride, ethylene dichloride, tetrahydrofuran (THF), glycol dimethyl ether etc. and alkali use for example triphosgene (Y=OCCl of phosgene (Y=Cl) or phosgene equivalent for example in triethylamine, diisopropylethylamine, the N-methylmorpholine etc. at solvent
3) or carbonyl-diimidazole (Y=imidazoles) etc. amino alcohol 4-2 cyclization is become oxazolidone 4-3.Perhaps, by at solvent for example in methylene dichloride, ethylene dichloride, tetrahydrofuran (THF), the glycol dimethyl ether etc., at alkali triethylamine for example, diisopropylethylamine etc. exist down, with for example two dimethyl benzyls or chloroformic acid benzyl ester processing of reagent, amino alcohol 4-2 can be changed into suitable carbamate.Then by solvent for example in tetrahydrofuran (THF), the glycol dimethyl ether etc. with alkali for example hexamethyldisilazane lithium, sodium or potassium handle, this carbamate can be changed into oxazolidinedione 4-3.The enantiomer-pure product can obtain by chiral chromatography.
Reaction scheme 5
Wherein R, R
a, p, A
2, A
3Can shown in reaction scheme 5, make as defined The compounds of this invention 5-5 in claims with n.Suitably the amino alcohol 5-1 that replaces can make as shown in reaction scheme 4, and preferably for example t-butyl carbamate (BOC) or benzyl carbamate (Cbz) protect as carbamate.Other carbamate and other nitrogen-protecting group can be referring to " Protective Groups in Organic Synthesis ", 3
RdEd.JohnWiley and Sons, New York, pp 494.Nitrogen can be undertaken by 5-1 and tert-Butyl dicarbonate or two dimethyl benzyls are for example reacted in methylene dichloride, ethylene dichloride, tetrahydrofuran (THF), the glycol dimethyl ether etc. at suitable solvent with the protection of BOC or Cbz group.By at suitable alkali for example in the presence of triethylamine, diisopropylethylamine, the N-methylmorpholine etc., at methylene dichloride, ethylene dichloride, tetrahydrofuran (THF) with the methylsulfonyl chloride reaction, can change into trinitride 5-3 with pure 5-2 in the glycol dimethyl ether etc.In addition, alcohol can be changed into other leavings group for example tosylate, iodide, bromide etc.Then at suitable solvent for example among DMF, the DMPU etc., with appropriate azide source NaN for example
3, LiN
3, Bu
4NN
3Deng methanesulfonates is replaced.Trinitride 5-3 can also make by in THF pure 5-2 being handled with diphenylphosphine acylazide, diethyl azodiformate and triphenylphosphine.Can for example among EtOAc, THF, the EtOH etc., adopt for example PtO of metal catalyst at suitable solvent
2Or Pd/C etc., by hydrogenation trinitride 5-3 is reduced.Reduction and remove protecting group after, obtain diamines 5-4.For BOC protecting group, TFA/CH
2Cl
2It is preferred deprotection method; For the CBZ protecting group, for example adopt for example PtO of metal catalyst among EtOAc, THF, the EtOH etc. at suitable solvent
2Or the hydrogenation of Pd/C is preferred deprotection method.For example methylene dichloride, ethylene dichloride, tetrahydrofuran (THF), glycol dimethyl ether etc. and alkali use for example triphosgene (Y=OCCl of phosgene (Y=Cl) or phosgene equivalent for example in triethylamine, diisopropylethylamine, the N-methylmorpholine etc. at solvent
3) or carbonyl-diimidazole (Y=imidazoles) etc. diamines 5-4 cyclization is become imidazolidone 5-5.The enantiomer-pure product can obtain by chiral chromatography.
Reaction scheme 6
Wherein R, R
a, p, A
2, A
3Can shown in reaction scheme 6, make as defined The compounds of this invention 6-4 in claims with n.In methyl alcohol, ethanol, ethylene dichloride, tetrahydrofuran (THF) etc., at reductive agent sodium borohydride for example, sodium cyanoborohydride, sodium triacetoxy borohydrides etc. exist down, perhaps according to Smith, and M.B. and March, J. " March ' sAdvanced Organic Chemistry ", 5
ThEd., John Wiley and Sons, NewYork, the method for describing in pp.1187-1189 (2001) and the reference wherein quoted is handled 6-1 with the amino-aldehyde of the protection of the suitable replacement that can buy or make by currently known methods, obtain 6-2.Transform for this, preferred condition is to use sodium cyanoborohydride in the methyl alcohol that contains catalytic acetate.With the 6-2 deprotection, obtain 6-3.For BOC protecting group, TFA/CH
2Cl
2It is preferred deprotection method.For example methylene dichloride, ethylene dichloride, tetrahydrofuran (THF), glycol dimethyl ether etc. and alkali use for example triphosgene (Y=OCCl of phosgene (Y=Cl) or phosgene equivalent for example in triethylamine, diisopropylethylamine, the N-methylmorpholine etc. at solvent then
3) or carbonyl-diimidazole (Y=imidazoles) etc. diamines 6-3 cyclization is become imidazolidone 6-4.The enantiomer-pure product can obtain by chiral chromatography.
Reaction scheme 7
Wherein R, R
a, p, A
2, A
3Can shown in reaction scheme 7, make as defined The compounds of this invention 7-5 in claims with n.To handle with two suitable carbonic ethers or chloro-formic ester as the amine 7-1 that makes as described in the reaction scheme 4, obtain 7-2.By in methylene dichloride, ethylene dichloride, tetrahydrofuran (THF), glycol dimethyl ether etc., for example react with methylsulfonyl chloride in the presence of triethylamine, diisopropylethylamine, the N-methylmorpholine etc. at suitable alkali, 7-2 can be changed into trinitride 7-3.Perhaps, this alcohol can be changed into other leavings group for example tosylate, iodide, bromide etc.Then at suitable solvent for example among DMF, the DMPU etc., with appropriate azide source NaN for example
3, LiN
3, Bu
4NN
3Deng methanesulfonates is replaced.Trinitride 7-3 can also make by in THF pure 5-2 being handled with diphenylphosphine acylazide, diethyl azodiformate and triphenylphosphine.Work as R
4When being benzyl, can adopt THF, use PtO as solvent
2Pass through H
2Trinitride 7-3 is reduced into amine 7-4.By at suitable solvent for example among THF, glycol dimethyl ether, DMF, the DMA etc., for example lithium diisopropylamine or two (trimethyl silyl) Lithamide, sodium or potassium etc. become imidazolidone 7-5 with the 7-4 cyclization to use suitable alkali.The enantiomer-pure product can obtain by chiral chromatography.
Reaction scheme 8
By at suitable solvent for example among THF, glycol dimethyl ether, DMF, the DMA etc., at suitable alkali for example in the presence of lithium diisopropylamine or two (trimethyl silyl) Lithamide, sodium or the potassium etc., with suitable alkylating agent for example alkylogen, toluenesulphonic acids alkyl ester, methylsulfonic acid alkyl ester etc. (for example methyl-iodides) handle, can be with wherein R, R
a, A
2, A
3, p and n change into 8-2 as defined compound 8-1 in claims (making) described in reaction scheme 5,6 and 7.
Reaction scheme 9
R wherein
a, p and A
3Can described in reaction scheme 9, make as defined intermediate 9-3 and 9-4 in claims.Can with the benzyl nitrile 9-1 of the suitable replacement that shown in reaction scheme 2, makes and alkali for example sodium hydroxide or potassium hydroxide etc. in for example heating in ethanol, the propyl alcohol etc. of suitable aqueous alcohol, the phenylformic acid 9-2 that acquisition suitably replaces (referring to: Smith, M.B. and March, J. " March ' s Advanced Organic Chemistry ", 5
ThEd., John Wiley and Sons, New York, pp.1179-1180 (2001) and the reference of wherein quoting).Can solvent for example use in the tetrahydrofuran (THF) etc. reductive agent for example borine phenylformic acid 9-2 is reduced into phenylcarbinol 9-3 (referring to Smith, M.B. and March, J. " March ' s Advanced OrganicChemistry ", 5
ThEd., John Wiley and Sons, New York, pp.1549 (2001) and the reference of wherein quoting).Perhaps, can pass through currently known methods, comprise with the trimethyl silyl diazomethane and handle esterification, and use LiAIH 9-2
4Deng the gained ester is reduced into pure 9-3.Can be for example in diamino methane, the ethylene dichloride etc. at solvent, for example triphenylphosphine and carbon tetrabromide change into bromotoluene 9-4 (referring to Smith with intermediate 9-3 to use reagent, M.B. and March, J. " March ' s Advanced Organic Chemistry ", 5
ThEd., John Wiley and Sons, New York, pp.518-519 (2001) and the reference of wherein quoting).
Reaction scheme 10
Wherein R, R
1, A
2, p and n can make like this as defined intermediate 10-4 of the present invention in claims: shown in reaction scheme 10,, obtain the nitroalcohol 10-2 of replacement with phenyl aldehyde 10-1 and the nitro-paraffin condensation that suitably replaces.This reaction can solvent for example in ethanol, the methyl alcohol etc. by alkali aqueous solution for example aqueous sodium hydroxide solution come catalysis.Can be for example in methyl alcohol, the ethanol etc. at alcoholic solvent, in the presence of hydrogen and aqueous acid, original reagent is gone back in employing, and for example Raney nickel, palladium carbon or platinum oxide are reduced into amino alcohol 10-3 (referring to Langer with nitroalcohol 10-2, O., Deng the people, Bioorg.Med.Chem., 2001,9,677-694).For example in methylene dichloride, diamino ethane, tetrahydrofuran (THF), the glycol dimethyl ether etc., use reagent for example phosgene (Y=Cl), triphosgene (Y=OCCl at solvent
3) or carbonyl dimidazoles (Y=imidazoles) for example triethylamine, diisopropylethylamine etc. become oxazolidone 10-4 with amino alcohol 10-3 cyclization with alkali.
Reaction scheme 11
Wherein R, R
1, A
2, p and n can make shown in reaction scheme 11 as defined intermediate 11-4 of the present invention in claims.N-formamyl-(N-methoxyl group-N-methyl) acid amides of the amino acid/11 1-1 that can buy or make by currently known methods with grignard reagent or other organometallic reagent for example organolithium handle, obtain corresponding ketone 11-2.This ketone is reduced with sodium borohydride or zinc borohydride in alcoholic solvent or THF, perhaps in THF, use for example phenyl dimethylsilane reduction of other reductive agent, obtain pure 11-3, by solvent for example in MeOH, EtOH etc. and THF, dioxane, the glycol dimethyl ether etc. with alkali for example KOH handle, the 11-3 cyclization can be become oxazolidone 11-4.
Reaction scheme 12
Wherein R, R
1, R
a, A
2, A
3, p and n can make shown in reaction scheme 12 as defined The compounds of this invention 12-3 in claims.At solvent for example in tetrahydrofuran (THF), glycol dimethyl ether, ether, dimethyl formamide, the N,N-DIMETHYLACETAMIDE etc., adopt alkali for example hexamethyldisilazane sodium or sodium hydride, oxazolidone 12-2 alkylation with the bromotoluene 12-1 that makes shown in reaction scheme 9 will make shown in reaction scheme 10 and 11 obtains product 12-3.
Reaction scheme 13
Wherein R, R
1, R
a, A
2, A
3, p and n can make shown in reaction scheme 13 as defined The compounds of this invention 13-4 in claims.At solvent for example in tetrahydrofuran (THF), glycol dimethyl ether, the ether etc., adopt alkali for example hexamethyldisilazane sodium or sodium hydride, oxazolidone 13-2 alkylation with the bromotoluene 13-1 that makes shown in reaction scheme 1 will make shown in reaction scheme 10 and 11 obtains product 13-3.Compound 13-4 is by Suzuki or Stille reaction or its modification, adopt iodide 13-3 and the aryl that suitably replaces or the catalytic crosslinking reaction of palladium of heteroaryl boric acid, boric acid ester or trialkyl tin compound to make, this reaction is as people such as Miyaua, Chem.Rev.95,2457 (1995) and the document wherein quoted described, and as Smith, M.B. and March, J. " March ' s Advanced OrganicChemistry ", 5
ThEd., John Wiley and Sons, New York, pp.868-869 (2001) reaches described in the reference of wherein quoting.
Reaction scheme 14
Wherein R, R
a, A
2, A
3, p and n make shown in reaction scheme 14 as defined The compounds of this invention 14-5 in claims.Phenylcarbinol 14-1 can buy or make according to reaction scheme 9 described methods.With 14-1 and Dess-Martin periodinane reaction, obtain corresponding phenyl aldehyde 14-2.Can also use other method that is used for primary hydroxyl is oxidized to aldehyde, for example Swern oxidizing condition, mistake ruthenic acid tetrapropyl ammonium, pyridine chloro-chromic acid salt, sulphur trioxide-pyridine etc.2-amino-1-phenylethyl alcohol 14-3 can then with the reduction of reductive agents such as lithium aluminium hydride, and be made by 14-2 via corresponding silylanizing cyano group alcohol by handling with trimethylsilyl cyanide and catalytic zinc iodide.Perhaps, 2-amino-1-phenylethyl alcohol 14-3 can be by handling with potassium cyanide, reduction then, and make by 14-2 via corresponding cyano group alcohol.For example in methylene dichloride, ethylene dichloride, tetrahydrofuran (THF), the glycol dimethyl ether etc., use reagent for example phosgene (Y=Cl), triphosgene (Y=OCCl at solvent
3) or carbonyl dimidazoles (Y=imidazoles) for example triethylamine, diisopropylethylamine etc. can become oxazolidone 14-4 with 2-amino-1-phenylethyl alcohol 14-3 cyclization with alkali.Can for example in tetrahydrofuran (THF), glycol dimethyl ether, the ether etc., adopt alkali for example hexamethyldisilazane sodium or sodium hydride at solvent, with oxazolidone 14-4 alkylation, obtain product 14-5 with alkyl, assorted alkyl, aryl or heteroaryl bromide.The enantiomer-pure product can obtain by chiral chromatography.
Reaction scheme 15
Wherein R, R
1, R
a, A
2, A
3, p and n can make shown in reaction scheme 15 as defined The compounds of this invention 15-6 in claims.Aldehyde 15-1 can buy or make according to the method for describing in the reaction scheme 1.With 15-1 and nitro-paraffin condensation, obtain the nitroalcohol 15-2 that replaces.This reaction can solvent for example in ethanol, the methyl alcohol etc. by alkali aqueous solution for example aqueous sodium hydroxide solution come catalysis.Can be for example in methyl alcohol, the ethanol etc. at alcoholic solvent, in the presence of hydrogen and aqueous acid, original reagent is gone back in employing, and for example Raney nickel, palladium carbon or platinum oxide are reduced into amino alcohol 15-3 (referring to Langer with nitroalcohol 15-2, O., Deng the people, Bioorg.Med.Chem., 2001,9,677-694).Can for example in methylene dichloride, ethylene dichloride, tetrahydrofuran (THF), the glycol dimethyl ether etc., use reagent for example phosgene (Y=Cl), triphosgene (Y=OCCl at solvent
3) or carbonyl dimidazoles (Y=imidazoles) for example triethylamine, diisopropylethylamine etc. become oxazolidone 15-4 with amino alcohol 15-3 cyclization with alkali. oxazolidone 15-5 is by Suzuki or Stille reaction or its modification, adopt iodide 15-4 and the aryl that suitably replaces or the catalytic crosslinking reaction of palladium of heteroaryl boric acid, boric acid ester or trialkyl tin compound to make, this reaction is as people such as Miyaua, Chem.Rev.95,2457 (1995) and the document wherein quoted described, and as Smith, M.B. and March, J. " March ' s Advanced OrganicChemistry ", 5
ThEd., John Wiley and Sons, New York, pp.868-869 (2001) reaches described in the reference of wherein quoting.Can for example in tetrahydrofuran (THF), glycol dimethyl ether, the ether etc., adopt alkali for example hexamethyldisilazane sodium or sodium hydride at solvent, with oxazolidone 15-5 alkylation, obtain product 15-6 with alkyl, assorted alkyl, aryl or heteroaryl bromide.The enantiomer-pure product can obtain by chiral chromatography.
Reaction scheme 16
Wherein R, R
1, R
a, A
2, A
3, p and n can make shown in reaction scheme 16 as defined The compounds of this invention 16-5 in claims.Aldehyde 16-1 can buy or make according to the method for describing in the reaction scheme 1.With 16-1 and the condensation of chirality N-acyl group oxazolidone, obtain pure affixture 16-2, as Evans, people such as D.A., J.Am.Chem.Soc, 2002,124, described in the 392-3.Chirality N-acyl group oxazolidone can be bought or according to Ager, DJ.; Allen, D.A.; Schaad, D.R.Synthesis 1996, and the method for describing among the 1283-5 makes.Compound 16-2 can be hydrolyzed into corresponding carboxylic acid, use diphenyl phosphate azide (diphenylphosphorazidate) and trialkylamine alkaline purification then, reset, obtain chirality oxazolidone 16-3 to carry out Curtius. oxazolidone 16-4 is by Suzuki or Stille reaction or its modification, adopt iodide 16-3 and the aryl that suitably replaces or the catalytic crosslinking reaction of palladium of heteroaryl boric acid, boric acid ester or trialkyl tin compound to make, this reaction is as people such as Miyaua, Chem.Rev.95,2457 (1995) and the document wherein quoted described, and as Smith, M.B. and March, J. " March ' s Advanced Organic Chemistry ", 5
ThEd., John Wiley and Sons, New York, pp.868-869 (2001) reaches described in the reference of wherein quoting.Can for example in tetrahydrofuran (THF), glycol dimethyl ether, the ether etc., adopt alkali for example hexamethyldisilazane sodium or sodium hydride at solvent, with oxazolidone 16-4 alkylation, obtain product 16-5 with alkyl, assorted alkyl, aryl or heteroaryl bromide.Perhaps, available suitable bromide obtains compound 16-6 with oxazolidone 16-3 alkylation, adopts aryl or heteroaryl boric acid, boric acid ester or trialkyl tin compound, allow compound 16-6 carry out Suzuki or Stille reaction or its modification, obtain product 16-5.The enantiomer-pure product can obtain by chiral chromatography.
Embodiment 1
2-amino-5-(trifluoromethyl) benzonitrile
In 2 liters of flasks, add 100g (0.348mol) 4-amino-3-iodine phenylfluoroform, 40gCuCN and 750mL DMF.This mixture heating up is kept refluxing 1 hour to refluxing then.With this reaction cooling and pour in the 3L water that contains the dense ammonium hydroxide of 300mL.In this mixture, add 1L CH
2Cl
2Then with this mixture via diatomite filtration.Separate each layer, use CH
2Cl
2The reextraction water layer.Organic extract liquid is merged, solvent removed under reduced pressure.Resistates is dissolved in the 1.5L ether, with gained solution 1N ammonium hydroxide, aqueous solution of sodium bisulfite, 1N hydrochloric acid and salt water washing.With this solution anhydrous magnesium sulfate drying, filter via the silica gel plug that contains the sal epsom layer at the top.Wash this silica gel plug with the 0.5L ether.Diethyl ether solution is merged, be concentrated into 750mL, leave standstill in room temperature.After 2 days, collect the gained solid, use hexane wash, and drying under reduced pressure, 2-amino-5-(trifluoromethyl) benzonitrile obtained.
1H NMR(CDCl
3，500MHz)δ7.68(s，1H)，7.58(d，J＝8.5Hz，1H)，6.81(d，J＝8.5Hz，1H)，4.80(brs，2H).
Embodiment 2
2-iodo-5-(trifluoromethyl) benzonitrile
At 35 ℃, drip nitrite tert-butyl (21mL) in the solution in acetonitrile (150mL) to 2-amino-5-(trifluoromethyl) benzonitrile (15.1g) and methylene iodide (24mL).During adding, this reaction is remained on 330-35 ℃.Allow this reaction wear out 30 minutes, then 60 ℃ of heating 30 minutes.With this reaction mixture cooling,, use 2 * water, 2 * aqueous solution of sodium bisulfite, water and salt water washing successively with the ether washing.With this solution anhydrous magnesium sulfate drying, filter via silica gel plug, concentrate then, obtain the 100g red oil.By the silica gel chromatography purified product, use hexane, 3: 1 hexane/CH successively
2Cl
2With 1: 1 hexane/CH
2Cl
2Wash-out has obtained 2-iodo-5-(trifluoromethyl) benzonitrile.
1HNMR(CDCl
3，500MHz)δ8.10(d，J＝8.5Hz，1H)，7.85(d，J＝1.8Hz，1H)，7.52(dd，J＝8.5，1.8Hz，1H).
Embodiment 3
5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-formonitrile HCN
(2.0g, 6.7mmol) (1.6g 8.4mmol) adds 2M Na in the solution in dimethyl ethylene glycol (30.4mL) with (5-sec.-propyl-2-p-methoxy-phenyl) boric acid to 2-iodo-5-(trifluoromethyl) benzonitrile
2CO
3(6.8mL), ethanol (9.6mL) and water (10mL).This solution was outgased 2 minutes with nitrogen.Add Pd (PPh
3)
4(774mg, 0.67mmol), and with this solution once more with the nitrogen degassing 2 minutes.This solution is distributed in two 40mL microwave tubes.Each effective nitrogen degassing 1 minute, sealing, and place microwave reactor.Wattage is set at 200W reaches 150 ℃, then temperature was kept 10 minutes at 150 ℃ until temperature.Afterwards microwave tube is cooled to room temperature, merges, pour H into
2O (50mL), and extract with EtOAc (100mL).Organic layer with salt solution (50mL) washing, is used dried over sodium sulfate, filter, and concentrate.By purified by flash chromatography, use 15%CH
2Cl
2/ hexane wash-out, obtained 5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-formonitrile HCN, be light yellow oil.R
f=0.65 (25%EtOAc/ hexane).
1H NMR(CDCl
3，500MHz)δ7.97(s，1H)，7.85(d，J＝8.0Hz，1H)，7.63(d，J＝8.0Hz，1H)，7.31(dd，J＝8.5，2.0Hz，1H)，7.12(d，J＝2.0Hz，1H)，6.97(d，J＝8.5Hz，1H)，3.82(s，3H)，2.93(m，1H)，1.27(d，J＝7.0Hz，6H)
Embodiment 4
1-[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methylamine
5 generals '-sec.-propyl-2 '-(996.2mg 3.12mmol) is dissolved in the ether (33mL) methoxyl group-4-(trifluoromethyl) biphenyl-2-formonitrile HCN, is cooled to 0 ℃.By syringe drip LAH (solution of 12.49mL 1M in ether, 12.49mmol).0 ℃ stir 10 minutes after, this reaction is warmed to room temperature and stirring at room 6 hours.Then this solution is dripped 1.5mLH lentamente
2O (acutely discharging gas) comes stopped reaction, adds 1.5 mL 30%NaOH then, adds 3.0mL H then
2O.With the gained gelatinous precipitate with 5 * 20mL CH
2Cl
2Washing; With organic washings dried over sodium sulfate, filter and concentrate.By the purified by flash chromatography resistates, use and contain 0.1%Et
3The 2%MeOH/CH of N
2Cl
2Wash-out, obtained 1-[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methylamine.Rf＝0.30(10％MeOH/CH
2Cl
2)。
LCMS＝324.3(M+1)
+.
1H NMR(CDCl
3，500MHz)δ7.77(s，1H)，7.55(d，J＝6.8Hz，1H)，7.32(d，J＝7.8Hz，1H)，7.25(dd，J＝83，2.1Hz，1H)，7.00(d，J＝2.1Hz，1H)，6.92(d，J＝8.4 Hz，1H)，3.66-3.74(m，5H)，2.91(m，1H)，1.26(d，J＝6.9Hz，6H)，
Embodiment 5
4-[3,5-two (trifluoromethyl) phenyl]-3-{[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-1,3- azoles alkane-2-ketone
Steps A: [3,5-two (trifluoromethyl) phenyl] (hydroxyl) methyl acetate
To [3,5-two (trifluoromethyl) phenyl] (hydroxyl) acetate (510mg, 1.77mmol) add MeOH (1.5mL) in the solution in benzene (10mL), add then (trimethyl silyl) diazomethane (solution of 1.06mL 2M in hexane, 2.12mmol).After 10 minutes, come stopped reaction by adding several HOAc (add until yellow and disappear).Should react concentrated, and,, obtain [3,5-two (trifluoromethyl) phenyl] (hydroxyl) methyl acetate with 10-80%EtOAc/ hexane wash-out by purified by flash chromatography.
1HNMR(CDCl
3，500MHz)δ7.94(s，2H)，7.85(s，1H)，5.32(s，1H)，3.83(s，3H)，3.68(bs，1H).
Step B:[3,5-two (trifluoromethyl) phenyl] (bromine) methyl acetate
(300mg 0.993mmol) is dissolved in CH with [3,5-two (trifluoromethyl) phenyl] (hydroxyl) methyl acetate
2Cl
2(10mL).This solution is cooled to 0 ℃, adds CBr
4(659mg 1.986mmol), adds PPh then
3(521mg, 1.986mmol).After 1 hour, this reaction is warmed to room temperature and stirring at room 1 hour.This reaction is filtered via short silica gel plug, use CH
2Cl
2Washing.This filtrate concentrated and with resistates by purified by flash chromatography, with 5%EtOAc/ hexane wash-out, obtained [3,5-two (trifluoromethyl) phenyl] (bromine) methyl acetate.R
f=0.24 (5%EtOAc/ hexane).
1H NMR(CDCl
3，500 MHz)δ8.02(s，2H)，7.87(s，1H)，5.41(s，1H)，3.83(s，3H).
Step C:[3,5-two (trifluoromethyl) phenyl] ([5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } amino) methyl acetate
(237.7mg is added in CH in flask 0.651mmol) to (bromine) methyl acetate to containing [3,5-two (trifluoromethyl) phenyl]
2Cl
21-[5 ' (4mL)-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] and methylamine (102.1mg, 0.316mmol).This is reflected at stirring at room 5 hours, uses EtOAc (50ml) dilution then.With this organic solution water and salt solution (being respectively 15mL) washing.With the organic extract liquid dried over sodium sulfate, filter, and concentrate.By purified by flash chromatography (5-15%EtOAc/ hexane), obtained [3,5-two (trifluoromethyl) phenyl] ([5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl amino) methyl acetate.R
f=0.33 (15%EtOAc/ hexane).
LCMS＝608.4(M+1)
+.
1H NMR(CDCl
3，500MHz)δ7.76-7.79(m，3H)，7.62(s，1H)，7.56(d，J＝7.8Hz，1H)，7.31(d，J＝7.8Hz，1H)，7.23(dd，J＝8.2，1.9Hz，1H)，6.96(m，1H)，6.89(d，J＝8.5Hz，1H)，4.30(m，1H)，3.54-3.70(m，8H)，2.87(m，1H)，1.21-1.23(m，6H).
Step D:2-[3,5-two (trifluoromethyl) phenyl]-2-([5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } amino) ethanol
With [3,5-two (trifluoromethyl) phenyl] ([5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl amino) (13.2mg 0.0217mmol) is dissolved in Et to methyl acetate
2Among the O (1.5mL), be cooled to 0 ℃.By syringe drip LAH (solution of 108.5 μ L 1M in LAH, 0.1085mmol).This reaction is warmed to room temperature and stirring at room 1 hour.Then by adding H
2O (100 μ L) comes stopped reaction, adds 1N NaOH (100 μ L), adds H then
2O (300 μ L).With this gelatinous precipitate CH
2Cl
2Washing several times.Organic washings is filtered via silica gel plug, use 2%MeOH/CH
2Cl
2Washing, and this filtrate is concentrated.By PTLC purifying resistates, use 25%EtOAc/ hexane wash-out, obtained 2-[3,5-two (trifluoromethyl) phenyl]-2-([5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } amino) ethanol.R
f=0.27 (25%EtOAc/ hexane).
LCMS＝580.4(M+1)
+.
1H NMR(CD
2Cl
2，500MHz)δ7.79(s，1H)，7.75(s，2H)，7.63-7.68(m，1H)，7.55(d，J＝7.8Hz，1H)，7.31(d，J＝7.8Hz，1H)，7.23 (m，1H)，6.94(m，1H)，6.89(m，1H)，3.43-3.76(m，9H)，2.86(m，1H)，1.90(bs，1H)，1.20(d，J＝6.8Hz，6H).
Step e: 4-[3,5-two (trifluoromethyl) phenyl]-3-{[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-1,3- azoles alkane-2-ketone
To phosgene (solution of 21 μ L 20% in toluene ,～0.0535mmol) at CH
2Cl
2(0.5mL) be added in CH in Nei the solution
2Cl
22-[3 (0.5mL), 5-two (trifluoromethyl) phenyl]-2-([5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl amino) ethanol (3.1mg, 0.00535mmol), add then DIPEA (19 μ L, 0.107mmol).Stir after 5 minutes, this reaction is poured in the water (1mL), this mixture is extracted (20mL) with EtOAc.With organic extract liquid H
2O, saturated NaHCO
3And salt solution (being respectively 5mL) washing.With the organic layer dried over sodium sulfate, filter then, and concentrate.By PTLC purifying resistates, obtained 4-[3,5-two (trifluoromethyl) phenyl]-3-{[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-1,3- azoles alkane-2-ketone.R
f=0.27 (25%EtOAc/ hexane).LCMS＝606.3(M+1)
+。
1H NMR (CD
2Cl
2, 500MHz) (observe some peak overlapping; Atropisomer exists with 1: 1 ratio)
δ 7.84 (s, 1H), 7.19-7.60 (m, 6H), 6.80-6.87 (m, 2H), 3.84-4.68 (m, 5H), 3.68﹠amp; 3.64 (2 is unimodal, 3H), 2.82 (m, 1H), 1.17-1.21 (m, 6H).
Embodiment 6
5-[3,5-two (trifluoromethyl) phenyl]-3-{[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-1,3- azoles alkane-2-ketone
Steps A: 2-[3,5-two (trifluoromethyl) phenyl] oxyethane
In anhydrous flask, add NaH (1.09g60%NaH, 27.27mmol).Add DMSO (90mL), add then trimethyl sulfonium iodide (7.0g, 31.82mmol).Should react and stir 5 minutes, add 3 then, 5-two (trifluoromethyl) phenyl aldehyde (1.5mL, 9.09mmol) solution in DMSO (15mL).This was reflected at stirring at room 1 hour, pours into then in ice/water (300mL).(3 * 150mL) extract with pentane with this mixture.Merge the pentane extraction liquid, and filter, use 10%Et via short silica gel plug
2The washing of O/ pentane.This filtrate concentrated and with resistates by purified by flash chromatography, use 10%Et
2O/ pentane wash-out has obtained 2-[3,5-two (trifluoromethyl) phenyl] oxyethane.R
f=0.42 (10%Et
2The O/ pentane).
1H NMR(CDCl
3，500MHz)7.82(s，1H)，7.74(s，2H)，3.99(dd，J＝3.9，2.5 Hz，1H)，3.23(dd，J＝5.2，4.1 Hz，1H)，2.79(dd，J＝5.5，2.5Hz，1H).
Step B:1-[3,5-two (trifluoromethyl) phenyl]-2-([5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } amino) ethanol
With 1-[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methylamine (300mg, 0.929mmol) and 2-[3,5-two (trifluoromethyl) phenyl] (297mg, 1.161mmol) vlil in 2-propyl alcohol (9mL) is 15 hours, is cooled to room temperature then for oxyethane.With this solution concentration, and by the purified by flash chromatography resistates, use 10-80%EtOAc/ hexane wash-out, obtained 1-[3,5-two (trifluoromethyl) phenyl]-2-([5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } amino) ethanol.R
f=0.24 (25%EtOAc/ hexane).
LCMS＝580.3(M+1)
+.
1H NMR(CDCl
3，500MHz)δ7.75-7.76(m，3H)，7.69(s，1H)，7.58(d，J＝7.8Hz，1H)，7.34 (d，J＝7.7Hz，1H)，7.25(m，1H)，6.98(bs，1H)，6.92(d，J＝8.5Hz，1H)，4.62(m，1H)，3.65-3.82(m，5H)，2.89(m，1H)，2.79(dd，J＝12.4，3.0 Hz，1H)，248(m，1H)，1.23(d，J＝6.8Hz，6H).
Step C:5-[3,5-two (trifluoromethyl) phenyl]-3-{[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-1,3- azoles alkane-2-ketone
At 0 ℃, to 1-[3,5-two (trifluoromethyl) phenyl]-2-([5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } amino) (31.9mg is 0.0551mmol) at CH for ethanol
2Cl
2(5mL) add in Nei the solution DIPEA (67 μ L, 0.386mmol), add then triphosgene (8.2mg, 0.0276mmol).This is reflected at 0 ℃ stirred 30 minutes.Pour this solution into saturated NaHCO then
3(15mL), this mixture is extracted with EtOAc (50mL).Organic layer with salt solution (15mL) washing, is used dried over sodium sulfate, filter, and concentrate.By purified by flash chromatography (20%EtOAc/ hexane), obtained 5-[3,5-two (trifluoromethyl) phenyl]-3-{[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-1,3- azoles alkane-2-ketone.R
f=0.32 (25%EtOAc/ hexane).LCMS＝606.3(M+1)
+。
1H NMR (CD
2Cl
2, 500MHz) (atropisomer exists with 1: 1 ratio, some peak overlapping)
δ 7.90 (s, 1H), 7.77 (s, 2H), 7.57-7.62 (m, 2H), 7.37 (d, J=8.0Hz, 1H), 7.27 (m, 1H), 6.98 (s, 1H), 6.93 (dd, J=8.4,3.2Hz, 1H), 5.42-5.53 (m, 1H), 4.15-4.59 (m, 2H), 3.72﹠amp; 3.73 (2 is unimodal, 3H), 3.05-3.65 (m, 2H), 2.88 (m, 1H), 1.19-1.23 (m, 6H).
These two kinds of enantiomorphs can pass through chirality HPLC, use 15%IP A/ heptane to separate with the AD chiral column.
Embodiment 7
3-{[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-5-pyridine-2-base-1,3- azoles alkane-2-ketone
Steps A: 2-([5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } amino)-1-pyridine-2-base ethanol
With 1-[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methylamine (300mg, 0.929mmol) and the vlil of 2-oxyethane-2-yl pyridines (640mg) [making by 2-pyridylaldehyde and NaH and trimethyl sulfonium iodide reacted in DMSO] in 2-propyl alcohol (9mL) 5 hours, be cooled to room temperature then.With this solution concentration, and with resistates by purified by flash chromatography, with containing 0.5%Et
3The 50-100%EtOAc/ hexane wash-out of N, obtained 2-([5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl amino)-1-pyridine-2-base ethanol.Show that by lcms analysis required product contains several small amount of impurities.This product need not be further purified or analyze and be directly used in next reaction.
Step B:(2-hydroxyl-2-pyridine-2-base ethyl) [5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } benzyl carbamate
In room temperature under nitrogen, with (PhCH
2OCO)
2(103 mg are 0.360mmol) at anhydrous CH for O
2Cl
2(2mL) in Nei the solution by sleeve pipe be added to 2-([5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl amino)-(160mg is 0.360mmol) at anhydrous CH for 1-pyridine-2-base ethanol
2Cl
2(10mL) in Nei the solution that is stirring.This is reflected at stirring at room 2 hours and vacuum concentration, has obtained crude product.It is passed through purified by flash chromatography (Si, 25 * 160mm, the mixture gradient of 0-50%EtOAc in hexane), obtained (2-hydroxyl-2-pyridine-2-base ethyl) [5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl benzyl carbamate.R
f=0.63 (50%EtOAc/ hexane).LCMS calculated value=579.25; Measured value=579.2 (M+1)
+
Step C:3-{[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-5-pyridine-2-base-1,3- azoles alkane-2-ketone
In room temperature under nitrogen, with two (trimethyl silyl) Lithamide (solution of 464 μ L 0.5M in toluene, 0.232mmol) be added drop-wise to (2-hydroxyl-2-pyridine-2-base ethyl) [5 '-sec.-propyl-2 '～methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl (134.3mg is 0.232mmol) in the solution that is stirring in anhydrous THF (10mL) for benzyl carbamate.After 1 hour, use saturated NH in stirring at room
4Cl (10mL) stopped reaction is with EtOAc (3 * 20 mL) extraction.With the extraction liquid drying (sodium sulfate) that merges, and vacuum concentration, crude product obtained.It is passed through purified by flash chromatography (Si, 25 * 160mm, the mixture gradient of 0-70%EtOAc in hexane), obtained 3-{[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl-5-pyridine-2-base-1,3- azoles alkane-2-ketone.R
f=0.58 (50%EtOAc/ hexane).LCMS calculated value=471.19; Measured value=471.2 (M+1)
+
Embodiment 8
5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-formic acid
With 5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-formonitrile HCN (727mg, 2.28mmol) and KOH (767mg is 13.7mmol) at H
2Solution among O (7.70mL) and the i-PrOH (11.55mL) carries out microwave irradiation (130 ℃ of 300W, 4 hours) in sealed tube.With this reaction mixture vacuum concentration to remove i-PrOH.With gained aqueous slurry water (50 mL) dilution, with EtOAc extraction (50mL).With organic extract liquid drying (Na
2SO
4) and vacuum concentration, obtained 5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-methane amide.With concentrated hydrochloric acid with the water layer acidifying, and with EtOAc (3 * 50mL) extraction.With the organic extract liquid drying (Na that merges
2SO
4) and vacuum concentration, obtained 5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-formic acid, be colorless solid.
1H NMR (CDCl
3, 500MHz) δ 8.01 (s, 1H), 7.71 (d, J=7.8Hz, 1H), 7.41 (d, J=7.8Hz, 1H), 7.14 (d, J=8.1Hz, 1H), 7.04 (s, 1H), 6.77 (d, J=8.1,1H), 3.68 (s, 3H), 2.84 (septet, J=6.7Hz, 1H), 1.19 (d, J=6.7Hz, 6H).
Embodiment 9
[5 '-sec.-propyl-2-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl alcohol
In room temperature under nitrogen, with the solution (1M of borine in THF, 859 μ L, 0.859mmol) be added drop-wise to 5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-formic acid and 5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-methane amide (3: 1,96.8mg, 0.286mmol) in the solution that is stirring in anhydrous THF.This was reflected at stirring at room 3 hours, and water (10mL) stopped reaction carefully.With this mixture with EtOAc (3 * 20mL) extractions, and with the extraction liquid salt water washing that merges, drying (Na
2SO
4) and vacuum concentration, obtained crude product.It is passed through purified by flash chromatography (Si, 125 * 160mm, the 0-30%EtOAc mixture gradient in hexane), obtained [5 '-sec.-propyl-2-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl alcohol, be colorless oil.R
f=0.27 (10%EtOAc/ hexane).
1H NMR (CDCl
3, 500MHz) δ 7.89 (brs, 1H), 7.62 (dd, J=8.0,1.3Hz, 1H), 7.36 (d, J=8.0Hz, 1H), 7.29 (dd, J=8.5,2.3Hz, 1H), 7.03 (d, J=2.3Hz, 1H), 6.96 (d, J=8.5,1H), 4.51 (m, 2H), 3.74 (s, 3H), 2.93 (septet, J=7.0Hz, 1H), 2.51 (s, 1H), 1.29 (d, J=7.0Hz, 6H).
Embodiment 10
2-(brooethyl)-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl
At 0 ℃ under nitrogen, with CBr
4(112mg, 0.211mmol) and Ph
3P (55mg, 0.211mmol) be added to successively [5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] (57.1mg is 0.176mmol) at anhydrous CH for methyl alcohol
2Cl
2(1mL) in Nei the solution that is stirring.This solution stirring at room 1 hour, and with this reaction mixture vacuum concentration, has been obtained crude product.With it by purified by flash chromatography (Si, 12 * 160mm, the 0-20%EtOAc mixture gradient in hexane), obtained 2-(brooethyl)-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl, be colorless oil.R
f=0.95 (20%EtOAc/ hexane).LCMS calculated value=387.05; Measured value=387.0 (M+1)
+
1H NMR (CDCl
3, 500 MHz) and δ 7.83 (brs, 1H), 7.60 (dd, J=8.0,1.3Hz, 1H), 7.37 (d, J=8.0Hz, 1H), 7.29 (dd, J=8.5,2.3Hz, 1H), 7.14 (d, J=2.3Hz, 1H), 6.95 (d, J=8.5,1H), 4.45 (d, J=10.6Hz, 1H), 4.33 (d, J=10.6Hz, 1H), 3.76 (s, 3H), 2.94 (septets, J=6.9Hz, 1H), 1.29 (d, J=6.9Hz, 6H).
Embodiment 11
1-(4-aminomethyl phenyl)-2-nitroethyl alcohol
At 0 ℃, with 4-tolyl aldehyde (325mg, 319 μ L, 2.71mmol) and Nitromethane 99Min. (531 μ L, 9.89mmol) the solution that is stirring in anhydrous EtOH (20mL) is with the 10%NaOH aqueous solution (m/v) (1.14mL, 2.84mmol) handle, also (8.54mL 2.84mmol) handles with 2% acetic acid aqueous solution (m/v) to stir 1 hour.This was reflected at stirring at room 1 hour, between water (50mL) and EtOAc (50mL), distributes then.(2 * 50mL) extractions are with the saturated NaHCO of organic extract liquid that merges with EtOAc with water layer
3(50mL) and salt solution (50mL) washing, dry (Na
2SO
4) and vacuum concentration, obtained 1-(4-aminomethyl phenyl)-2-nitroethyl alcohol, be colorless oil.
1H NMR(CDCl
3，500MHz)δ7.28(d，J＝8.1Hz，2H)，7.21(d，J＝8.1Hz，2H)，5.42(dt，J＝9.6，3.3Hz，1H)，4.60(dd，J＝13.3，9.7Hz，1H)，4.49(dd，J＝13.3，3.1Hz，1H)，2.79(d，J＝3.7，1H)，2.36(s，3H).
Embodiment 12
2-amino-1-(4-aminomethyl phenyl) ethanol
With 10%Pd/C (24mg) 1-(4-aminomethyl phenyl)-2-nitroethyl alcohol (50mg, 0.276mmol) suspension in the solution in anhydrous EtOH (1mL) in room temperature in 15psi H
2Following stirring is spent the night.This reaction mixture via diatomite filtration and with this filtrate vacuum concentration, is obtained 2-amino-1-(4-aminomethyl phenyl) ethanol, be oily matter.LCMS calculated value=152.10; Measured value=152 (M+1)
+
1H NMR(CDCl
3，500MHz)δ7.20(d，J＝8.0Hz，2H)，7.13(d，J＝8.0Hz，2H)，4.57(dd，J＝7.9，3.9Hz，1H)，2.86(dd，J＝12.7，3.9Hz，1H)，2.76(dd，J＝12.7，7.9Hz，1H)，2.33(s，3H).
Embodiment 13
5-(4-aminomethyl phenyl)-1,3- azoles alkane-2-ketone
0 ℃ under nitrogen, with diisopropylethylamine (181mg, 244 μ L, 1.40mmol) and triphosgene (138mg, (35.2mg is 0.233mmol) at anhydrous CH 0.466mmol) to be added to 2-amino-1-(4-aminomethyl phenyl) ethanol successively
2Cl
2(22mL) in Nei the solution that is stirring.This is reflected at 0 ℃ stirred 1 hour, vacuum concentration is to the volume of about 5mL then.This mixture water (50mL) is diluted, and (3 * 50mL) extract with EtOAc.With the organic extract liquid drying (Na that merges
2SO
4) and vacuum concentration, obtained crude product.It by purified by flash chromatography (Si, 12 * 160mm, the 0-80%EtOAc mixture gradient in hexane), has been obtained 5-(4-aminomethyl phenyl)-1,3- azoles alkane-2-ketone.R
f=0.41 (50%EtOAc/ hexane).LCMS calculated value=178.08; Measured value=178.1 (M+1)
+
1H NMR(CDCl
3，500MHz)δ7.25(d，J＝7.4Hz，2H)，7.19(d，J＝7.4Hz，2H)，6.69(brs，1H)，5.55(t，J＝7.8Hz，1H)，3.93(t，J＝8.6Hz，1H)，3.52(t，J＝8.1Hz，1H)，2.35 (s，3H).
Embodiment 14
3-{[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-5-(4-aminomethyl phenyl)-1,3- azoles alkane-2-ketone
Under nitrogen, (dispersion liquid of 6.4mg 60% in mineral oil 0.161mmol) is added to 5-(4-aminomethyl phenyl)-1, and (37.7mg is 0.0973mmol) in the solution that is stirring in anhydrous THF (1mL) for 3- azoles alkane-2-ketone with sodium hydride in room temperature.Should react and stir 30 minutes, by sleeve pipe add 2-(brooethyl)-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl (19.0mg, 0.107mmol) solution in anhydrous THF (2mL).This was reflected at stirring at room 3 days.Use saturated NH
4Cl (10mL) stopped reaction is with EtOAc (3 * 20mL) extractions.The organic extract liquid that merges is washed dry (Na with salt solution (10mL)
2SO
4) and vacuum concentration, obtained crude product.It is passed through purified by flash chromatography (Si, 12 * 160mm, the 0-80%EtOAc mixture gradient in hexane), obtained 3-{[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl-5-(4-aminomethyl phenyl)-1,3- azoles alkane-2-ketone is colorless oil.R
f=0.37 (20%EtOAc/ hexane).LCMS calculated value=484.21; Measured value=484.2 (M+1)
+ 1H NMR (benzene-d
6, 500MHz, 1: 1 mixture of atropisomer)
δ 7.76 (s, 0.5H), 7.65 (s, 0.5H), 7.31 (d, J=7.7Hz, 1H), 7.08 (dd, J=8.4,2.4Hz, 1H), 7.05 (br d, J=7.8Hz, 1H), 6.95-6.86 (m, 5H), 6.58 (t, J=7.7Hz, 1H), 4.74 (t, J=8.0Hz, 0.5H), 4.70 (t, J=8.0Hz, 0.5H), 4.50 (d, J=15.7Hz, 0.5H), 4.42 (d, J=15.7Hz, 0.5H), 4.25 (d, J=15.7Hz, 0.5H), 4.11 (d, J=15.7Hz, 0.5H), 3.26 (s, 1.5H), 3.21 (s, 1.5H), 2.81 (t, J=8.6Hz, 0.5H), 2.76 (septet, J=7.0Hz, 1H), 2.68 (t, J=8.6Hz, 0.5H), 2.55 (t, J=8.6Hz, 0.5H), 2.53 (t, J=8.6Hz, 0.5H), 2.04 (s, 3H), 1.20 (t, J=7.0Hz, 3H), 1.19 (t, J=7.0Hz, 3H).
Embodiment 15
1-[3,5-two (trifluoromethyl) phenyl]-2-nitro third-1-alcohol
At 0 ℃, with 3,5-two (trifluoromethyl) phenyl aldehyde (1.00g, 4.13mmol) and nitroethane (1.13g, 1.08mL, 15.1mmol) the 10%NaOH aqueous solution (the m/v) (1.73mL of the solution that is stirring in anhydrous EtOH (20mL), 4.34mmol) handle, stirred 1 hour, (13.0mL 4.32mmol) handles with 2% acetic acid aqueous solution (m/v).This was reflected at stirring at room 1 hour, between water (50 mL) and EtOAc (50mL), distributes then.(2 * 50mL) extractions are with the saturated NaHCO of organic extract liquid that merges with EtOAc with water layer
3(50mL) and salt solution (50mL) washing, dry (Na
2SO
4) and vacuum concentration, obtained Soviet Union-and red-1-[3,5-two (trifluoromethyl) phenyl]-1.5: 1 mixtures of 2-nitro third-1-alcohol, be colorless oil.
1H NMR (CDCl
3, 500MHz) Soviet Union-diastereomer:
δ 7.88 (br s, 1H), 7.86 (br s, 2H), 5.22 (d, J=8.4 Hz, 1H), 4.77 (dq, J=8.4,6.9Hz, 1H), 3.03 (br s 1H), 1.42 (d, J=6.9Hz, 3H), red-diastereomer:
δ7.90(br s，1H)，7.86(br s，2H)，5.59(d，J＝3.2Hz，1H)，4.72(dq，J＝3.2，6.9Hz，1H)，3.03(br s 1H)，1.50(d，J＝6.9Hz，3H).
Embodiment 16
2-amino-1-[3,5-two (trifluoromethyl) phenyl] third-1-alcohol
With Raney nickel (50mg) at Soviet Union-and red-1-[3,5-two (trifluoromethyl) phenyl]-(50mg is 0.158mmol) at 30% (v/v) HCO for 1.5: 1 mixtures of 2-nitro third-1-alcohol
2Suspension in the solution among the H aqueous solution (0.75mL) and the MeOH (10mL) in room temperature in 15psi H
2Following stirring is spent the night.With this reaction mixture via diatomite filtration, and with this filtrate vacuum concentration to remove MeOH.Use 28%NH
4The OH aqueous solution is adjusted to pH9-10 with this aqueous slurry, and water (20mL) dilutes, and (3 * 20mL) extract with EtOAc.The extraction liquid that merges is washed dry (Na with salt solution (10mL)
2SO
4) and vacuum concentration, obtained Soviet Union-and red-2-amino-1-[3,5-two (trifluoromethyl) phenyl] mixture of third-1-alcohol, be colorless solid.LCMS calculated value=288.08; Measured value=288.1 (M+1)
+ 1H NMR (CDCl
3, 500MHz) threo form-diastereomer:
δ 7.79 (br s, 3H), 4.35 (br s, 1H), 3.25 (br s, 1H), 2.59 (br s, 3H), 0.86 (d, J=6.1Hz, 3H), erythro-diastereomer:
δ7.79(br s，3H)，4.71(br s，1H)，3.00(br s，1H)，2.59(br s，3H)，1.06(d，J＝5.0Hz，3H).
Embodiment 17
5-[3,5-two (trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
0 ℃ under nitrogen, with diisopropylethylamine (106mg, 142 μ L, 0.817 mmol) and triphosgene (20.2mg 0.068mmol) is added to 2-amino-1-[3 successively, 5-two (trifluoromethyl) phenyl] (39.1mg is 0.136mmol) at anhydrous CH for third-1-alcohol
2Cl
2In the solution that is stirring in (10 mL).This is reflected at 0 ℃ stirred 1 hour, vacuum concentration is to the volume of about 5mL then.With this mixture water (50mL) dilution, with EtOAc (3 * 50mL) extractions.With the organic extract liquid drying (Na that merges
2SO
4) and vacuum concentration, obtained crude product.It is passed through purified by flash chromatography (Si, 12 * 160mm, the mixture gradient of 0-70%EtOAc in hexane), obtained Soviet Union-5-[3,5-two (trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone (17.5mg) and red-5-[3,5-two (trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone (14.4mg) is colorless solid, threo form-diastereomer: R
f=0.63 (50%EtOAc/ hexane).LCMS calculated value=314.06; Measured value=314.1 (M+1)
+
1H NMR (CDCl
3.600MHz) δ 7.90 (br s, 1H), 7 83 (br s, 2H), 6.71 (br s, 1H), 5.17 (d, J=7.0Hz, 1H), 3.86 (br pentet, J=6.2Hz, 1H), 1.48 (d, J=6.2Hz, 1H). use chirality HPLC (AS post, 20 * 250mm, the mixture of 20%i-PrOH in heptane) this compound separation is become its enantiomorph (4R, 5R)-and 5-[3,5-two (trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone and (4S, 5S)-5-[3,5-two (trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone, erythro-diastereomer: R
f=0.38 (50%EtOAc/ hexane).LCMS calculated value=314.06; Measured value=314.1 (M+1)
+
1H NMR(CDCl
3，600 MHz)δ7.90(br s，1H)，7.79(br s，2H)，5.83(d，J＝8.0Hz，1H)， 5.34(br s，1H)，4.31(br pentet，J＝7.0Hz，1H)，0.84(d，J＝6.6Hz，1H).
Use chirality HPLC (AS post, 20 * 250mm, the mixture of 15%i-PrOH in heptane) this compound separation is become its two kinds of enantiomorph (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone and (4R, 5S)-5-[3,5-two (trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone.
Chirality synthetic (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
This intermediate can directly be made by chiral raw material CBZ-1-L-Ala by following three-step approach.Compound (4R, 5S)-5-[3,5-two (trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone can be made by the CBZ-D-L-Ala by similar approach.
Step 1
Under nitrogen, with the CBZ-1-L-Ala (6.5kg, 28.5mol), the HOBT-hydrate (4.8kg, 34.8mol), Weinreb amine-HCl salt (3.4kg, 36.2mol) and THF (32L) be added in the clean flask.This mixture is cooled to 0-10 ℃, adds DFEA (12.4L) lentamente being lower than under 25 ℃ the temperature then.Under 15 ℃ of-25 ℃ of coolings, add lentamente afterwards EDC-HCl (7Kg, 36.2mol).With these slurries at 20 ℃～25 ℃ age overnights.Then this mixture is cooled to 0 ℃-10 ℃, adds 3 N HCl (12L) lentamente.Add IPAC (32L) then, and separate each layer.With organic layer once, use 8%NaHCO with HCl (13L) washing
3(13L) washed twice (noting: form foam).Then with organic layer at 50 ℃ of vacuum concentration to about 15L.This settled solution is cooled to room temperature lentamente, allows the product crystallization.Add lentamente then heptane (～70L).This dope filtration, with heptane (18L) washing, in the filter container in drying at room temperature.Obtained to have＞product of 99.9%ee, measured by chirality HPLC.
Step 2
(6kg, 22.5mol) and 3, (4.85L 28.1mol) is dissolved among the anhydrous THF (24L) 5-two (trifluoromethyl) bromobenzene with the Weinreb acid amides that derives from step 1.With this solution with nitrogen purging to remove oxygen.This be water-content should＜500ppm.If necessary, carrying out air distillation anhydrates to remove.This solution is cooled to-10 ℃, by addition funnel in this reaction lentamente (2 hours) add the solution (56.4mol) of different-PrMgCl in THF, keep temperature of reaction≤-5 ℃.Allow this solution be warmed to 20 ℃, at 20 ℃ of age overnights until acid amides＜0.5LCAP.This solution is cooled to-10 ℃ then under nitrogen, was added to lentamente among the 5N HCl (14L) that remains on 0-5 ℃ with 2 hours.Add MTBE (12L), this biphase mixture was stirred 5 minutes.After being warmed to 20 ℃-25 ℃, it was placed 30 minutes, separate each layer then.With organic layer water (12L) washed twice.Organic layer is transferred in the distilling flask by 1 micron online PTEE container, then vacuum concentration (interior temperature＜40 ℃) to～12L to keep stirred volume.This solution with stirring azeotropic drying, is concentrated into minimum stirred volume once more, and this solution is directly used in next step.
Solid product is added to heptane in the organic layer if desired, is concentrated into minimum stirred volume then.It is 40L until final volume that continuation is carried out vacuum distilling at 40 ℃-55 ℃.This solution is cooled to 35 ℃-37 ℃, adds crystal seed (0.5%, 30 gram), wear out 30 minutes then with full-grown seed bed.With 2-3 hour these slurries are cooled to 10 ℃.With this dope filtration,, use vacuum to purge to spend the night and be allowed to condition at complete drying in the filter container then with 5 ℃ of heptane (18L) washing.The exsiccant solid that obtains, it has＞99.9ee%.If the insufficient words of polarimetry purity can be with this acid amides recrystallization from pure heptane.
Step 3
Under inert atmosphere, TFA (9L) is added in the 100L Buchi reactor, and is cooled to-5 ℃.(5.50kg 13.1mol), adds TFA washings (2L) to the ketone product that derives from step 2 of adding solid form then.This solution is cooled to-5 ℃, and stirring is dissolved until all solids.(2.18kg 15.7mol), remains on temperature＜0 ℃ simultaneously to add silicomethane lentamente with 1 hour (in two batches).Allow this be reflected at-2 to-6 ℃ aging 15-20 hour, at this moment LC shows the ketone of residue＜2%.By 13.6kg KOH ball (87w%) is added in the 10L water lentamente, keep this high heat release dissolving to prepare 50w/w%KOH solution for＜30 ℃ simultaneously.This solution is preserved in refrigerator.
With～this reaction of termination under vigorous stirring and cooling of 2L 50w/w%KOH solution, temperature is maintained at about 20 ℃.Add THF (16.5L, above-mentioned preserve) in refrigerator, add residue KOH solution (about 13.7L) then lentamente, adding 2L water washing liquor keeps temperature＜20 ℃ simultaneously.After the adding of KOH is finished, this is reflected at aged at room temperature.After 3 hours, the 27.5L PAC and the 20L 20%w/v NaCl aqueous solution are handled this reaction.
Isolate water layer and organic layer.Organic layer is used the 26L 20%w/v NaCl aqueous solution, 36L water, 31L 0.5N HCl and 32L water washing successively.Organic layer is concentrated into about 10L.Add heptane (20L), formed crystal.Organic layer is concentrated into about 10L.Add heptane (20L) once more, and organic layer is concentrated into about 10L.Add heptane (22L), these slurries in aged at room temperature.Filter out solid, use the 24L heptane wash.Obtained solid product (98.8% purity,＞99.95%ee measure by LC).Solid is dissolved in (heat release) among the 12.5L MeOH again.Add 3L water in room temperature, with this mixture ageing with the beginning crystallization.In room temperature with adding entry (9.5L) in 60 minutes.Aging after 60 minutes, this dope filtration, with solid 5L MeOH/ water (1/1.5), 5L MeOH/ water (1/4) and 4L water washing.With solid product 50 ℃ of vacuum-dryings (99.9% purity is measured by LC,＞99.95%ee).
Also use Al (O-i-Pr)
3Reaction in carry out step 3 as reductive agent.For example, with ketone (6kg) and 0.3 equivalent Al (O-i-Pr)
3(790g) in 12L IPA and 18L toluene, heated 15.5 hours in 50 ℃.This solution is cooled to room temperature, under vigorous stirring, adds solid KOH ball (1.35kg), simultaneously temperature is remained on＜25 ℃.After about 2 hours, when HPLC show＞during 99.5% crystallization, add 33L 1N HCl solution with stopped reaction, hold it in＜25 ℃.If formed the debris layer solid, it should be filtered to improve enantiomeric excess.Then organic layer is at first washed with 36L 0.5N HCl.With the mixture washing of 6L IPA and 45L water, the mixture with 6L IPA and 36L water washs at last then.Organic layer is transferred in the online filter.About 40 ℃ solvent replacing be heptane (target volume is～42L) until the toluene of residue＜2v%.Aged at room temperature 2 hours, obtained solid product.
The HPLC method that is used for the used analysis of step 3:
Ace-C8 post 250 * 4.6mm A:MeCN; B:0.1%H
3PO
4H
2O solution;
Gradient: the 5A at 0 minute: 95B is at 9 minutes 95A: 5B; Keep 95A: 5B until 13 minutes; Return 5A: 95B keeps 13-15 minute condition: 35 ℃, and 1.5mL/ minute, 210nm
Embodiment 18
Erythro-5-[3,5-two (trifluoromethyl) phenyl]-3-{[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
In room temperature under nitrogen, with two (trimethyl silyl) Lithamide (solution of 172 μ L 1M in THF, 0.172mmol) be added to red-5-[3,5-two (trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, (50mg is 0.129mmol) in the solution that is stirring in anhydrous THF (1mL) for 3- azoles alkane-2-ketone.Should react and stir 15 minutes, by sleeve pipe add 2-(brooethyl)-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl (27.0mg, 0.0861mmol) solution in anhydrous THF (2mL).This was reflected at stirring at room 3 days.Use saturated NH
4Cl (10mL) stopped reaction is with EtOAc (3 * 20mL) extractions.The organic extract liquid that merges is washed dry (Na with salt solution (10mL)
2SO
4) and vacuum concentration, obtained crude product.It is passed through purified by flash chromatography (Si, 12 * 160mm, the mixture gradient of 0-40%EtOAc in hexane), obtained erythro-5-[3,5-two (trifluoromethyl) phenyl]-3-{[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone is colorless oil.R
f=0.64 (20%EtOAc/ hexane).LCMS calculated value=620.18; Measured value=620.2 (M+1)
+
1H NMR (benzene-d6,600MHz, 1: 1 mixture of atropisomer)
δ 7.94 (s, 0.5H), 7.72 (s, 0.5H), 7.64 (s, 0.5H), 7.63 (s, 0.5H), 7.39-7.34 (m, 3H), 7.12-7.04 (m, 2H), 6.95 (d, J=2.1Hz, 0.5H), 6.86 (d, J=1.7Hz, 0.5H), 6.64 (d, J=8.5Hz, 0.5H), 6.56 (d, J=8.5Hz, 0.5H), 4.99 (d, J=15.9Hz, 0.5H), 4.93 (d, J=15.9Hz, 0.5H), 4.73 (d, J=7.9Hz, 0.5H), 4.61 (d, J=7.9Hz, 0.5H), 3.88 (d, J=15.9Hz, 0.5H), 3.82 (d, J=15.9Hz, 0.5H), 3.35 (s, 1.5H), 3.24 (s, 1.5H), 3.05 (septet, J=6.9Hz, 0.5H), 3.01 (septets, J=6.9Hz, 0.5H), 2.75 (m, 1H), 1.19 (dd, J=6.9,2.7Hz, 3H), 1.17 (dd, J=10.9,6.9Hz, 3H) ,-0.18 (d, J=6.4Hz, 1.5H) ,-0.33 (t, J=6.4Hz, 1.5H).
Use chirality HPLC (AD post, 20 * 250mm, the mixture of 3%i-PrOH in heptane) this compound separation is become its two kinds of enantiomorph (4R, 5S)-5-[3,5-two (trifluoromethyl) phenyl]-3-{[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone and (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-{[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone.
Embodiment 19
4-[3,5-two (trifluoromethyl) phenyl]-1-{[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } imidazolidin-2-one
Steps A: 2-[3,5-two (trifluoromethyl) phenyl]-the 2-hydroxyethyl } [5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } t-butyl carbamate
To 1-[3,5-two (trifluoromethyl) phenyl]-2-([5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } amino) (embodiment 6 step B, 325.0mg is 0.561mmol) at CH for ethanol
2Cl
2(15mL) add BOC in Nei the solution
2O (122mg, 0.561mmol) and DIPEA (98 μ L, 0.561mmol).This is reflected at stirring at room.After 5 hours, add BOC again
2O (50mg, 0.229mmol) and DIPEA (50 μ L, 0.287mmol).This was reflected at stirring at room 48 hours.Then with this solution concentration to～2mL, dilute with hexane (8mL), pass through purified by flash chromatography, with 10-20%EtOAc/ hexane wash-out, obtained 2-[3,5-two (trifluoromethyl) phenyl]-the 2-hydroxyethyl } [5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } t-butyl carbamate.R
f=0.38 (25%EtOAc/ hexane).
LCMS＝580.3(M+1-BOC)
+.
1H NMR(CD
2Cl
2，500MHz)δ7.78(s，1H)，7.54-7.67(m，4H)，7.23-7.33(m，2H)，6.90-6.95(m，2H)，3.15-4.82(m，9H)，2.87(m，1H)，1.19-1.43(m，15H).
Step B: methylsulfonic acid 1-[3,5-two (trifluoromethyl) phenyl]-2-((tert-butoxycarbonyl) { [5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } amino) ethyl ester
To 2-[3,5-two (trifluoromethyl) phenyl]-the 2-hydroxyethyl } [5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } (350.1mg is 0.516mmol) at CH for t-butyl carbamate
2Cl
2(15mL) add in Nei the solution DIPEA (450 μ L, 2.58mmol).This solution is cooled to 0 ℃, and adding MsCl (100 μ L, 1.29mmol).After 45 minutes, should react dilution 0 ℃ of stirring, use saturated NaHCO with EtOAc (100mL)
3(25mL), salt solution (25mL), 1N HCl (25mL) and salt solution (2 * 25mL) washings.With the organic layer dried over sodium sulfate, filter, and concentrate.Allow resistates pass through short silica gel plug, with 25%EtOAc/ hexane wash and concentrated.Product methylsulfonic acid 1-[3,5-two (trifluoromethyl) phenyl]-2-((tert-butoxycarbonyl) { [5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } amino) the further characterized and be used for next reaction immediately of ethyl ester.R
f=0.33 (25%EtOAc/ hexane).
Step C:{2-azido--2-[3,5-two (trifluoromethyl) phenyl] ethyl } [5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } t-butyl carbamate
To derive from the methylsulfonic acid 1-[3 of last reaction, 5-two (trifluoromethyl) phenyl]-2-((tert-butoxycarbonyl) [5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl amino) ethyl ester be dissolved in DMPU (15mL) and in, use NaN
3(140mg 2.15mmol) handles.This is reflected at stirring at room 15 hours, uses EtOAc (75ml) dilution then. with this solution H
2O (5 * 40mL) and salt solution (40mL) washing.With the organic layer dried over sodium sulfate, filter, and concentrate.With 20%EtOAc/ hexane purifying resistates, obtained 2-azido--2-[3,5-two (trifluoromethyl) phenyl] ethyl [5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } t-butyl carbamate.R
f=0.52 (15%EtOAc/ hexane).
LCMS＝605.3(M+1-BOC)
+.
1H NMR(C
6D
6，500MHz，70℃)δ7.80(s，1H)，7.67(s，1H)，7.48(s，2H)，7.36(d，J＝7.8Hz，1H)，7.01-7.11(m，2H)，6.89(m，1H)，6.64(d，J＝8.6Hz，1H)，4.22-4 69(m，3H)，3.2g(s，3H)，2.61-3.16(m，3H)，1.34(s，9H)，1.13-1.18(m，6H).
Step D:{2-amino-2-[3,5-two (trifluoromethyl) phenyl] ethyl } [5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } t-butyl carbamate and [1-[3,5-two (trifluoromethyl) phenyl]-2-([5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } amino) ethyl] mixture of t-butyl carbamate
To { 2-azido--2-[3,5-two (trifluoromethyl) phenyl] ethyl } [5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } (300mg 0.426mmol) adds 10%Pd/C (100mg) in the solution in EtOAc (15mL) to t-butyl carbamate.This reaction is placed H
2Down and stirring at room 5 hours.At this moment react completely, two kinds of mixture of products have been obtained, { 2-amino-2-[3,5-two (trifluoromethyl) phenyl] ethyl } [5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } t-butyl carbamate and [1-[3,5-two (trifluoromethyl) phenyl]-2-([5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } amino) ethyl] t-butyl carbamate.Filter out catalyzer and this filtrate is concentrated, obtained product mixtures.LCMS＝679.3(M+1)
+。Product need not be further purified or characterized and be used for next reaction.
Step e: 1-[3,5-two (trifluoromethyl) phenyl]-N
2-[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } ethane-1, the 2-diamines
To 283.5mg (0.418mmol) { 2-amino-2-[3,5-two (trifluoromethyl) phenyl] ethyl } [5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } t-butyl carbamate and [1-[3,5-two (trifluoromethyl) phenyl]-2-([5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } amino) ethyl] mixture of t-butyl carbamate is at CH
2Cl
2(15mL) add TFA (1.5mL) in Nei the solution.This was reflected at stirring at room 5 hours, pours into then in the 1N NaOH (50mL).With this mixture CH
2Cl
2(3 * 50mL) extractions merge organic extract liquid, use dried over sodium sulfate, filter, and concentrate.By the purified by flash chromatography resistates, use 5-10%MeOH/CH
2Cl
2Wash-out has obtained 1-[3,5-two (trifluoromethyl) phenyl]-N
2-[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } ethane-1, the 2-diamines.R
f＝0.46(10％MeOH/CH
2Cl
2)。
LCMS＝579.2(M+1)
+.
1H NMR(CD
2Cl
2，500MHz)δ7.83(s，2H)，7.77(s，2H)，7.55(d，J＝7.8Hz，1H)，7.31(d，J＝8.1Hz，1H)，7.24(dd，J＝8.4，2.3Hz，1H)，6.99(d，J＝2.0Hz，1H)，6.92(d，J＝8.5Hz，1H)，4.06(m，1H)，3.59-3.76(m，2H)，3.69(s，3H)，2.88(m，1H)，2.67(dd，J＝11.9，4.3Hz，1H)，2.51(m，1H)，1.22(d，J＝6.9Hz，6H).
Step F: 4-[3,5-two (trifluoromethyl) phenyl]-1-{[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } imidazolidin-2-one
With 1-[3,5-two (trifluoromethyl) phenyl]-N
2-[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } ethane-1, (125.2mg is 0.217mmol) at CH for the 2-diamines
2Cl
2Solution (30mL) is cooled to 0 ℃, and adding DIPEA (227 μ L, 1.30mmol).Add then triphosgene (32.2mg, 0.109mmol).This is reflected at 0 ℃ stirred 45 minutes, pour saturated NaHCO then into
3(20mL).This mixture with EtOAc (100mL) extraction, with salt solution (25mL) washing, is used dried over sodium sulfate with organic layer, filter and concentrate.Resistates by purified by flash chromatography, with 40%EtOAc/ hexane wash-out, has been obtained 4-[3,5-two (trifluoromethyl) phenyl]-1-{[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } imidazolidin-2-one.R
f=0.22 (40%EtOAc/ hexane).LCMS＝605.2(M+1)
+。
1H NMR (CDCl
3, 500MHz) (atropisomer exists with 1: 1 ratio; Observe some peak overlapping)
δ 7.83 (s, 1H), 7.78 (s, 2H), 7.55-7.62 (m, 2H), 7.32 (d, J=7.8Hz, 1H), 7.22 (m, 1H), 6.94 (s, 1H), 6.88 (d, J=8.3 Hz, 1H), 5.33﹠amp; 5.24 (2 is unimodal, 1H), 4.80-4.88 (m, 1H), 4.00-4.61 (m, 2H), 3.72﹠amp; 3.70 (2 is unimodal, 3H), 3.55-3.59 (m, 1H), 2.83-2.93 (m, 2H), 1.17-1.23 (m, 6H).
Can use the AD chiral column, use 5%IPA/ heptane wash-out, isolate two kinds of enantiomorphs of this compound.
Embodiment 20
(4R)-1-{[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-4-phenylimidazolidines,-2-ketone
Steps A: [(1 R)-2-hydroxyl-1-phenylethyl] t-butyl carbamate
(400mg is 2.91mmol) at CH to (2R)-2-amino-2-phenylethyl alcohol
2Cl
2(15mL) add BOC in Nei the solution
2O (636mg, 2.91mmol) and DIPEA (507 μ L, 2.91mmol).This was reflected at stirring at room 18 hours,, uses H with EtOAc (75mL) dilution
2O, salt solution, 1N HCl, salt solution, saturated NaHCO
3And salt solution (being respectively 25mL) washing.With the organic layer dried over sodium sulfate, filter, and concentrate.By the purified by flash chromatography resistates, use 50%EtOAc/ hexane wash-out, obtained [(1R)-and 2-hydroxyl-1-phenylethyl] t-butyl carbamate.R
f=0.23 (40%EtOAc/ hexane).
1HNMR(CDCl
3，600MHz)δ7.27-7.37(m，5H)，5.27(bs，1H)，4.78(bs，1H)，3.83(bs，2H)，2.46(bs，1H)，1.44(bs，9H).
Step B:[(1 R)-and 2-oxo-1-phenylethyl] t-butyl carbamate
At 0 ℃, to [(1R)-and 2-hydroxyl-1-phenylethyl] (200mg is 0.844mmol) at CH for t-butyl carbamate
2Cl
2(20mL) add in Nei the solution Dess-Martin periodinane (447mg, 1.05mmol).This is reflected at 0 ℃ stirred 15 minutes, then stirring at room 30 minutes.Then this solution is diluted with EtOAc (75mL), use 10%K
2CO
3(2 * 30mL) washings rapidly.With the organic layer dried over sodium sulfate, filter, and concentrate.Purifying resistates on short silicagel column, with 50%EtOAc/ hexane wash-out, obtained [(1R)-and 2-oxo-1-phenylethyl] t-butyl carbamate.
1H NMR (CDCl
3, 600MHz) (observe main and less important conformer) and provide the data of main conformer)
δ9.53(s，1H)，7.29-7.40(m，5H)，5.80(bs，1H)，5.31(m，1H)，1.42(s，9H).
This product is used for following reaction immediately.
Step C:[(1 R)-2-([5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } amino)-the 1-phenylethyl] t-butyl carbamate
To [(1R)-and 2-oxo-1-phenylethyl] t-butyl carbamate (113.8 mg, 0.484mmol) add in the solution in MeOH (7mL) 1-[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methylamine (98mg, 0.303mmol), add NaCNBH then
3(30mg, 0.477mmol) and HOAc (2).This is reflected at stirred overnight at room temperature, with EtOAc dilution (75mL), with 1N NaOH (25mL) and salt solution (25mL) washing.With the organic layer dried over sodium sulfate, filter, and concentrate.By the purified by flash chromatography resistates, use 5-25%EtOAc/ hexane wash-out, obtained [(1R)-2-([5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } amino)-the 1-phenylethyl] t-butyl carbamate.R
f=0.30 (25%EtOAc/ hexane).LCMS＝543.4(M+1)
+。
Step D:(1R)-N
2-[5-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-1-diphenylphosphino ethane-1, the 2-diamines
To contain small amount of impurities [(1R)-2-([5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl amino)-the 1-phenylethyl] (150mg is 0.277mmol) at CH for t-butyl carbamate
2Cl
2(10mL) add TFA (1mL) in Nei the solution.This is reflected at stirring at room 2 hours, pours 1N NaOH (25mL) then into.With this mixture CH
2Cl
2(3 * 25mL) extractions.With the organic extract liquid dried over sodium sulfate that merges, filter, and concentrate.By purified by flash chromatography gained resistates, use 0-10%MeOH/CH
2Cl
2Wash-out has obtained (1R)-N
2-[5-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-1-diphenylphosphino ethane-1, the 2-diamines.R
f＝0.27(10％MeOH/CH
2Cl
2)。LCMS＝443.4(M+1)
+。
Step e: (4R)-1-{[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-4-phenylimidazolidines,-2-ketone
With (1R)-N
2-[5-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-1-diphenylphosphino ethane-1, (96.0mg is 0.22mmol) at CH for the 2-diamines
2Cl
2Solution (15mL) is cooled to 0 ℃, add DIPEA (230 μ L, 1.32mmol), add then triphosgene (32.6mg, 0.11mmol).After 45 minutes, pour this reaction into saturated NaHCO
3(25mL).This mixture is extracted with EtOAc (75mL).With organic layer salt water washing, use dried over sodium sulfate, filter, and concentrate.By the purified by flash chromatography resistates, use 10-60%EtOAc/ hexane wash-out, obtained (4R)-1-{[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl-4-phenylimidazolidines,-2-ketone.By chirality HPLC, use AD chiral column and 15%IP A/ heptane to remove less important enantiomorph, obtained the product of enantiomer-pure.R
f=0.16 (40%EtOAc/ hexane).LCMS＝469.3(M+1)
+。1H NMR (CDCl
3, 500MHz) (atropisomer exists with 1: 1 ratio, observes some peak overlapping)
δ 7.65 (m, 1H), 7.54 (d, J=7.7Hz, 1H), 7.21-7.36 (m, 7H), 6.87-6.94 (m, 2H), 4.65-4.77 (m, 2H), 4.10-4.49 (m, 2H), 3.71 ﹠amp; 3.72 (2 is unimodal, 3H), 3.49-3.53 (m, 1H), 2.94-2.97 (m, 1H), 2.87 (m, 1H), 1.19-1.24 (m, 6H),
Embodiment 21
4-(4-chloro-phenyl-)-1-{[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } imidazolidin-2-one
Steps A: 1-(4-chloro-phenyl-)-2-([5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } amino) ethanol
With 1-[5 '-sec.-propyl-2 '-methoxyl group-5-(trifluoromethyl) biphenyl-2-yl] methylamine (300mg, 1.1mmol) and 2-(4-chloro-phenyl-) oxyethane (143 μ L, 1.2mmol) vlil in Virahol (10.5mL) is 24 hours.Should react and concentrated, and by purified by flash chromatography, with 5%-80%EtOAc/ hexane wash-out, obtained 1-(4-chloro-phenyl-)-2-([5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl amino) ethanol.R
f=0.37 (50%EtOAc/ hexane).
LCMS＝478.1(M+1)
+.1H NMR(CDCl
3，500MHz)δ7.70(s，1H)，7.55(d，J＝7.5Hz，1H)，7.33-7.19(m，6H)，6.97(s，1H)，6.90(d，J＝8.5Hz，1H)，4.52(m，1H)，3.77-3.62(m，5H)，2.89(m，1H)，2.71(m，1H)，2.51(m，1H)，1.24(d，J＝7.0Hz，6H).
Step B:[2-(4-chloro-phenyl-)-2-hydroxyethyl] [5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } benzyl carbamate
To 1-(4-chloro-phenyl-)-2-([5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl amino) (40mg is 0.08mmol) at CH for ethanol
2Cl
2(2mL) add in Nei the solution two dimethyl benzyls (24mg, 0.08mmol).This is reflected at stirring at room 24 hours, pours H then into
2In the O (15mL).The gained mixture with EtOAc (50mL) extraction, with salt solution (15mL) washing, is used dried over sodium sulfate with organic layer, filter, and concentrate.By the purified by flash chromatography resistates, use 5%-60%EtOAc/ hexane wash-out, obtained [2-(4-chloro-phenyl-)-2-hydroxyethyl] [5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl benzyl carbamate.R
f=0.20 (25%EtOAc/ hexane).LCMS＝612.2(M+1)
+。
1H NMR (C
6D
6, 600MHz, the peak broadens and/or is overlapping; There are rotational isomer and/or atropisomer)
δ7.98-6.45(m，15H)，5.00-3.46(m，6H)，3.20-2.96(m，5H)，2.72(m，1H)，1.20-1.15(m，6H).
Step C:[2-azido--2-(4-chloro-phenyl-) ethyl] [5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } benzyl carbamate
With [2-(4-chloro-phenyl-)-2-hydroxyethyl] [5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl (44mg is 0.07mmol) at CH for benzyl carbamate
2Cl
2Solution (6mL) is cooled to 0 ℃, adds N, the N-diisopropylethylamine (63 μ L, 0.36mmol), add then methylsulfonyl chloride (14 μ L, 0.18mmol).This is reflected at 0 ℃ stirred 30 minutes, pour into then in the saturated sodium bicarbonate (15mL).The gained mixture is extracted with EtOAc (50mL), and organic layer is washed with salt solution (15mL), use dried over sodium sulfate, filter via short silicagel column, and concentrated.Resistates is dissolved in the DMPU (6mL) again, and the adding sodiumazide (12mg, 0.18mmol).This is reflected at stirring at room 24 hours, pours H then into
2In the O (15mL).The gained mixture is extracted with EtOAc (50mL), with organic layer H
2O (2 * 15mL) and salt solution (15mL) washing, use dried over sodium sulfate, filter, and concentrated.By the purified by flash chromatography resistates, use 25%EtOAc/ hexane wash-out, obtained [2-azido--2-(4-chloro-phenyl-) ethyl] [5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl benzyl carbamate.R
f=0.66 (25%EtOAc/ hexane).LCMS＝637.3(M+1)
+。
1HNMR (C
6D
6, 600MHz, peak overlapping; There are rotational isomer and/or atropisomer)
δ8.03-6.52(m，15H)，5.00-5.08(m，2H)，4.76-4.12(m，3H)，3.28-2.86(m，5H)，2.77(m，1H)，1.23-1.18(m，6H).
Step D:[2-amino-2-(4-aminophenyl) ethyl] [5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } benzyl carbamate
To [2-azido--2-(4-chloro-phenyl-) ethyl] [5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl (30 mg 0.05mmol) add PtO in the solution in THF (1mL) to benzyl carbamate
2(8mg), this being reflected at room temperature stirred 1 hour down in hydrogen.Remove catalyzer by filtering via plug of celite, wash with 100%EtOAc, and this filtrate concentrated, obtained [2-amino-2-(4-chloro-phenyl-) ethyl] [5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl the benzyl carbamate crude product.R
f=0.66 (25%EtOAc/ hexane).LCMS＝611.3(M+1)
+。
Step e: 4-(4-fluorophenyl)-1-{[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } imidazolidin-2-one
To [2-amino-2-(4-chloro-phenyl-) ethyl] [5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl benzyl carbamate (30mg, 0.05mmol) add two (trimethyl silyl) Lithamide (solution of 295 μ L 0.5M in toluene in the solution in THF (2mL), 0.147mmol), this is reflected at stirring at room 30 minutes, uses saturated NH then
4Cl (15mL) stopped reaction.The gained mixture is extracted with EtOAc (25mL), with organic layer H
2Dried over sodium sulfate is used in O (15mL) and salt solution (15mL) washing, filters, and concentrates.By the purified by flash chromatography resistates, use 5%-60%EtOAc/ hexane wash-out, obtained 4-(4-chloro-phenyl-)-1-{[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl imidazolidin-2-one.R
f＝0.46(5％MeOH/CH
2Cl
2)。LCMS＝503.1(M+1)
+。
1H NMR (C
6D6,600MHz observes atropisomer; Peak overlapping)
δ7.90-7.03 (m，6H)，6.89-6.20(m，4H)，4.69-3.88(m，3H)，3.16(s，3H)，2.88-2.30 (m，3H)，1.18-1.13(m，6H).
Embodiment 22
(4R)-1-{[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-3-methyl-4-phenylimidazolidines,-2-ketone
To (4R)-1-{[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl-4-phenylimidazolidines,-2-ketone (12.6mg, 0.0269mmol) add MeI (10 μ L in the solution in THF (1.5mL), 0.162mmol), add then KHMDS (solution of 162 μ L 0.5M in toluene, 0.081mmol).This was reflected at stirring at room 10 minutes, pours into then in the water (10mL).This mixture with EtOAc (30mL) extraction, with salt solution (10mL) washing, is used dried over sodium sulfate with organic layer, filter, and concentrate.By the purified by flash chromatography resistates, use 50%EtOAc/ hexane wash-out, obtained (4R)-1-{[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl-3-methyl-4-phenylimidazolidines,-2-ketone.R
f=0.26 (40%EtOAc/ hexane).LCMS＝483.2(M+1)
+。
1H NMR (CDCl
3, 500MHz observes atropisomer; Peak overlapping)
δ 7.68-7.53 (m, 2H), 7.21-7.36 (m, 7H), 6.87-6.94 (m, 2H), 4.08-4.56 (m, 3H), 3.72﹠amp; 3.71 (2 is unimodal, 3H), 3.34-3.38 (m, 1H), 2.77-2.89 (m, 2H), 2.67﹠amp; 2.63 (2 is unimodal, 3H), 1.18-1.26 (m, 6H).
Made the compound of in table 1, listing according to the method for describing among the embodiment 1-22:
Table 1
Embodiment 50
4-[3,5-two (trifluoromethyl) phenyl]-2-{[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-1,2,5-thiadiazolidine 1,1-dioxide
With 1-[3,5-two (trifluoromethyl) phenyl]-N
2-[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl ethane-1, the 2-diamines (8.0mg, 0.014mmol) and sulphonamide (2.0mg, 0.021mmol) solution in pyridine (300 μ L) is heated to 120 ℃ in sealed tube.After 3 hours, this reaction is cooled to room temperature, with 25mL EtOAc dilution.With this organic solution with 1N HCl (2 * 5mL) and salt solution (dried over sodium sulfate use in 1 * 5mL) washing, filtration, and concentrated.By PTLC purifying resistates, use 25%EtOAc/ hexane wash-out, obtained 4-[3,5-two (trifluoromethyl) phenyl]-2-{[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-1,2,5-thiadiazolidine 1,1-dioxide.R
f=0.29 (25%EtOAc/ hexane).LCMS＝641.1(M+1)
+。
1H NMR (CDCl
3, 500MHz; There is atropisomer)
δ7.58-7.85(m，5H)，7.35-6.86(m，4H)，4.82-4.94(m，2H)，3.54-4.42(m，6H)，2.71-2.91(m，2H)，1.11-1.26(m，6H).
Embodiment 51
5-[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl]-1,3- azoles alkane-2-ketone
Steps A: [5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl alcohol
To 1.08 g 5 '-sec.-propyls-2 '-add 0.97g KOH in methoxyl group-4-(trifluoromethyl) biphenyl-solution of 2-formonitrile HCN (embodiment 3) in 25mL n-PrOH.This mixture heating up to refluxing, and was stirred 36 hours under this temperature, cool off then and be concentrated into clarification oily matter.With this oily matter at 15mL water and 10mL Et
2Distribute between the O.With water 10mL Et
2The O extraction.The organic layer that merges is washed with salt solution (15mL), use dried over sodium sulfate, and concentrate.Resistates is passed through purified by flash chromatography on Biotage Horizon 4OS post, use the mixture wash-out of 1CV95% hexane-5%5% formic acid in acetone, use the mixture of 5-100% acetone in hexane to carry out linear gradient elution then with 10CV.The gained white solid is dissolved among 9: 1 benzene-MeOH of 10mL, adds excessive TMSCH
2N
2With this mixture stirring at room 10 minutes, then with the trifluoroacetic acid stopped reaction and concentrate.Be dissolved in resistates in the 15mL ether and be cooled to 0 ℃.Drip 1-M LiAlH via addition funnel
4Solution in ether (5.4mL).In case add fully, remove cooling bath, this mixture stirring at room 2 hours, and then is cooled to 0 ℃, come stopped reaction by dripping 0.2mL water, the 0.2mL 15%NaOH aqueous solution and 0.5mL water.In case add fully, remove cooling bath, and with this mixture stirring at room 30 minutes, filter and (use Et
2O washs solid) and concentrate.At Biotage Horizon, carry out purified by flash chromatography on the 4OS post, use the mixture wash-out of 1CV 4%EtOAc in hexane, use the mixture of 4-100%EtOAc in hexane to carry out linear gradient elution then, obtained this title compound with 10CV.Mass spectrum (ESI) 307.2 (M-17).
1HNMR (500MHz, CDCl
3): δ 7.85 (s, 1H), 7.60 (d, J=8Hz, 1H), 7.33 (d, J=8Hz, 1H), 7.25 (dd, J=2Hz, 9Hz, 1H), 6.99 (d, J=2.5Hz, 1H), 6.93 (d, J=8.5Hz, 1H), 4.49 (m, 2H), 3.74 (s, 3H), 2.90 (septet, J=7Hz, 1H), 1.25 (d, J=7Hz, 6H).
Step B:5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-formaldehyde
To 0.725g [5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl alcohol is at 10mL CH
2Cl
2Add 1.14g Dess-Martin periodinane in the interior solution.This mixture stirring at room 30 minutes, is filtered then and concentrates.With resistates at BiotageHorizon, pass through purified by flash chromatography on the 4OS post, with the mixture wash-out of 1CV 1%EtOAc in hexane, use the mixture of 1-100%EtOAc in hexane to carry out linear gradient elution then with 10CV, obtained this title compound.Mass spectrum (ESI) 323.2 (M+1).
1H NMR (500MHz, CDCl
3): δ 9.81 (s, 1H), 8.28 (s, 1H), 7.88 (dd, J=1.5Hz, 8Hz, 1H), 7.54 (d, J=8Hz, 1H), 7.33 (dd, J=2Hz, 8Hz, 1H), 7.16 (d, J=2.5Hz, 1H), 6.95 (d, J=8.5Hz, 1H), 3.74 (s, 3H), 2.95 (septet, J=7Hz, 1H), 1.29 (d, J=7Hz, 6H).
Step C:2-amino-1-[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] ethanol
To 0.679g 5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-formaldehyde is at 1.5mLCH
2Cl
2Add about 5mg ZnI in the interior solution
2, add the 0.23g trimethylsilyl cyanide then.With this mixture stirring at room 3 hours, then at 15mL water and 10mLEt
2Distribute between the O.With water with 2 * 10mL Et
2The O extraction.The organic phase that merges is also concentrated with dried over sodium sulfate.Resistates is dissolved in the 15mL ether, is cooled to 0 ℃.Drip 1-M L1AIH via addition funnel
4Solution in ether (4.2mL).In case add fully, remove cooling bath, this mixture in stirred overnight at room temperature, is being cooled to 0 ℃ then, drip 0.15mL water, the 0.15mL 15%NaOH aqueous solution and 0.4mL water and come stopped reaction.In case add fully, remove cooling bath, this mixture stirring at room 30 minutes, is filtered and (uses Et
2O washs solid) and concentrate, having obtained this title compound, it need not be further purified direct use.Mass spectrum (ESI) 354.2 (M+1).Some
1H NMR signal is because atropisomerism and overlapping.
1H NMR (500MHz, CDCl
3): δ 7.88 (s, 1H), 7.55 (app t, J=7.5Hz, 1H), 7.22-7.28 (m, 2H), 6.99,6.95 (d, J=2.5Hz, 1H), 6.92,6.90 (sm 1H), 4.52 (m, 1H), 3.70 (s, 3H), 2.90 (septets, J=7Hz, 1H), 2.81 (m, 1H), 2.60-2.70 (m, 2H), 1.23-1.28 (m, 6H).
Step D:5-[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl]-1,3- azoles alkane-2-ketone
To 0.44g 2-amino-1-[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] ethanol is at 15mL CH
2Cl
2Add the 0.241g diisopropylethylamine in 0 ℃ of interior solution, add the 0.185g triphosgene then.This mixture was stirred 30 minutes at 0 ℃, use the saturated NaHCO of 30mLEtOAc and 20mL then
3Dilution.Separate each phase, with organic phase 20mL salt water washing, dry (Na
2SO
4) and concentrate.With resistates at Biotage Horizon, pass through purified by flash chromatography on the 4OS post, with the mixture wash-out of 1CV 5%EtOAc in hexane, use the mixture of 5-100%EtOAc in hexane to carry out linear gradient elution then with 10CV, obtained this title compound.Mass spectrum (ESI) 380.2 (M+1).
1H NMR signal is because atropisomerism and overlapping
1H NMR (500MHz, CDCl
3): δ 7.90,7.86 (s, 1H), 7.66 (d, J=8 Hz, 1H), 7.35 (d, J=8Hz, 1H), 7.27 (dd, J=2.5Hz, 8.5Hz 1H), 7.03 (d, J=2.5Hz, 0.5H), 6.87-6.93 (m, 1.5H), 5.65,5.50 (t, J=8Hz, 1H), 5.23,5.09 (s, 1H), 3.75 (s, 1.5H), 3.69 (s, 1.5H), 3.68,3.51 (t, J=9Hz, 1H), 3.31,3.19 (t, J=8.5Hz, 0.5H), 2.90 (septet, J=7 Hz, 1H), 1.25,1.24 (d, J=7Hz, 6H).
Be further purified by HPLC in that Chiralpak AD 2 * 25cm is last, use the mixture of 10% Virahol in heptane, obtained two kinds of enantiomorphs: enantiomorph A, t with 9mL/ minute wash-out
R=15.1 minutes; Enantiomorph B, t
R=17.4 minutes.
Embodiment 52
3-benzyl-5-[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl]-1,3- azoles alkane-2-ketone
To 44mg 5-[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl]-1, add the 10mg sodium hydride in 0 ℃ of solution of 3- azoles alkane-2-ketone in 1mL DMF.This mixture stirring at room 10 minutes, is added the 24mg bromotoluene then.This mixture in stirred overnight at room temperature, is diluted with 15mL EtOAc and 5mL water then.Separate each phase, organic phase with each 5mL water and salt water washing, is also concentrated with dried over sodium sulfate.At BiotageHorizon, by purified by flash chromatography,, use the mixture of 0-50%EtOAc in hexane to carry out linear gradient elution then on the 25S post resistates, obtained this title compound with 10CV with 1CV hexane wash-out.Mass spectrum (ESI) 470.1 (M+1).
1H NMR (500MHz, CDCl
3): δ 7.86,7.76 (s, 1H), 7.62 (d, J=8Hz, 1H), 7.14-7.40 (m, 7H), 7.01,6.77 (d, J=2.5Hz, 1H), 6.87,6.83 (d, J=8.5 Hz, 1H), 5.45,5.53 (m, 1H), 4.30-4.53 (m, 2H), 3.73,3.55 (s, 3H), 3.48,3.30 (m, 1H), 3.10,2.96 (t, J～8.5 Hz, 1H), 2.89,2.82 (septet, J=7Hz, 1H), 1.24,1.16 (m, 6H).
Embodiment 53
3-[3,5-two (trifluoromethyl) benzyl]-5-[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl]-1,3- azoles alkane-2-ketone (racemize)
According to the method for describing among the embodiment 50, use 43mg 5-[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl]-1,3- azoles alkane-2-ketone and 43mg 3,5-two (trifluoromethyl) bromotoluene has obtained this title compound.Mass spectrum (ESI) 606.1 (M+1).
1H NMR signal is because atropisomerism and overlapping.
1H NMR (500MHz, CDCl
3): δ 7.58-7.88 (m, 5H), 7.34 (d, J=8Hz, 1H), 7.23 (m, 1H), 7.02,6.79 (d, J=2Hz, 1H), 6.88,6.85 (d, J=8.5Hz, 1H), 5.45,5.42 (m, 1H), 4.52-4.64 (m, 1.5H), 4.36 (d, J=15.5Hz, 0.5H), 3.74,3.57 (s, 3H), 3.49,3.34 (m, 1H), 3.09,2.99 (t, J～8.5Hz, 1H), 2.89,2.81 (septet, J=7Hz, 1H), 1.24,1.12 (m, 6H).
Embodiment 54
3-[3,5-two (trifluoromethyl) benzyl]-5-[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl]-1,3- azoles alkane-2-ketone (enantiomorph A)
According to the method for describing among the embodiment 50, use 43mg 5-[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl]-1,3- azoles alkane-2-ketone, enantiomorph A and 43mg 3,5-two (trifluoromethyl) bromotoluene has obtained this title compound.On Chiralpak AS 4.6 * 250mm, analyze HPLC, with the mixture of 5% Virahol in heptane with 0.5mL/ minute wash-out: t
R=9.9 minutes
Embodiment 55
3-[3,5-two (trifluoromethyl) benzyl]-5-[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl]-1,3- azoles alkane-2-ketone (enantiomorph B)
According to the method for describing among the embodiment 50, use 44mg 5-[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl]-1,3- azoles alkane-2-ketone, enantiomorph B and 43mg 3,5-two (trifluoromethyl) bromotoluene has obtained this title compound.On Chiralpak AS 4.6 * 250mm, analyze HPLC, with the mixture of 5% Virahol in heptane with 0.5mL/ minute wash-out: t
R=11.0 minutes
Embodiment 56
1-(4-fluorophenyl)-1-pyruvic alcohol
Under nitrogen atmosphere, with LaCl
3(26mg, 0.104mmol) suspension in anhydrous THF (7.8mL) is cooled to-78 ℃ and stirred 1 minute.(solution of 1.6M in hexane, 195 μ L 0.312mmol) add and continuation was stirred 15 minutes to add n-BuLi solution.This reaction is warmed to 0 ℃ and stirred 30 minutes.(31mg, 42 μ L 0.312mmol), are reflected at 0 ℃ with this and stirred 30 minutes, and with being warmed to room temperature in 30 minutes to add trimethylsilyl cyanide.Add ethanoyl trimethyl silyl (Cunico by sleeve pipe; R.F.; Kuan, C.-P., J.Org.Chem.; 1985; 50,5410-5413) (121mg is 1.04mmol) with 4-fluorobenzaldehyde (1 42 mg; 1.14 mmol) in the solution in anhydrous THF (19mL), and this was reflected at stirring at room 2 hours.Add 1N HCl (24mL) then, should react and stir 1 hour.Add Et
2O (25mL) isolates (2 * 25mL) washings of organic layer and water.With water layer ether (3 * 50mL) extractions that merge.With the organic extract liquid drying (MgSO that merges
4) and vacuum concentration, obtained crude product.It by purified by flash chromatography (Si, 25 * 160mm, the 0-50%EtOAc mixture gradient in hexane), is obtained 1-(4-fluorophenyl)-1-pyruvic alcohol, be colorless solid.R
f=0.31 (20%EtOAc/ hexane).
1H NMR(CDCl
3，500MHz)δ7.29(m，2H)，7.08-7.04(m，2H)，5.06(d，J＝3.6 Hz，1H)，4.35(d，J＝6.5 Hz，1H)，2.05(s，3H).
Embodiment 57
Erythro-and threo form-1-(4-fluorophenyl)-2-([5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } amino) third-1-alcohol
In room temperature, with NaCNBH
3(19mg, 0.306mmol) be added to [5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } amine (67mg, 0.204mmol) and 1-(3,5-two aminophenyls)-1-pyruvic alcohol (45mg, 0.204mmol) in the solution in MeOH, add acetate (2) then.This was reflected at stirring at room 5 hours.With this reaction mixture EtOAc (20mL), H
2O (20mL) and salt solution (5mL) dilution.(2 * 20mL) extract with EtOAc with water layer.With the organic extract liquid drying (Na that merges
2SO
4) and vacuum concentration, obtained crude product.It is passed through purified by flash chromatography (Si, 12 * 160mm, the mixture gradient of 0-50%EtOAc in hexane), two kinds of possible diastereomers have been obtained, erythro-1-(4-fluorophenyl)-2-([5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } amino) third-1-alcohol (68.4mg) and threo form-1-(4-fluorophenyl)-2-([5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } amino) third-1-alcohol (48.9mg), be colorless oil.Erythro-diastereomer: R
f=0.40 (20%EtOAc/ hexane).LCMS calculated value=476.22; Measured value=476.2 (M+1)
+
1H NMR(500MHz，CDCl
3)δ7.72(s，1H)，7.60(d，J＝7.8Hz，1H)，7.36(m，1H)，7.27(dd，J＝8.5，23Hz，1H)，7.19(m，2H)，7.04-6.92(m，4H)，4.63-4.56(m，1H)，3.85-3.65(m，7H)，2.92(m，1H)，2.72(m，1H)，1.26(t，J＝8.0Hz，6H)，0.64(t，J＝5.4Hz，3H).
Threo form-diastereomer: R
f=0.20 (20%EtOAc/ hexane).LCMS calculated value=476.22; Measured value=476.2 (M+1)
+
1H NMR(500MHz，CDCl
3)δ7.73(d，J＝9.0Hz，1H)，7.58(d，J＝7.9Hz，1H)，7.32(m，1H)，7.24(m，3H)，7.07-6.97(m，3H)，6.92(d，J＝8.5Hz，1H)，4.05(d，J＝7.9Hz，1H)，3.82-3.70(m，5H)，3.59 (d，J＝13Hz，1H)，3.51(d，J＝13 Hz，1H)，2.90(m，1H)，2.51(m，1H)，1.25(m，6H)，0.73(d，J＝6.4Hz，3H)
Embodiment 58
Erythro-5-(4-fluorophenyl)-3-{[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
Be prepared according to the method in embodiment 7 steps 3.R
f=0.38 (20%EtOAc/ hexane).LCMS calculated value=502.20; Measured value=502.2 (M+1)
+ 1H NMR (500MHz, benzene-d
6, 1: 1 mixture of atropisomer)
δ7.96(s，0.5H)，7.75(s，0.5H)，7.35(d，J＝7.7Hz，1H)，7.10-7.06(m，2H)，6.94(d，J＝2.1Hz，0.5H)，6.88(d，J＝2.1Hz，0.5H)，6.69-6.62(m，4.5H)，6.55(d，J＝8.4Hz，0.5H)，4 95(d，J＝15.9Hz，0.5H)，4.86(d，J＝15.8Hz，0.5H)，4.80(d，J＝7.9Hz，0.5 H)，4.70(d，J＝7.8Hz，0.5H)，4.04(d，J＝15.8Hz，0.5H)，3.93(d，J＝15.9Hz，0.5H)，3.36(s，1.5H)，3.22(s，1.5H)，3.14(m，0.5H)，3.05(m，0.5H)，2.79-2.71(m，1H)，1.18(m，6H)，0.02(d，J＝6.5Hz，1.5H)，-0.04(d，J＝6.5Hz，1.5H)
Use chirality HPLC (AD post, 20 * 250mm, the mixture of 3%EtOH in heptane) this compound separation is become its two kinds of enantiomorph (4R, 5S)-5-(4-fluorophenyl)-3-{[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone and (4S, 5R)-5-(4-fluorophenyl)-3-{[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone.
Made the compound of in table 2, listing according to the method for describing among the embodiment 58:
Table 2
Embodiment 64
1-{[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-4-Phenylpyrrolidine-2-ketone
Room temperature under nitrogen with two (trimethyl silyl) sodium amide (solution of 114 μ L 1M in THF, 0.114mmol) be added to 4-Phenylpyrrolidine-2-ketone (Winans, C.F., Adkins, H., J.Am.Chem.Soc, 1933,55,4167-4176) (17mg is 0.103mmol) in the solution that is stirring in anhydrous THF (1mL).Should react and stir 5 minutes, by sleeve pipe add 2-(brooethyl)-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl (20mg, 0.0516mmol) solution in anhydrous THF (2mL).This was reflected at stirring at room 3 days.Should react and use saturated NH
4Cl (10mL) handles, with EtOAc (3 * 20mL) extractions.The organic extract liquid that merges is washed dry (Na with salt solution (10mL)
2SO
4) and vacuum concentration, obtained crude product.It is passed through purified by flash chromatography (Si, 12 * 160mm, the mixture gradient of 0-90%EtOAc in hexane), obtained 1-{[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl-4-Phenylpyrrolidine-2-ketone, be colorless oil.R
f=0.11 (20%EtOAc/ hexane).LCMS calculated value=468.22; Measured value=468.2 (M+1)
+ 1H NMR (600MHz, benzene-d
6, 1: 1 mixture of atropisomer)
δ7.79(s，0.5H)，7.73(s，0.5H)，7.33(d，J＝7.7Hz，1H)，7.08-7.04(m，4H)，6.99(m，1H)，6.92(s，0.5H)，6.88(s，0.5H)，6.76(dd，J＝16.0，7.4Hz，2H)，6.60(dd，J＝8.5，3.1Hz，1H)，4.58(d，J＝15.4Hz，1H)，4.38(t，J＝13.9Hz，1H)，3.29(s，1.5H)，3.26(s，1.5H)，2.85-2.73(m，3H)，2.63-2.57(m，1H)，2.38-2.28(m，1H)，2.21-2.11(m，1H)，1.20-1.16(m，6H).
Embodiment 65
4-(3, the 4-difluorophenyl)-1-{[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } pyrrolidin-2-one
According to being similar to the method for describing among the embodiment 64, use 4-(3, the 4-difluorophenyl) pyrrolidin-2-one (by being similar to Marivet, M.C, Bourguignon, J.-J.; Lugnier, C, Mann, A., Stoclet, J.-C, Wermuth, C.-G.J.Med.Chem., 1989,32, the method for describing among the 1450-1457 makes) make.LCMS calculated value=504.20; Measured value=504.2 (M+1)
+
Embodiment 66
5-[3,5-two (trifluoromethyl) phenyl]-3-[2-iodo-5-(trifluoromethyl) benzyl]-1,3- azoles alkane-2-ketone
At 0 ℃ under nitrogen atmosphere, with sodium hydride (60% dispersion liquid in oil, 167mg, 4.18mmol) the suspension that is stirring in THF (5mL) is with the 5-[3 that is dissolved among the THF (1mL), 5-two (trifluoromethyl) phenyl]-1, (500mg 1.67mmol) handles 3- azoles alkane-2-ketone.Should react and stir 20 minutes, drip 2-(brooethyl)-1-iodo-4-(trifluoromethyl) benzene (610mg, 1.67mmol) solution in THF (1mL).This was reflected at stirring at room 18 hours.With this reaction H
2O (1mL) handles, at EtOAc (80mL) and H
2Distribute between the O (25mL).Water is used EtOAc again, and (2 * 20mL) extractions are washed the organic extract liquid that merges with salt solution (30mL), dry (MgSO
4) and vacuum concentration, obtained crude product.By fast silica gel chromatogram purifying (the mixture gradient of 0-30%EtOAc in hexane), obtained 5-[3,5-two (trifluoromethyl) phenyl]-3-[2-iodo-5-(trifluoromethyl) benzyl]-1,3- azoles alkane-2-ketone.R
f=0.55 (515%EtOAc/ hexane).
LCMS 584(M+1)
+.
1H NMR(CDCl
3，500MHz)δ8.05(d，J＝8.2Hz，1H)，7.95(br s，1H)，7.85(br s，2H)，7.51(brs，1H)，7.32(m，1H)，5.72(t，J＝8.0Hz，1H)，4.74(d，J＝15.5Hz，1H)，4.64(d，J＝15.3Hz)，4.14(t，J＝7.1Hz，1H)，3.47(dd，J＝7.1，1.6Hz).
Embodiment 67
(4S)-4-benzyl-3-{[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-1,3- azoles alkane-2-ketone
Steps A: (4S)-4-benzyl-3-[2-iodo-5-(trifluoromethyl) benzyl] 1,3- azoles alkane-2-ketone
0 ℃ under nitrogen atmosphere, (0.68mmol) (49mg 0.27mmol) handles the suspension that is stirring in THF (3mL) with being dissolved in (S)-4-benzyl-2- oxazolidone among the THF (1mL) for 60% dispersion liquid in oil, 27mg with sodium hydride.Should react and stir 20 minutes, drip 2-(brooethyl)-1-iodo-4-(trifluoromethyl) benzene (100mg, 0.27mmol) solution in THF (1mL).This was reflected at stirring at room 18 hours.With this reaction H
2O (1mL) handles, at EtOAc (80mL) and H
2Distribute between the O (25mL).Water is used EtOAc again, and (2 * 20mL) extractions are washed the organic extract liquid that merges with salt solution (30mL), dry (MgSO
4) and vacuum concentration, obtained crude product.By fast silica gel chromatogram purifying (the mixture gradient of 0-30%EtOAc in hexane), obtained (4S)-4-benzyl-3-[2-iodo-5-(trifluoromethyl) benzyl] 1,3- azoles alkane-2-ketone.R
f=0.45 (15%EtOAc/ hexane).
LCMS 462(M+1)
+.
1H NMR(CDCl
3，500MHz)δ8.04(d，J＝8.2Hz，1H)，7.54(br s，1H)，7.33-7.27(m，5H)，7.11-7.10(m，2H)，7.32(m，1H)，4.80(d，J＝16.0Hz，1H)，4.49(d，J＝16.1Hz)，4.28(t，J＝8.7Hz，1H)，4.25(t，J＝9.1，4.8Hz，1H)，3.94(m，1H)，3.16(dd，J＝13.5，4.8Hz，1H)，2.73(dd，J＝9.1，4.4Hz，1H).
Step B:(4S)-4-benzyl-3-{[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-1,3- azoles alkane-2-ketone
With (45)-4-benzyl-3-[2-iodo-5-(trifluoromethyl) benzyl] 1,3- azoles alkane-2-ketone (63mg, 0.137mmol), 2-methoxyl group-5-isopropyl benzene ylboronic acid (52mg, 0.274mmol), K
2CO
3(47mg, 0.34mmol) and Pd (OAc)
2(9.2mg is 0.0137mmol) at acetone: H
2The suspension reflux that stirring of O (5: 1) in (6mL) 1 hour.With this reaction mixture vacuum concentration, use H
2O (15mL) dilution is with EtOAc (3 * 30mL) extractions.The organic extract liquid that merges is washed dry (MgSO with salt solution (30mL)
4), filter and concentrate.Crude product is by fast silica gel chromatogram purifying (the mixture gradient of 0-20%EtOAc in hexane), obtained (4S)-4-benzyl-3-{[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl-1,3- azoles alkane-2-ketone.R
f=0.35 (15%EtOAc/ hexane).LCMS 484(M+1)
+。
1H NMR (CDCl
3, 500MHz) (have atropisomer;
1Observe some peak overlapping among the H NMR)
δ7.72(br s1H)，7.65(br s，1H)，7.42(m，1H)，7.32-7.22(m，3H)，7.08(d，J＝2.3Hz，1H)，6.90-6.84(m，3H)，4.80(d，J＝15.8Hz，1H)，4.35(d，J＝15.8Hz)，4.28(t，J＝8.7Hz，1H)，3.96-3.92(m，3H)，3.78(s，3H)，3.62-3.52(m，1H)，2.94-2.86(m，1H)，2.82(dd，J＝9.4，3.9Hz，1H)，2.42(dd，J＝9.6，3.9Hz)，1.26(s，3H)，1.10(s，3H).
Embodiment 68
2-iodo-5-(trifluoromethyl) phenylformic acid
With potassium hydroxide (3.78g; 0.0673mol) (embodiment 2 to be added to 2-iodo-5-(trifluoromethyl) benzonitrile; 4g; 0.0135mol) at 1: 1 Virahol: H
2In the solution that is stirring in the O solution (60mL).Should react reflux 14 hours, then at H
2Distribute between O (50mL) and the EtOAc (50mL).Water layer is extracted with EtOAc (50mL), and be acidified to pH5 with 6N HCl.Water layer is further used EtOAc, and (4 * 50mL) extractions are washed the extraction liquid that merges with salt solution (50mL), use dried over mgso, and filtration, and vacuum concentration have obtained 2-iodo-5-(trifluoromethyl) phenylformic acid, are yellow solid.
LCMS＝317.0(M+1)
+.
1H NMR(CDCl
3，500MHz)δ8.27(d，J＝1.6Hz，1H)，8.25(d，J＝8.2Hz，1H)，7.47(dd，J＝8.2，1.8Hz，1H).
Embodiment 69
[2-iodo-5-(trifluoromethyl) phenyl] methyl alcohol
At 0 ℃ under nitrogen atmosphere, with the borine-THF (solution of 1.0M in THF; 94mL; 94mmol) be added to 2-iodo-5-(trifluoromethyl) phenylformic acid (2.97g; 9.4mmol) in the solution that is stirring in THF (300mL).Should react reflux 90 minutes, handle until there not being gas release to come out with 6N HCl carefully then.Should react water (250mL) dilution, with EtOAc (3 * 250mL) extractions.The extraction liquid that merges is washed with salt solution (300mL), use dried over mgso, filter, and vacuum concentration.By purified by flash chromatography crude product (0-25%EtOAc/ hexane gradient), obtained [2-iodo-5-(trifluoromethyl) phenyl] methyl alcohol, be white solid.
LCMS＝285.0(M-17)
+.
1H NMR(CDCl
3，500MHz)：δ7.97(d，J＝8.3Hz，1H)，7.79(s，1H)，7.28(d，J＝8.4Hz，1H)，4.75(s，2H).
Another kind method is as described below: (embodiment 80, and steps A 9g) adds NaBH in the solution in THF (100mL) and water (10mL) to 2-iodo-5-(trifluoromethyl) phenyl aldehyde at 0 ℃
4(0.5g).Should react and stir 30 minutes.In this reaction mixture, add dilute hydrochloric acid (carefully).With this mixture extracted with diethyl ether, with ether layer water successively and salt water washing.With the ether layer anhydrous magnesium sulfate drying, filter and concentrate then.By silicon-dioxide chromatogram purification crude product, use 1: 3 CH successively
2Cl
2/ hexane, 1: 1 CH
2Cl
2/ hexane and 100%CH
2Cl
2Carry out gradient elution, obtained [2-iodo-5-(trifluoromethyl) phenyl] methyl alcohol, be white solid.
Embodiment 70
2-(bromotrifluoromethane)-1-iodo-4-(trifluoromethyl) benzene
At 0 ℃ under nitrogen atmosphere, with carbon tetrabromide (1.86g; 5.6mmol) and triphenylphosphine (1.47g; 5.6mmol) be added to [2-iodo-5-(trifluoromethyl) phenyl] methyl alcohol (1.13g successively; 3.74mmol) at CH
2Cl
2(25mL) in Nei the solution that is stirring.This was reflected at stirring at room 48 hours.Add a part of carbon tetrabromide (1.2g again; 3.74mmol) and triphenylphosphine (0.98g; 3.74mmol), should react restir 14 hours.Solvent removed in vacuo and with resistates by purified by flash chromatography (0-25%EtOAc/ hexane gradient), obtained 2-(bromotrifluoromethane)-1-iodo-4-(trifluoromethyl) benzene, be clarification oily matter.
1HNMR(CDCl
3，500MHz)：δ8.02(d，J＝8.2Hz，1H)，7.73(d，J＝1.8Hz，1H)，7.26(dd，J＝8.3，1.8Hz，1H)，4.64(s，2H).
Embodiment 71
5-[3,5-two (trifluoromethyl) phenyl]-1,3- azoles alkane-2-ketone
According to the method for describing among the embodiment 13, use 5.46g 2-amino-1-[3,5-two (trifluoromethyl) phenyl] ethanol, obtained 5-[3,5-two (trifluoromethyl) phenyl]-1,3- azoles alkane-2-ketone is pale solid.
LCMS＝300.1(M+1)
+.
1H NMR(CDCl
3，500MHz)：δ7.94(s，1H)，7.89(s，2H)，5.81-5.77(m，1H)，5.29(s，1H)，4.17-4.12(m，1H)，3.59-3.55(m，1H)
Embodiment 72
5-[3,5-two (trifluoromethyl) phenyl]-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-1,3- azoles alkane-2-ketone
With 5-[3,5-two (trifluoromethyl) phenyl]-3-[2-iodo-5-(trifluoromethyl) benzyl]-1,3- azoles alkane-2-ketone (60mg; 0.103mmol), (4-fluoro-5-sec.-propyl-2-p-methoxy-phenyl) boric acid (27mg; 0.129mmol), acid chloride (7mg; 0.0103mmol) and salt of wormwood (36mg; 0.257mmol) mixture heating up in 5: 1 acetone (6mL) refluxed 1 hour.Vacuum is removed acetone, resistates water (10mL) dilution, uses CH
2Cl
2(3 * 10mL) extractions.The extraction liquid that merges is washed with salt solution (10mL), use dried over sodium sulfate, filter, and vacuum concentration.Resistates is passed through purified by flash chromatography (0-25%EtOAc/ hexane gradient), obtained 5-[3,5-two (trifluoromethyl) phenyl]-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-1,3- azoles alkane-2-ketone is fining glass shape thing.LCMS＝624.2(M+1)
+。
1H NMR (benzene-d
6, 500MHz, 1: 1 mixture of atropisomer):
δ7.60(s，1.5H)，7.45(s，0.5H)，7.31-7.25(m，3H)，6.98-6.94(m，1H)，6.87-6.82(m，1H)，6.43-6.37(m，1H)，4.54(d，J＝15.6Hz，0.5 H)，4.40-4.36(m，1H)，4.47(d，J＝15.6Hz，0.5H)，3.96(d，J＝15.5Hz，0.5H)，3.80(d，J＝15.8Hz，0.5H)，3.24-3.15(m，1H)，3.02(s，3H)，2.62-2.58(m，0.5H)，2.53-2.48(m，0.5H)，2.12-2.07(m，0.5H)，2.04-2.00(m，0.5H)1.22-1.11(m，6H).
Use 15%IP A/ heptane and OD post, racemic product is separated into its two kinds of enantiomorphs by chirality HPLC.
(5R)-and 5-[3,5-two (trifluoromethyl) phenyl]-3-{[4 '-fluoro-5 ' sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-1,3- azoles alkane-2-ketone: LCMS=624.2 (M+1)
+ 1H NMR (benzene-d
6, 500MHz, 1: 1 mixture of atropisomer):
δ7.62(s，1.5H)，7.47(s，0.5H)，7.34-7.27(m，3H)，6.99-6.95(m，1H)，6.88-6.83(m，1H)，6.44-6.39(m，1H)，4.54(d，J＝15.5Hz，0.5H)，4.47-4.41(m，1H)，4.33(d，J＝15.6 Hz，0.5H)，3.98(d，J＝15.7Hz，0.5H)，3.82(d，J＝15.8Hz，0.5H)，3.24-3.15(m，1H)，3.05(s，3H)，2.67-2.62(m，0.5H)，2.57-2.52(m，0.5H)，2.16-2.11(m，0.5H)，2.09-2.04(m，0.5H)1.22-1.11(m，6H).
(5S)-and 5-[3,5-two (trifluoromethyl) phenyl]-3-{[4 '-fluoro-5 ' sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-1,3- azoles alkane-2-ketone: LCMS=624.2 (M+1)
+ 1H NMR (benzene-d
6, 500MHz, 1: 1 mixture of atropisomer):
δ7.63(s，1.5H)，7.48(s，0.5H)，7.35-7.27(m，3H)，7.00-6.95(m，1H)，6.88-6.83(m，1H)，6.44-6.38(m，1H)，4.54(d，J＝15.8Hz，0.5H)，4.48-4.42(m，1H)，4.34(d，J＝15.8Hz，0.5H)，3.99(d，J＝158Hz，0.5H)，3.83(d，J＝15.8Hz，0.5H)，3 25-3.15(m，1H)，3.05(s，3H)，2.68-2.63(m，0.5H)，2.58-2.53(m，0.5H)，2.18-2.12(m，0.5H)，2.10-2.05(m，0.5H)1.23-1.11(m，6H).
Embodiment 73
Step 1:(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[2-iodo-5-(trifluoromethyl) benzyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
At 0 ℃ under nitrogen atmosphere, to sodium hydride (60% dispersion liquid in mineral oil; 1.3g; 0.0325mol) drip in the suspension that is stirring in THF (60mL) (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone (embodiment 17) (4.077g; 0.013mol) solution in THF (50mL).Observing gas release comes out.The gained mixture was stirred 30 minutes at 0 ℃, add 2-(brooethyl)-1-iodo-4-(trifluoromethyl) benzene (4.754g then; 0.013mol) solution in THF (20mL).This reaction is warmed to room temperature and stirred 14 hours.This is reacted water (15mL) processing carefully, at EtOAc (250mL) and H
2Distribute between the O (75mL).(3 * 100mL) extract with EtOAc with water layer.The organic layer that merges is washed dry (MgSO with salt solution (100mL)
4), filter and vacuum concentration.Resistates is passed through purified by flash chromatography (0-20%EtOAc/ hexane gradient), obtained 6.4g (82.5%) (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[2-iodo-5-(trifluoromethyl) benzyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone is white solid.
LCMS＝598.1(M+1)
+.
1H NMR(CDCl
3，500MHz)：δ 8.03(d，J＝8.2Hz，1H)，7.90(s，1H)，7.79(s，2H)，7.58(s，1H)，7.30(dd，J＝8.2Hz，J＝2.0Hz，1H)，5.76(d，J＝8Hz，1H)，4.88(d，J＝15.8Hz，1H)，4.37(d，J＝15.8Hz，1H)，4.09-4.02(m，1H)，0.8(d，J＝6.6Hz，3H)
Step 2:(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
Will (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[2-iodo-5-(trifluoromethyl) benzyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone (4.29g; 7.19mmol), (4-fluoro-5-sec.-propyl-2-p-methoxy-phenyl) boric acid (embodiment 78) (4.57g; 21.57mmol), tetrakis triphenylphosphine palladium (0) (1.0g; 0.86mmol) and yellow soda ash (6.35g) at C
6H
6/ EtOH/H
2The mixture that is stirring among the O (120mL/17mL/51mL) reflux (100 ℃) 14 hours under nitrogen atmosphere.This is reflected at EtOAc (200mL) and H
2Distribute between the O (100mL).(3 * 200mL) extract with EtOAc with water.The organic phase that merges is washed dry (MgSO with salt solution (100mL)
4), filter and vacuum concentration.Resistates is passed through fast silica gel chromatogram purifying (0-25%EtOAc/ hexane gradient), obtained (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-{[4 '-fluoro-5 ' sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone is yellow solid.In order to remove yellow impurities, 2.7 g are dissolved among the 165mL EtOH, adding 275mg decolouring charcoal (gac, Darco, G-60,100 order powder, Aldrich).This mixture stirring at room 40 minutes, is filtered, and vacuum concentration.With about 25mL hexane development, obtained this title compound of 2.46g, be white solid.
1H NMR shows the trace impurity of removing by fast silica gel chromatogram (0-15%EtOAc/ hexane gradient).Remove residual solvent by lyophilize from acetonitrile.LCMS＝638.3(M+1)
+。
1H NMR (benzene-d
6, 500MHz, 1: 1 mixture of atropisomer):
δ7.82(s，0.5H)，7.60(s，0.5H)，7.57(s，1H)，7.33(d，J＝8Hz，1H)，7.27(d，J＝9.9Hz，2H)，7.02-6.98(m，1H)，6.89(d，J＝8.5Hz，0.5H)，6.82(d，J＝85Hz，0.5H)，6.45(d，J＝12.1Hz，0.5H)，6.35(d，J＝11.9Hz，0.5H)，4.94(d，J＝16.0Hz，0.5 H)，4.87(d，J＝15.8Hz，0.5 H)，4.54(d，J＝8.0Hz，0.5H)，4.50(d，J＝7.8Hz，0.5H)，3.74-3.66(m，1H)，3.23-3.15(m，1H)，3.12(s，1.5H)，2.99(s，1.5H)，2.97-2.92(m，0.5H)，2.89-2.84(m，0.5H)，1.21-1.09(m，6H)，-0.27(d，J＝6.7Hz，1.5H)，-0.40(d，J＝6.7Hz，1.5H).
Preparation (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl 1-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, the another kind of method of 3- azoles alkane-2-ketone:
Will (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[2-iodo-5-(trifluoromethyl) benzyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone (50mg; 0.084mmol), (4-fluoro-5-sec.-propyl-2-p-methoxy-phenyl) (embodiment 78,22mg for boric acid; 0.105mmol), acid chloride (6mg; 0.0103mmol) and salt of wormwood (29 mg; 0.257 mmol) mixture heating up in 5: 1 acetone (6mL) refluxed 1 hour.Vacuum is removed acetone, and resistates with the dilution of (10mL) water, is used CH
2Cl
2(3 * 10mL) extractions.With extraction liquid (10mL) salt water washing that merges, use dried over sodium sulfate, filter, and vacuum concentration.Resistates is passed through purified by flash chromatography (0-25%EtOAc/ hexane gradient), obtained (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-{[4 '-fluoro-5 ' sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone is fining glass shape thing.This product can also make by the method for describing among the embodiment 372.
Embodiment 74
(4R, 5S)-4-[3,5-two (trifluoromethyl) phenyl]-1-{[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-5-Methylimidazole alkane-2-ketone
Steps A: (4S, 5S)-5-[3,5-two (trifluoromethyl) phenyl]-3-{[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
Will ((4S, 5S)-5-[3,5-two (trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone) (46.2mg 0.148mmol) places anhydrous flask, adds DMA (3mL).(solution of 296 μ L 1M in THF 0.296mmol), should react stirring minute to add NaHMDS.By sleeve pipe be added in 2 among the DMA (2mL) '-(brooethyl)-5-sec.-propyl-4 '-(trifluoromethyl) biphenyl-2-ylmethyl ether (80.0mg, 0.207mmol).After 30 minutes, should react and use saturated NH
4Cl (2mL) handles.This mixture is diluted with EtOAc (40mL).With organic layer water (15mL) and salt solution (15mL) washing, use dried over sodium sulfate, filter, and concentrate.By the purified by flash chromatography resistates, use 25%EtOAc/ hexane wash-out, obtained (4S, 5S)-5-[3,5-two (trifluoromethyl) phenyl]-3-{[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone.R
f=0.27 (25%EtOAc/ hexane).LCMS＝620.2(M+1)
+。
1H NMR (CDCl
3, 500MHz; There is atropisomer)
δ 6.90-7.88 (m, 9H), 4.04-5.05 (m, 3H), and 3.25-3.74 (m, 4H), 2.88 (m, 1H), and 1.19-1.24 (m, 6H), 0.99-1.07 (m, 3H). step B:(1S, 2S)-and 1-[3,5-two (trifluoromethyl) phenyl]-2-([5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } amino) third-1-alcohol
To (4S, 5S)-5-[3,5-two (trifluoromethyl) phenyl]-3-{[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, (147.7mg 0.239mmol) adds H in the solution in EtOH (7.5mL) to 3- azoles alkane-2-ketone
2O (1.5mL) and KOH (150mg, 2.67mmol).This solution in 75 ℃ of heating 30 hours, is cooled to room temperature then.Add in the solution in the EtOAc (75mL), organic layer H
2(2 * 15mL) washings of O (15mL) and salt solution.With the organic layer dried over sodium sulfate, filter, and concentrate.Resistates is passed through purified by flash chromatography, obtained (1S, 2S)-1-[3,5-two (trifluoromethyl) phenyl]-2-([5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } amino) third-1-alcohol.R
f=0.44 (40%EtOAc/ hexane).
LCMS＝594.2(M+1)
+.
1H NMR(CDCl
3，500MHz)δ6.93-7.78(m，9H)，3.51-4.20(m，6H)，2.91(m，1H)，2.49(m，1H)，1.22-1.26(m，6H)，0.79-0.81(m，3H).
Step C:{ (1S, 2S)-2-[3,5-two (trifluoromethyl) phenyl]-2-hydroxyl-1-methylethyl } [5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } t-butyl carbamate
To (1S, 2S)-1-[3,5-two (trifluoromethyl) phenyl]-2-([5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } amino) (135.5mg is 0.228mmol) at CH for third-1-alcohol
2Cl
2(5mL) add BOC in Nei the solution
2O (49.7mg, 0.228mmol).This was reflected at stirring at room 2 days; Add two crowdes of BOC during this time again
2O (25mg each).After 2 days, should react and concentrate, and resistates passed through purified by flash chromatography, with 20%EtOAc/ hexane wash-out, obtained { (1S, 2S)-and 2-[3,5-two (trifluoromethyl) phenyl]-2-hydroxyl-1-methylethyl } [5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-base J methyl } t-butyl carbamate.R
f=0.41 (40%EtOAc/ hexane).LCMS＝594.2(M+1-BOC)
+。
Step D:{ (1S, 2R)-2-azido--2-[3,5-two (trifluoromethyl) phenyl]-the 1-methylethyl } [5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } t-butyl carbamate
In dry flask, add THF (1mL), diethyl azodiformate (DEAD) (11 μ L, 0.0698mmol) and diphenylphosphine acylazide (DPPA) (15 μ L, 0.0698mmol).Be added in { (1S among the THF (1mL) by sleeve pipe, 2S)-2-[3,5-two (trifluoromethyl) phenyl]-2-hydroxyl-1-methylethyl } [5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } t-butyl carbamate (20.7mg, 0.0698mmol).Add Ph then
3P (18.3mg, 0.0698mmol).This was reflected at stirring at room 30 minutes, and then add DEAD (11 μ L, 0.0698mmol), DPPA (15 μ L, 0.0698mmol) and Ph
3P (18.3mg, 0.0698mmol).After 30 minutes, should react dilution, water and salt water washing (being respectively 15mL) with EtOAc (40mL).With the organic layer dried over sodium sulfate, filter, and concentrate.By the purified by flash chromatography resistates, use 15%EtOAc/ hexane wash-out, obtained (1S, 2R)-2-azido--2-[3,5-two (trifluoromethyl) phenyl]-the 1-methylethyl } [5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } t-butyl carbamate.R
f=0.60 (25%EtOAc/ hexane).LCMS＝619.3(M+1-BOC)
+。
Step e: (1R, 2S)-1-azido--1-[3,5-two (trifluoromethyl) phenyl]-N-{[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } third-2-amine
To (1S, 2R)-2-azido--2-[3,5-two (trifluoromethyl) phenyl]-the 1-methylethyl } [5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } (21.7mg is 0.030mmol) at CH for t-butyl carbamate
2Cl
2(2mL) add TFA (200 μ L) in Nei the solution.This is reflected at stirring at room 1 hour, uses CH then
2Cl
2(25mL) dilution.With this CH
2Cl
2Solution is used CH with 1N NaOH (15mL) washing again with water
2Cl
2(25mL) extraction.Organic extract liquid is merged,, use dried over sodium sulfate, filter, and concentrate with salt solution (20mL) washing.By the purified by flash chromatography resistates, use 15%EtOAc/ hexane wash-out, obtained (1R, 2S)-1-azido--1-[3,5-two (trifluoromethyl) phenyl]-N-{[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } third-2-amine.R
f=0.45 (15%EtOAc/ hexane).LCMS＝619.2(M+1)
+。
Step F: (1R, 2S)-1-[3,5-two (trifluoromethyl) phenyl]-N
2-[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } the third-1, the 2-diamines
To (1R, 2S)-1-azido--1-[3,5-two (trifluoromethyl) phenyl]-N-{[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } (17.8mg 0.0288mmol) adds PtO in the solution in THF (3mL) to third-2-amine
2(12mg, 0.053mmol).This reaction is placed under the hydrogen capsule atmosphere, and stirring at room 3 hours.By removing by filter catalyzer and this filtrate being concentrated.Allow resistates pass through short silica gel plug, use 0-10%MeOH/CH
2Cl
2Washing, obtained (1R, 2S)-1-[3,5-two (trifluoromethyl) phenyl]-N
2-[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } the third-1, the 2-diamines.LCMS＝619.2(M+1)
+。
Step G:(4R, 5S)-4-[3,5-two (trifluoromethyl) phenyl]-1-{[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-5-Methylimidazole alkane-2-ketone
Will (1R, 2S)-1-[3,5-two (trifluoromethyl) phenyl]-N
2-[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } the third-1, (8.0mg is 0.0135mmol) at CH for the 2-diamines
2Cl
2Solution (2mL) is cooled to 0 ℃, add DIPEA (14 μ L, 0.081mmol), add then triphosgene (2mg, 0.00657mmol).This is reflected at 0 ℃ stirred 30 minutes, use EtOAc (30mL) dilution then.Should react with saturated sodium bicarbonate (10mL) and salt solution (10mL) washing.With the organic layer dried over sodium sulfate, filter, and concentrate.By the purified by flash chromatography resistates, use 40%EtOAc/ hexane wash-out, obtained (4R, 5S)-4-[3,5-two (trifluoromethyl) phenyl]-1-{[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-5-Methylimidazole alkane-2-ketone.R
f=0.24 (40%EtOAc/ hexane).LCMS＝619.2(M+1)
+。
1H NMR (CD
2Cl
2, 600MHz; There is atropisomer)
δ6.91-7.84(m，9H)，3.84-4.94(m，4H)，3.64-3.80(m，4H)，2.88(m，1H)，1.18-1.26(m，6H)，0.27-0.42(m，3H).
Embodiment 75
(3S, 4R)-4-[3,5-two (trifluoromethyl) phenyl]-2-{[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 3-methyl isophthalic acid, 2,5-thiadiazolidine 1,1-dioxide
In glass reaction tube, add (1R, 2S)-1-[3,5-two (trifluoromethyl) phenyl]-N
2-[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl the third-1, the 2-diamines (15.9mg, 0.0269mmol), sulphonamide (4mg, 0.0403mmol) and pyridine (600 μ L).With the reaction tubes nitrogen purging, sealing was 120 ℃ of heating 2 hours.Then this solution is cooled to room temperature,, uses H with EtOAc (40mL) dilution
2O, 1N HCl and salt solution (being respectively 10mL) washing.With the organic layer dried over sodium sulfate, filter, and concentrate.By the purified by flash chromatography resistates, use 25%EtOAc/ hexane wash-out, obtained (3S, 4R)-and 4-[3,5-two (trifluoromethyl) phenyl]-2-{[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 3-methyl isophthalic acid, 2,5-thiadiazolidine 1, the 1-dioxide.R
f=0.27 (25%EtOAc/ hexane).LCMS＝655.2(M+1)
+。
1H NMR (C
6D
6, 500MHz; There is atropisomer)
δ6.51-8.19(m，9H)，3.64-4.53(m，4H)，3.00-3.18(m，4H)，2.73(m，1H)，1.13-1.20(m，6H)，-0.03-0.09(m，3H).
Embodiment 76
2-fluoro-1-pseudoallyl-4-anisole
Steps A: 2-(2-fluoro-4-p-methoxy-phenyl) propan-2-ol
At 0 ℃, to 2 '-fluoro-4 '-methoxyacetophenone (4.45g, 26.5mmol) add in the solution in THF (50ml) 2.4M MeMgBr solution (11.6mmol, 27.8mmol).With this mixture 0 ℃ of stirring, then stirring at room 4 hours.Should react and handle with saturated ammonium chloride solution.(3 * 50ml) extract with ethyl acetate with organic phase.Merging is reached ethyl acetate layer with the salt water washing and use dried over sodium sulfate.By quick column purification, use EtOAc: hexane=2: 8 has obtained gained alcohol as eluent, is oily matter.
Step B:2-fluoro-1-pseudoallyl-4-anisole
0 ℃ to the 2-that derives from steps A (2-fluoro-4-p-methoxy-phenyl) propan-2-ol (3.89g, 21.14mmol) add in the solution in methylene dichloride (50ml) MsCl (1.95ml, 25.4mmol) and triethylamine (6.52ml, 46.5mmol).With this solution 0 ℃ of stirring, then stirring at room 2 hours.This solution with methylene dichloride (100ml) dilution, is washed with water, and uses dried over sodium sulfate.By quick column purification, use EtOAc: hexane=1: 9 has obtained this title compound as eluent, is oily matter.
1H NMR(CDCl
3，500MHz)δ7.25(t，J＝9.0Hz，1H)，6.68(dd，J＝8.5，2.5Hz，1H)，6.63(dd，J＝13，2.5Hz，1H)，5.20(d，J＝17.0Hz，2H)，3.82(s，3H)，2.18(s，3H).
The another kind of method of preparation 2-fluoro-1-pseudoallyl-4-anisole:
With two (trimethyl silyl) sodium amide, (714ml 0.714m) is added to Diethylaminoethyl triphenyl (255g, 0.714m) using in the molten suspension of ice bath refrigerative in THF (2.50L) to the solution of 1.0M in tetrahydrofuran (THF).The gained yellow suspension was stirred 30 minutes in the ice bath temperature, be cooled to-78 ℃ then.(100g 0.595m), stirred 1.5 hours at-78 ℃ dropping all 2-fluoro-4-methoxyacetophenones in THF (200mL).This reaction mixture be warmed to room temperature and keep hour, with acetate (～80ml) handle, observe color and become canescence, and stir 30 minutes (pH～7) (noticing slight heat release) from yellow.This mixture is concentrated into slurries, and with 7: 2 hexanes: the ethyl acetate dilution allowed its standing over night.Also this filtrate is concentrated into yellow oil by solids removed by filtration.By quick column purification, use 9: 1 hexanes: ethyl acetate has obtained this title compound as eluent.
Embodiment 77
1-fluoro-4-iodo-2-sec.-propyl-5-anisole
With 2-fluoro-1-pseudoallyl-4-anisole (embodiment 76,1.96g, 11.81mmol) solution in MeOH (30ml) applies the Pd/C of 1atm hydrogen and catalytic amount.With this mixture stirring at room 1 hour.With this mixture via diatomite filtration.Then filtrate be added to Sulfuric acid disilver salt (3.68g, 11.81mmol) and iodine (3.00g is 11.81mmol) in the mixture in MeOH (10ml).3 hour until solution colour become light yellow in stirring at room this mixture.This mixture is filtered and this filtrate is concentrated.By quick column purification, use EtOAe hexane as eluent has obtained this title compound at 5: 95.
1H NMR(CDCl
3，500MHz)δ 7.61(d，J＝8.0Hz，1H)，6.56(d，J＝12.5Hz，1H)，3.90(s，3H)，3.18(m，1H)，1.28(m，6H).
Embodiment 78
(4-fluoro-5-sec.-propyl-2-p-methoxy-phenyl) boric acid
At-78 ℃, to 1-fluoro-4-iodo-2-sec.-propyl-5-anisole (embodiment 77,2.61g, 8.88mmol) drip in the solution in THF n-BuLi (4.26ml, 10.65mmol, 2.5M).This solution was stirred 30 minutes at-78 ℃.The adding trimethyl borate (2.98ml, 26.6mmol).Then this solution was stirred 3 hours at-78 ℃.This is reflected at-78 ℃ with the saturated ammonium chloride processing, this mixture is warmed to room temperature.(3 * 50ml) extract with ethyl acetate with organic phase.With the ethyl acetate layer that merges with the salt water washing and use dried over sodium sulfate.Obtain this title compound, be enough to be used in the solid of next step for purity.Be further purified by silica gel, because product decomposes.
1H NMR(CDCl
3，500MHz)δ 7.74(d，J＝10.0Hz，1H)，6.62 (d，J＝12.5Hz，1H)，5.65(br s，2H)，3.92(s，3H)，3.20(m，1H)，1.22(m，6H).
This boric acid intermediate can also make by following four step rule:
Change into 2 with 1:
In room temperature THF (24L) is added in the 100L cylindrical reactor.To wherein adding 2.75kg CeCl
3The gained slurries aged at room temperature 1.5 hours.Then in the microscopically monitor sample, to confirm to have taken place desired form.Slurries are cooled to 9 ℃, add MeMgCl.Regulate adding speed and be lower than 19 ℃ with temperature in keeping.This mixture is cooled to-11 ℃, drips methyl phenyl ketone 1 (4.0kg is diluted to 10L with THF).Temperature is lower than 0 ℃ in keeping.Then this reaction mixture was worn out 1 hour in the temperature below 0 ℃.Dropwise 5 .7L 3NHCl in this reaction, temperature is lower than 15 ℃ in keeping.This reaction mixture that to handle then wore out 1.5 hours at 5-10 ℃, filtered via Solka Floe plug.
Be hydrogenated to 3 with 2:
With the solvent replacing in 2 the THF solution is ethanol (～18L volume), adds 1.9LHCl, adds 190g 10%Pd/C (50% water) then.This mixture is reacted completely until the HPLC analysis revealed in 40 ℃ of placements under 15 psi hydrogen.This mixture is cooled to room temperature.By removing by filter catalyzer, use Solka-Flok as the filter auxiliary.Solvent switch with the phenylmethylether product in the ethanol is that acetonitrile is to be used for next step then.
3 brominations are become 4.
Phenylmethylether 3 is diluted (1.72L, 4mL MeCN/mMol 3) in acetonitrile.This mixture is warmed to 35 ℃, and disposable adding solid NBS (1.1eq, 84g).Be reflected in 2-4 hour complete.This solution concentration to the 400mL cumulative volume, is used the 1L dilution with toluene.Then with this solution with Sulfothiorine and water washing to remove the succinimide by product.Then organic layer is concentrated, and solvent is changed to toluene.
Aromatic bromide 4 is changed into boric acid 5:
Add 1.87kg aryl bromide 4 (7.6 MoI) in 75L glass reaction container, it is to add as the solution of 6.4kg29.1 wt%4 in toluene.This solution is diluted with 5.6L THF.Use nitrogen purging container, and the adding triisopropyl borate ester (1.35eq, 2.35L, 10.3Mol).This mixture is cooled to＜-70 ℃.Then with adding the solution (9.5Mol) of 5.9L 1.6Mn-BuLi in hexane in 4 hours lentamente, keep temperature＜-55 ℃.N-BuLi add finish after 30 minutes, react completely by the LC analysis revealed.This reaction is warmed to-35 ℃, uses 3.0MH
2SO
4Solution (5.6L) is handled.Post-treatment aqueous phase should be acid (pH～2).MTBE (7.5L) is added in this mixture with the dilution organic layer.This mixture is stirred (15 minutes), water layer is removed.With organic layer 5.6L 3.0M H
2SO
4Solution (15min) washing.After separating each layer once more, with MTBE/ toluene layer 1M KOH (at first 15.1L, 7.6L then) extracting twice.Two parts of KOH extraction liquids are merged,, be cooled to 15 ℃ with 2-propyl alcohol (6.4L) dilution.Use then 3.0 M sulfuric acid (～7.6L) this solution is acidified to pH～2 lentamente, simultaneously temperature is remained on 15-20 ℃.The gained slurries were stirred 1 hour, filter then.(2 * 6L) washings, drying is 1 day under airflow the filter cake water.Filtering solid was placed 50 ℃ of vacuum drying oven 2-3 days, to decompose diaryl impurity and drying solid.Isolate the pale solid crystallization, obtained 1.59kg boric acid 5.
Embodiment 79
(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[(4-chloro-4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl biphenyl-2-yl) methyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
Steps A: 1-bromo-2-(brooethyl)-4-chlorobenzene
With 2-bromo-5-chloro-toluene (2.00g, 9.75mmol), NBS (2.08g, 11.7mmol) and the mixture of AIBN in tetracol phenixin (50ml) of catalytic amount under refluxad stirred 4 hours.TLC (EtOAc: hexane=5: 95) show there is not raw material.This mixture is filtered and this filtrate is concentrated.By quick column purification, use EtOAc: hexane=5: 95 has obtained this title compound as eluent, is white solid.
1H NMR(CDCl
3，500MHz)δ7.53(d，J＝9.0Hz，1H)，7.47(d，J＝2.5Hz，1H)，7.18(dd，J＝8.5，2.5Hz，1H)，4.60(s，2H).
Step B. (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-(2-bromo-5-benzyl chloride base)-4-methyl isophthalic acid, 3- azoles alkane-2-ketone
At 0 ℃, to (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, (0.050g 0.16mmol) adds NaH (7.6mg, 0.19mmol, 60%) to 3- azoles alkane-2-ketone in the solution in THF (1ml).This mixture was stirred 30 minutes at 0 ℃.Add this title compound derive from steps A (0.059g, 0.21mmol).Whole mixture was stirred 1 hour at 0 ℃, be warmed to room temperature and kept 4 hours.Should react and handle with saturated ammonium chloride.(3 * 15ml) extract with ethyl acetate with organic phase.Merging is reached ethyl acetate layer with the salt water washing and use dried over sodium sulfate.Preparation TLC purifying, use EtOAc: hexane=2: 8 has obtained this title compound as eluent.
1H NMR(CDCl
3，500MHz)δ7.92(s，1H)，7.82(s，2H)，7.55(d，J＝8.5Hz，1H)，7.43(d，J＝2.5Hz，1H)，7.23(dd，J＝8.5，2.5Hz，1H)，5.77(d，J＝8.0Hz，1H)，4.86(d，J＝16.0Hz，1H)，4.36(d，J＝16.0Hz，1H)，4.11(m，1H)，0.82(d，J＝6.5Hz，3H).
Step C. (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[(4-chloro-4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl biphenyl-2-yl) methyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
With (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-(2-bromo-5-benzyl chloride base)-4-methyl isophthalic acid, 3- azoles alkane-2-ketone (44mg, 0.085mmol), (4-fluoro-5-sec.-propyl-2-p-methoxy-phenyl) (embodiment 78 for boric acid, 23mg, 0.11mmol), salt of wormwood (25mg, 0.18mmol) and the PdOA of the catalytic amount mixture heating up in 4: 1 mixtures of acetone refluxed 1 hour.Remove acetone, and add entry.(3 * 15ml) extract with methylene dichloride with organic layer.With the dichloromethane layer that merges with the salt water washing and use dried over sodium sulfate.By preparation reversed-phase HPLC purifying, obtained this title compound, be solid.
1H NMR (CDCl
3, 500MHz) 1: 1 mixture of rotational isomer
δ7.90(s，1H)，7.73(s，2H)，7.49(m，1H)，7.40(m，1H)，7.20(m，1H)，7.00(m，1H)，6.68(dd，J＝12.0，3.0Hz，1H)，5.63(d，J＝8.0Hz，1/2H)，5.44(d，J＝8.0Hz，1/2H)，4.85(d，J＝10.0Hz，1/2H)，4.82(d，J＝10.0Hz，1/2H)，4.03(d，J＝16.0Hz，1/2H)，3.84(m，11/2 H)，3.80(s，3H)，3.20(m，1H)，1.20(m，6H)，0.56(d，J＝6.5Hz，3/2 H)，0.38(d，J＝6.5H，3/2H).LC-MS(M+1)：604.3，4.61min.
Embodiment 80
5-[2-iodo-5-(trifluoromethyl) phenyl]-1,3- azoles alkane-2-ketone
Steps A: 2-iodo-5-(trifluoromethyl) phenyl aldehyde
At-78 ℃, to 2-iodo-5-(trifluoromethyl) benzonitrile (embodiment 2,42 g) at CH
2Cl
2(300mL) added DIBAL at CH with 30 minutes in Nei the solution
2Cl
2In solution (175mL, 1M).Formed precipitation.This reaction is warmed to 0 ℃.With 30 minutes dropping 25mL DIBAL solution.This reaction is poured in the 200mL 2N hydrochloric acid,, stirred 1 hour with the ether dilution.Still there is imines in the TLC analysis revealed, adds the 100mL 2N aqueous solution, should react to stir and spend the night.Still there is imines in the TLC analysis revealed, adds 200mL 2N hydrochloric acid, and this mixture was stirred 2 hours.Separate each layer, with the ether water layer of stripping.Merge ether extraction liquid, use the salt water washing, use anhydrous magnesium sulfate drying, filter and concentrate.By the silica gel chromatography purified product, use 95: 5 hexane/EtOAc wash-outs, obtained 2-iodo-5-(trifluoromethyl) phenyl aldehyde, be white solid.
1HNMR(500MHz，CDCl
3)：δ10.00(s，1H)，8.12(s，1H)，8.11(d，J＝8Hz，1H)，7.53(dd，J＝2Hz，8Hz，1H).
Step B:5-[2-iodo-5-(trifluoromethyl) phenyl]-1,3- azoles alkane-2-ketone
In the 0 ℃ solution of 0.2g 2-iodo-5-(trifluoromethyl) phenyl aldehyde in 3mL EtOH, add the 0.13mL Nitromethane 99Min., add 0.28mL 2.5N NaOH solution then.This mixture was stirred 3 hours at 0 ℃, neutralize by adding the 2.1mL 0.33N AcOH aqueous solution then.This mixture is distributed between 10mL water and 10mL EtOAc.Water is extracted with 2 * 5mL EtOAc.With the organic layer that merges 10mL salt water washing, use dried over sodium sulfate, and concentrate.Resistates is dissolved among the 4mL MeOH, adds 0.5mL 88% aqueous formic acid.Add about 200mg Raney nickel slurries,, under the hydrogen capsule, stirred 4 hours this mixture hydrogen purge.This mixture via diatomite filtration, is washed with MeOH, and this filtrate is concentrated.With resistates at 10mL 10%NH
4Distribute between the OH aqueous solution and the 20mLEtOAc.Water is extracted with 2 * 10mL EtOAc.With the organic layer that merges 10mL salt water washing, use dried over sodium sulfate, and concentrate.Resistates is dissolved in 2mLCH
2Cl
2In.In this solution, add the 0.114mL diisopropylethylamine, add the 0.065g triphosgene then.This mixture was stirred 30 minutes at 0 ℃, use the saturated NaHCO of 10mL EtOAc and 10mL then
3Dilution.Water is extracted with 2 * 10mL EtOAc.With the organic layer that merges 10mL salt water washing, use dried over sodium sulfate, and concentrate.With resistates at Biotage Horizon, pass through purified by flash chromatography on the 25S post, use the mixture wash-out of 1CV 4%EtOAc in hexane, use the mixture of 4-100%EtOAc in hexane to carry out linear gradient elution then, obtained this title compound with 10CV.Mass spectrum (ESI) 350.0 (M+1).
1H NMR(500MHz，CDCl
3)：δ8.00(d，J＝8Hz，1H)，7.74(br s，1H)，7.33(br d，J＝8Hz，1H)，5.80(dd，J＝7Hz，9Hz1H)，5.05-5.50(br，1H)，4.28(t，J＝9Hz，1.5H)，3.36(dd，J＝7Hz，9Hz，1H).
Embodiment 81
5-[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl]-1,3- azoles alkane-2-ketone
To 65mg 5-[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl]-1, add about 5mg acid chloride in 3- azoles alkane-2-ketone, 45mg (5-sec.-propyl-2-p-methoxy-phenyl) boric acid and the solution of 66mg salt of wormwood in 6mL acetone and 1.5mL water.This mixture heating up to refluxing, was stirred 1.5 hours under this temperature.Remove acetone and, use the dilution of 10mL EtOAc and 10mL water by rotary evaporation resistates.Water is extracted with 10mL EtOAc.With the organic layer that merges 10mL salt water washing, use dried over sodium sulfate, and concentrate.With resistates at Biotage Horizon, pass through purified by flash chromatography on the 25S post, use the mixture wash-out of 1 CV 10%EtOAc in hexane, use the mixture of 10-100%EtOAc in hexane to carry out linear gradient elution then, obtained this title compound with 10 CV.Spectroscopic data provides in embodiment 49.
Made the compound of in table 3, listing according to the method for describing among the embodiment 52.
Table 3
Embodiment 90
5-[2-iodo-5-(trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
According to the method for describing among the embodiment 80, use nitroethane, 0.2g 2-iodo-5-(trifluoromethyl) phenyl aldehyde, obtained the required product of 0.102g, by the following method it is separated into cis and trans diastereomer: at Biotage Horizon, carry out flash chromatography on the 25S post, use the mixture wash-out of 1 CV 10%EtOAc in hexane, use the mixture of 10-100%EtOAc in hexane to carry out linear gradient elution then with 10 CV.
Trans-5-[2-iodo-5-(trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone: mass spectrum (ESI) 372.1 (M+1).
1H NMR (500MHz, CDCl
3): δ 8.02 (d, J=8Hz, 1H), 7.61 (d, J=1.5Hz, 1H), 7.32 (dd, J=2Hz, 8Hz, 1H), 6.16 (s, 1H), 5.39 (d, J=4Hz, 1H), 3.76 (dq, J=6Hz, 4.5 Hz, 1H), 1.62 (d, J=6 Hz, 3H). cis-5-[2-iodo-5-(trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone: mass spectrum (ESI) 372.1 (M+1).
1H NMR(500MHz，CDCl
3)：δ7.98(d，J＝8Hz，1H)，7.60(br s，1H)，7.33(dd，J＝1.5 Hz，8Hz，1H)，6.25(s，1H)，5.85(d，J＝8Hz，1H)，3.76(dq，J＝8Hz，7Hz，1H)，0.81(d，J＝7Hz，3H).
Embodiment 91
Trans-5-[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone (racemize)
To 0.036g trans-5-[2-iodo-5-(trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, add the 2mg acid chloride in 3- azoles alkane-2-ketone, 0.024g (5-sec.-propyl-2-p-methoxy-phenyl) boric acid and the solution of 0.04g salt of wormwood in 2mL acetone and 0.5mL water.This mixture heating up to refluxing, was stirred 1.5 hours under this temperature.Remove acetone and, use the dilution of 10mLEtOAc and 10mL water by rotary evaporation resistates.Water is extracted with 10mL EtOAc.With the organic layer that merges 10mL salt water washing, use dried over sodium sulfate, and concentrate.With resistates at BiotageHorizon, pass through purified by flash chromatography on the 25S post, use the mixture wash-out of 1 CV 10%EtOAc in hexane, use the mixture of 10-100%EtOAc in hexane to carry out linear gradient elution then, obtained this title compound with 10 CV.Mass spectrum (ESI) 394.2 (M+1).
1H NMR signal is because atropisomerism and overlapping.
1H NMR(500MHz，CDCl
3)：δ7.80，7.78(s，1H)，7.64，7.63(d，J～8Hz，1H)，7.35(d，J＝7.5Hz，1H)，7.27，7.26(d，J-8Hz 1H)，7.00，6.95(d，J＝2.5Hz，1H)，6.93，6.92(d，J～8Hz，1H)，5.87，5.81(s，1H)，5.16，5.10(d，J～5Hz，1H)，3.70-3.78(m，3.5H)，3.49(m，0.5H)，2.89(m，1H)，1.24(m，6H)，0.90，0.70(d，J＝6.5Hz，3H).
Embodiment 92
Cis-5-[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone (racemize)
According to the method for describing among the embodiment 91, use 0.046g cis-5-[2-iodo-5-(trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone has obtained required product.Mass spectrum (ESI) 394.2 (M+1).
1H NMR signal is because atropisomerism and overlapping.
1H NMR(500MHz，CDCl
3)：δ7.89，7.88(s，1H)，7.65，7.64(d，J～7.5Hz，1H)，7.34，7.32(d，J～8Hz，1H)，7.26(d，J＝8.5Hz，1H)，6.98，6.86(d，J＝2.5Hz，1H)，6.91，6.89(d，J～8Hz，1H)，5.83，5.75(s，1H)，5.69，5.61(d，J～8Hz，1H)，3.75(s，1.8H)，3.58-3.70(m，2H)，3.32(m，0.6H)，2.88(m，1H)，1.23(m，6H)，0.89，0.71(d，J＝6.5Hz，3H).
Embodiment 93
Trans-3-[3,5-two (trifluoromethyl) benzyl]-5-[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone (racemize)
To 30mg trans-5-[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl]-the 4-methyl isophthalic acid, add the 8mg sodium hydride in 0 ℃ of solution of 3- azoles alkane-2-ketone in 1mL DMF.This mixture stirring at room 10 minutes, is added 32mg 3,5-two (trifluoromethyl) bromotoluene then.This mixture in stirred overnight at room temperature, is diluted with 10mL EtOAc and 10mL water then.Separate each layer and use 5mL EtOAC to extract water.With the organic layer that merges 5mL salt water washing, dry (Na
2SO
4) and concentrate.With resistates at BiotageHorizon, pass through purified by flash chromatography on the 25S post, use the mixture wash-out of 1CV 4%EtOAc in hexane, use the mixture of 4-100%EtOAc in hexane to carry out linear gradient elution then, obtained this title compound with 10CV.Mass spectrum (ESI) 620.2 (M+1).
1H NMR signal is because atropisomerism and overlapping.
1H NMR(500MHz，CDCl
3)：δ7.53-7.80(m，5H)，7.33(d，J＝8Hz，1H)，7.21-7.29(m，1H)，7.00，6.76(d，J＝2.5Hz，1H)，6.91，6.86(d，J＝8.5Hz，0.4H)，5.15，5.10(d，J＝4.5 Hz，1H)，4.80，4.74(d，J＝16Hz，1H)，4.25，4.21(d，16Hz，1H)，3.76(s，2H)，3.49(s，1H)，3.43(m，0.4H)，3.18(m，0.5H)，2.77-2.98(m，1H)，1.24(m，3H)，1.16(m，3H)，0.78，0.61(d，J＝6.5Hz，3H).
Embodiment 94
Cis-3-[3,5-two (trifluoromethyl) benzyl]-5-[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone (racemize)
According to the method for describing among the embodiment 93, use 40mg cis-5-[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone and 42mg 3,5-two (trifluoromethyl) bromotoluene has obtained this title compound.Mass spectrum (ESI) 620.2 (M+1).
1The HNMR signal is because atropisomerism and overlapping.
1H NMR(500MHz，CDCl
3)：δ7.82-7.94(m，2H)，7.62-7.74(m，3H)，7.39，7.37(d，J～8Hz，1H)，7.25，7.17(br d，J＝8.5Hz，1H)，7.00，6.78(s，1H)，6.87，6.84(d，J＝8.5Hz，1H)，5.59，5.56(d，J＝4.5Hz，1H)，4.96(d，J＝16Hz，1H)，4.22，4.11(d，J＝16 Hz，1H)，3.76(s，2H)，3.58(s，1H)，3.40(m，0.4H)，2.85-3.00(m，1H)，2.78(m，0.5H)，1.23(d，J＝7 Hz，3H)，1.06(m，3H)，0.88，0.69(d，J＝6.5Hz，3H).
Embodiment 95
(4R, 5R)-5-[2-iodo-5-(trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone steps A: (4S)-4-benzyl-3-{ (2R, 3S)-3-hydroxyl-3-[2-iodo-5-(trifluoromethyl) phenyl]-the 2-methylpropionyl }-1,3- azoles alkane-2-ketone
With 1.8g 5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-(embodiment 80 for 2-formaldehyde; steps A), 1.16g (4S)-4-benzyl-3-propionyl-1; 3- azoles alkane-2-ketone, 0.048 g magnesium chloride, 1.40mL triethylamine and the mixture of 0.91mL chlorine trimethyl silyl in 10mL EtOAc were in stirring at room 24 hours; filter then via 10 * 10cm silica gel plug and filter, use 400mL Et
2The O wash-out.This filtrate is concentrated, add 10mL MeOH and 2 trifluoroacetic acids.This solution stirring at room 30 minutes, is concentrated into light yellow oil.Resistates at Biotage Horizon, by purified by flash chromatography, is used the mixture wash-out of 15 CV10% acetone in hexane on the 65i post, obtained this title compound.Mass spectrum (ESI) 516.2 (M-OH).
1H NMR(500MHz，CDCl
3)：δ8.00(d，J＝8.5Hz，1H)，7.76(d，J＝2Hz，1H)，7.22-7.32(m，4H)，7.07(br d，J＝6.5Hz，2H)，5.18(dd，J＝6.5Hz，7.5 Hz，1H)，4.67(m，1H)，4.46(dq，J＝6.5Hz，7.5Hz，1H)，4.17(t，J＝9Hz，1H)，4.11(dd，J＝3Hz，9Hz，1H)，3.97(d，J＝8 Hz，1H)，3.19(dd，J＝7Hz，13.5Hz，1H)，2.57(dd，J＝9.5Hz，13.5Hz，1H)，1.34(d，J＝7.5Hz，3H)
Step B:(4R, 5R)-5-[2-iodo-5-(trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
To 0.65 g (4S)-4-benzyl-3-{ (2R; 3S)-3-hydroxyl-3-[2-iodo-5-(trifluoromethyl) phenyl]-the 2-methylpropionyl }-1; add the solution of 0.102g lithium hydroxide in 1.5mL water in 0 ℃ of solution of 3- azoles alkane-2-ketone in 3: 1 tetrahydrofuran (THF)-water of 6mL, add the 0.554mL30% aqueous hydrogen peroxide solution then.This solution was stirred 1 hour at 0 ℃, and at this moment the LC/MS analysis revealed is without any raw material.In this cold soln, add 1.5M sodium sulfite solution (3.7mL), pour into then in the separating funnel, with 2 * 10mL dichloromethane extraction.With the CH that merges
2Cl
2Extraction liquid is stripped with 3: 1 water-saturated sodium bicarbonate aqueous solutions of 20mL., extract the water layer acidifying (pH＜1) that merges with 6 N HCl with 4 * 10mL EtOAc.With the EtOAc extraction liquid that merges 10mL salt water washing, use dried over sodium sulfate, and concentrate.Resistates is dissolved in the 10m L toluene.Add diphenylphosphine acylazide (0.315mL) and 0.24mL triethylamine, this mixture is spent the night 100 ℃ of stirrings, cool off then and concentrated.With resistates at BiotageHorizon, pass through purified by flash chromatography on the 40S post, use the mixture wash-out of 1 CV 5%EtOAc in hexane, use the mixture of 5-100%EtOAc in hexane to carry out linear gradient elution then, obtained this title compound with 10CV.Mass spectrum (ESI) 372.1 (M+1).
1H NMR(500MHz，CDCl
3)：δ8.02(d，J＝8Hz，1H)，7.61(d，J＝1.5Hz，1H)，7.32(dd，J＝2Hz，8Hz，1H)，6.16(s，1H)，5.39(d，J＝4Hz，1H)，3.76(dq，J＝6Hz，4.5Hz，1H)，1.62(d，J＝6Hz，3H).
On Chiralpak AD 4.6 * 250mm, analyze HPLC, with the mixture of 4% ethanol in heptane with 0.75mL/ minute wash-out (t
R=21.56 minutes, for R, R; t
R=18.00 minutes,, S), show 98%e.e for S.
Embodiment 96
(4R, 5R)-3-[3,5-two (trifluoromethyl) benzyl]-5-[2-iodo-5-(trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
To 95 mg (4R, 5R)-5-[2-iodo-5-(trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, add 20 mg sodium hydrides in 0 ℃ of solution of 3- azoles alkane-2-ketone in 1mL DMF.This mixture was stirred 10 minutes at 0 ℃; Add 94 mg 3 then, 5-two (trifluoromethyl) bromotoluene.This mixture was stirred 10 minutes at 0 ℃, then with 10mL EtOAc and the dilution of 10mL water.Separate each layer and use 10mL EtOAc to extract water.With the organic phase that merges 10mL salt water washing, use dried over sodium sulfate, and concentrate.With resistates at Biotage Horizon, pass through purified by flash chromatography on the 25M post, use the mixture wash-out of 1 CV 2%EtOAc in hexane, use the mixture of 2-100%EtOAc in hexane to carry out linear gradient elution then, obtained this title compound with 10 CV.Mass spectrum (ESI) 598.1 (M+1).
1H NMR(500MHz，CDCl
3)：δ8.00(d，J＝8.5Hz，lH)，7.77(s，1H)，7.58(br s，3H)，7.34(dd，J＝1.5Hz，8Hz，lH)，5.36(d，J＝4Hz，lH)，4.89(d，J＝16Hz，1H)，4.31(d，J＝16Hz，1H)，4.48(dq，J＝6Hz，4Hz，1H)，1.55(d，J＝6.5Hz，3H).
Embodiment 97
(4R, 5R)-3-[3,5-two (trifluoromethyl) benzyl]-5-[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
According to the method for describing among the embodiment 81, use 41mg (4R, 5R)-3-[3,5-two (trifluoromethyl) benzyl-5-[2-iodo-5-(trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone and 17mg (5-sec.-propyl-2-p-methoxy-phenyl) boric acid has obtained this title compound.Mass spectrum (ESI) 620.4 (M+1).
1H NMR signal is because atropisomerism and overlapping.
1H NMR(500MHz，CDCl
3)：δ7.53-7.80(m，5H)，7.33(d，J＝8Hz，1H)，7.21-7.29(m，1H)，7.00，6.76(d，J＝2.5Hz，1H)，6.91，6.86(d，J＝8.5Hz，0.4H)，5.15，5.10(d，J＝4.5Hz，1H)，4.80，4.74(d，J＝16Hz，1H)，4.25，4.21(d，16Hz，1H)，3.76(s，2H)，3 49(s，1H)，3.43(m，0.4H)，3.18(m，0.5H)，2.77-2.98(m，1H)，1.24(m，3H)，1.16(m，3H)，0.78，0.61(d，J＝6.5Hz，3Hz).
Embodiment 98
(4R, 5R)-3-[3,5-two (trifluoromethyl) benzyl]-5-[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
According to the method for describing among the embodiment 81, use 38.5mg (4R, 5R)-3-[3,5-two (trifluoromethyl) benzyl]-5-[2-iodo-5-(trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone and 18mg (4-fluoro-5-sec.-propyl-2-p-methoxy-phenyl) boric acid (embodiment 78) has obtained this title compound.Mass spectrum (ESI) 638.3 (M+1).
1H NMR signal is because atropisomerism and overlapping.
1HNMR(500MHz，CDCl
3)：δ7.55-7.80(m，5H)，7.29(d，J＝8Hz，1H)，7.00，6.77(d，J＝8.5Hz，1H)，6.68，6.63(d，J-12Hz，1H)，5.08，5.04(d，J～5Hz，1H)，4.81，4.75(d，J＝16Hz，1H)，4.26，4.23(d，15.5Hz，1H)，3.75(s，2H)，3.50(s，1H)，3.43(m，0.5H)，3.12-3.24(m，1.5H)，1.24，1.22(d，J～5Hz，3H)，1.17，1.06(d，J＝7Hz，3H)，0.84，0.70(d，J＝6Hz，3H).
Embodiment 99
(4S, 5S)-5-[2-iodo-5-(trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone steps A: (4R)-4-benzyl-3-{ (25,3R)-3-hydroxyl-3-[2-iodo-5-(trifluoromethyl) phenyl]-the 2-methylpropionyl }-1,3- azoles alkane-2-ketone
According to the method for describing in embodiment 95 steps A; use 0.72g 5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-(embodiment 80 for 2-formaldehyde; steps A), 0.466g (4R)-4-benzyl-3-propionyl-1; 3- azoles alkane-2-ketone, 0.02g magnesium chloride, 0.56mL triethylamine and 0.38mL chlorine trimethyl silyl have obtained this title compound.Mass spectrum (ESI) 516.2 (M-OH).
1HNMR(500MHz ， CDCl
3)：δ 8.00(d，J＝8.5Hz，1H)，7.76(d，J＝2Hz，1H)，7.22-7.32(m.4H)，7.07(br d，J＝6.5Hz，2H)，5.18(dd，J＝6.5 Hz，7.5Hz，1H)，4.67(m，1H)，4.46(dq，J＝6.5Hz，7.5Hz，1H)，4.17(t，J＝9Hz，1H)，4.11(dd，J＝3Hz，9Hz，1H)，3.97(d，J＝8Hz，1H)，3.19(dd，J＝7Hz，13.5Hz，1H)，2.57(dd，J＝9.5Hz，13.5Hz，1H)，1.34(d，J＝7.5Hz，3H).
Step B:(4S, 5S)-5-[2-iodo-5-(trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
According to the method for describing among the embodiment 95 step B; use 0.214g (4R)-4-benzyl-3-{ (25; 3R)-3-hydroxyl-3-[2-iodo-5-(trifluoromethyl) phenyl]-the 2-methylpropionyl }-1; 3- azoles alkane-2-ketone, 0.034g lithium hydroxide, 0.16mL 30% aqueous hydrogen peroxide solution, 0.1mL diphenylphosphine acylazide and 0.072mL triethylamine have obtained this title compound.Mass spectrum (ESI) 372.1 (M+1).
1H NMR(500MHz，CDCl
3)：δ8.02(d，J＝8Hz，1H)，7.61(d，J＝1.5Hz，1H)，7.32(dd，J＝2Hz，8Hz，1H)，6.16(s，1H)，5.39(d，J＝4Hz，1H)，3.76(dq，J＝6Hz，4.5Hz，1H)，1.62(d，J＝6Hz，3H).
On Chiralpak AD 4.6 * 250mm, analyze HPLC, with the mixture of 4% ethanol in heptane with 0.75mL/ minute wash-out (t
R=21.56 minutes, for R, R; t
R=18.00 minutes,, S), show 99%e.e for S.
Embodiment 100
(4S, 5S)-3-[3,5-two (trifluoromethyl) benzyl]-5-[2-iodo-5-(trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
According to the method for describing among the embodiment 96, use 0.108g (4S, 5S)-5-[2-iodo-5-(trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone, 23mg sodium hydride and 107mg 3,5-two (trifluoromethyl) bromotoluene has obtained this title compound.Mass spectrum (ESI) 598.1 (M+1).
1HNMR(500MHz，CDCl
3)：δ8.00(d，J＝8.5Hz，1H)，7.77(s，1H)，758(br s，3H)，7.34(dd，J＝1.5Hz，8Hz，1H)，5.36(d，J＝4Hz，1H)，4.89(d，J＝16Hz，1H)，4.31(d，J＝16Hz，1H)，4.48(dq，J＝6Hz，4Hz，1H)，1.55(d，J＝6.5Hz，3H)
Embodiment 101
(4S, 5S)-3-[3,5-two (trifluoromethyl) benzyl]-5-[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
According to the method for describing among the embodiment 81, use 40mg (4S, 5S)-3-[3,5-two (trifluoromethyl) benzyl]-5-[2-iodo-5-(trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone and 17mg (5-sec.-propyl-2-p-methoxy-phenyl) boric acid has obtained this title compound.Mass spectrum (ESI) 620.4 (M+1).
1H NMR signal is because atropisomerism and overlapping.
1H NMR(500MHz，CDCl
3)：δ7.53-7.80(m，5H)，7.33(d，J＝8Hz，1H)，7.21-7.29(m，1H)，7.00，6.76(d，J＝2.5Hz，1H)，6.91，6.86(d，J＝8.5Hz，0.4H)，5.15，5.10(d，J＝4.5Hz，1H)，4.80，4.74(d，J＝16Hz，1H)，4.25，4.21(d，16Hz，1H)，3.76(s，2H)，3.49(s，1H)，3.43(m，0.4H)，3.18(m，0.5H)，2.77-2.98(m，1H)，1.24(m，3H)，1.16(m，3H)，0.78，0.61(d，J＝6.5Hz，3Hz).
Embodiment 102
(4R, 5R)-5-[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
According to the method for describing among the embodiment 81, use 240mg (4R, 5R)-5-[2-iodo-5-(trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone and 171mg (4-fluoro-5-sec.-propyl-2-p-methoxy-phenyl) boric acid (embodiment 78) has obtained this title compound.Mass spectrum (ESI) 412.3 (M+1).
1H NMR signal is because atropisomerism and overlapping.
1H NMR(500MHz，CDCl
3)：δ7.79，7.77(s，1H)，7.64，7.62(dd，J-2.5Hz，8Hz，1H)，7.32，7.31(d，J-8Hz，1H)，7.00，6.95(d，J＝8.5Hz，1H)，6.70，6.67(d，J＝12Hz，1H)，6.47，6.43(s，1H)，5.08，5.04(d，J＝5Hz，0.1H)，3.68-3.80(m，3.5H)，3.53(m，0.5H)，3.21(m，1H)，1.19-1.30(m，6H)，0.95，0.77(d，J＝6Hz，3H)
According to the method for describing among the embodiment 96, by (4R, 5R)-5-[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone has made the compound of listing in table 4:
Table 4
Embodiment 111
((4R, 5S)-4-[3,5-two (trifluoromethyl) phenyl]-1-{[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-5-Methylimidazole alkane-2-subunit) cyanamide
To (1R, 2S)-1-[3,5-two (trifluoromethyl) phenyl]-N
2-[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl } the third-1,2-diamines (25.1mg, 0.0424mmol) add in the solution in ethylene dichloride (1.5mL) triethylamine (15 μ L, 0.105mmol) and cyano group azomethine diphenyl phthalate (13mg, 0.053mmol).This is reflected at 60 ℃ of heated overnight, be cooled to room temperature, filter, directly load to silicagel column to pass through purified by flash chromatography, use 10-40%EtOAc/ hexane wash-out, obtained ((4R, 5S)-4-[3,5-two (trifluoromethyl) phenyl]-1-{[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-5-Methylimidazole alkane-2-subunit) cyanamide.R
f=0.20 (25%EtOAc/ hexane).LCMS＝643.3(M+1)
+。
1HNMR (C
6D
6, 500MHz; There is atropisomer, some peak overlapping)
δ6.53-8.83(m，10H)，3.61-4.91(m，3H)，3.28-2.70(m，5H)，1.14-1.25(m，6H)，-0.39--0.26(m，3H).
Made compound in table 5 according to above-mentioned general method:
Table 5
Intermediate 1
(4S, 5S)-5-(3, the 5-difluorophenyl)-4-methyl isophthalic acid, 3- azoles alkane-2-ketone steps A: [(1S)-and 2-(3, the 5-difluorophenyl)-1-methyl-2-oxoethyl] benzyl carbamate
To (1S)-2-[methoxyl group (methyl) amino]-1-methyl-2-oxoethyl benzyl carbamate (1.96g, 7.36mmol) add in-15 ℃ of solution in THF (9.4mL) isopropylmagnesium chloride (solution of 3.6mL 2M in ether, 7.2mmol).This is reflected at-15 ℃ and stirred 15 minutes, then 3,5-difluorophenyl magnesium bromide (solution of 29.44mL 0.5 M in THF, 14.72mmol).This reaction is warmed to room temperature and stirred 24 hours.Pour this solution into saturated NH then
4In the Cl (100mL), with EtOAc extraction (3 * 100mL).With organic extract liquid water and salt water washing (being respectively 100mL), use dried over sodium sulfate, filter, and concentrate.By fast silica gel chromatogram method purifying (15%EtOAc/ hexane), obtained [(1S)-and 2-(3, the 5-difluorophenyl)-1-methyl-2-oxoethyl] benzyl carbamate.R
f=0.34 (15%EtOAc/ hexane).LCMS＝342.3(M+Na)
+。
Step B:[(1S, 2S)-2-(3, the 5-difluorophenyl)-2-hydroxyl-1-methylethyl] benzyl carbamate
To [(1S)-2-(3, the 5-difluorophenyl)-1-methyl-2-oxoethyl] benzyl carbamate (1.35g, 4.23mmol) add in-78 ℃ of solution in THF (75mL) 1-Selectride (solution of 6.35mL 1M in THF, 6.35mmol)., after 1 hour this reaction is poured in the IN HCl (50 mL)-78 ℃ of stirrings.(2 * 100mL) extract with EtOAc with this mixture.With organic extract liquid water and salt water washing (being respectively 50mL), use dried over sodium sulfate, filter, and concentrate.By fast silica gel chromatogram method purifying (5-40%EtOAc/ hexane), obtained [(1S, 2S)-2-(3, the 5-difluorophenyl)-2-hydroxyl-1-methylethyl] benzyl carbamate (principal product).LCMS＝322.3(M+1)
+。
Step C:(4S, 5S)-5-(3, the 5-difluorophenyl)-4-methyl isophthalic acid, 3- azoles alkane-2-ketone
[(1S, 2S)-2-(3, the 5-difluorophenyl)-2-hydroxyl-1-methylethyl] (900mg 2.80mmol) adds MeOH (14.3mL) and 7.5N KOH (7.2mL) to benzyl carbamate in the solution in THF (28.6mL).This is reflected at stirring at room 4 hours, uses EtOAc (2 * 75mL) extractions then.With organic extract liquid water and salt water washing (being respectively 50mL), use dried over sodium sulfate, filter, and concentrate.By fast silica gel chromatogram method purifying (10-75%EtOAc/ hexane), obtained (4S, 5S)-5-(3, the 5-difluorophenyl)-4-methyl isophthalic acid, 3- azoles alkane-2-ketone.R
f=0.07 (25%EtOAc/ hexane).
LCMS＝214.3(M+1)
+.
1H NMR(CDCl
3，500MHz)δ6.89-6.93(m，2H)，6.82(m，1H)，6.24(bs，1H)，5.01(d，J＝6.8 Hz，1H)，3.79(m，1H)，1.42(d，J＝6.2Hz，3H)
Intermediate 2
6-chloro-5-fluoro-2-iodine pyridine-3-alcohol
(307.8mg 2.08mmol) adds Na in the solution in water (11mL) to 6-chloro-5-fluorine pyridine-3-alcohol
2CO
3(441mg, 4.16mmol) and I
2(549mg, 2.08mmol).After 2 hours, this reaction mixture is acidified to pH 3 with 1N HCl,, uses NaHSO with EtOAc (100mL) dilution
3The aqueous solution and salt solution (being respectively 50mL) washing.With the organic layer dried over sodium sulfate, filter and concentrate, obtained 6-chloro-5-fluoro-2-iodine pyridine-3-alcohol.
LCMS＝273.9(M+1)
+.
1H NMR(CDCl
3，500MHz)δ7.11(d，J＝8.5Hz，1H)，5.47(d，J＝1.4Hz，1H).
Intermediate 3
2-bromo-6-pseudoallyl-3-Methoxy Pyridine
Xiang Guanzhong add 2-bromo-6-iodo-3-Methoxy Pyridine (700mg, 2.236mmol), pseudoallyl boric acid (212mg, 2.460mmol), DME (7.5mL), EtOH (2.8mL) and 1MNa
2CO
3The aqueous solution (5.6mL).This mixture is outgased with nitrogen.Add Pd (PPh
3)
4(206mg 0.179mmol), outgases this mixture once more with nitrogen.With the seal of tube, 80 ℃ of heating 16 hours.Then this solution is cooled to room temperature,, uses saturated NaHCO with EtOAc (100mL) dilution
3And salt solution (being respectively 50mL) washing.With the organic layer dried over sodium sulfate, filter, and concentrate.By fast silica gel chromatogram method purifying (0-15%EtOAc/ hexane), obtained 2-bromo-6-pseudoallyl-3-Methoxy Pyridine.R
f=0.38 (25%EtOAc/ hexane).
LCMS＝230.0(M+1)
+.
1H NMR(CDCl
3，500MHz)δ7.36(d，J＝8.5Hz，1H)，7.07(d，J＝9.4Hz，1H)，5.81(s，1H)，5.21(s，1H)，3.92(s，3H)，2.16(s，3H)
Intermediate 4
2-iodo-3-Methoxy Pyridine
(45.3mg 0.205mmol) adds Cs in the solution in DMF (3mL) to 2-iodine pyridine-3-alcohol
2CO
3(334mg, 1.030mmol) and MeI (25 μ L, 0.410mmol).After 1 hour, this reaction is poured in the water (10mL), with EtOAc (20mL) dilution, water (3 * 10mL) and salt solution (10mL) wash.With the organic layer dried over sodium sulfate, filter, and concentrate.Obtained 2-iodo-3-Methoxy Pyridine.
LCMS＝236.1(M+1)
+.
1H NMR(CDCl
3，500MHz)δ8.00(dd，J＝1.4，4.6Hz，1H)，7.20(dd，J＝4.6，8.0Hz，1H)，7.00(dd，1.4，8.3Hz，1H)，3.90(s，3H)
Intermediate 5
2-bromo-6-iodine pyridine-3-alcohol
(1.00g 5.80mmol) adds Na in the solution in water (30mL) to 2-bromopyridine-3-alcohol
2CO
3(1.23g, 11.60mmol) and I
2(1.53g, 5.80mmol).After 1 hour, should react with N HCl (20 mL) and handle,, use NaHSO with EtOAc (2 * 100mL extraction)
3The aqueous solution and salt solution (being respectively 50mL) washing.With the organic layer dried over sodium sulfate, filter and concentrate.By fast silica gel chromatogram method purifying (20-40%EtOAc/ hexane), obtained 2-bromo-6-iodine pyridine-3-alcohol.R
f=0.44 (25%EtOAc/ hexane).
LCMS＝301.9(M+1)
+.
1H NMR(CDCl
3，500MHz)δ 7.56(d，J＝8.3Hz，1H)，6.99(d，J＝8.3Hz，1H)，5.65(s，1H).
Intermediate 6
1-(2-bromo-1,3-thiazoles-5-yl) ethanol
To 2-bromo-5-formyl thiazole (100.6mg, 0.524mmol) add in 0 ℃ of solution in THF (5mL) MeMgBr (solution of 175 μ L 3M in ether, 0.524mmol).After 30 minutes, and heating MeMgBr (solution of 50 μ L 3M in ether, 0.150mmol).After 30 minutes, pour this reaction into saturated NH
4In the Cl (20mL).This mixture is extracted with EtOAc (50mL), with organic layer water and salt water washing (being respectively 25mL).With the organic layer dried over sodium sulfate, filter, and concentrate.By purified by flash chromatography (0-80%EtOAc/ hexane), obtained 1-(2-bromo-1,3-thiazoles-5-yl) ethanol.R
f=0.13 (25%EtOAc/ hexane).
LCMS＝210.0(M+1)
+.
1H NMR(CDCl
3，500 MHz)δ7.40(s，1H)，5.12(q，J＝6.4Hz，1H)，1.59(d，J＝6.4Hz，3H).
Intermediate 7
4-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl)-2-iodo-1,3-thiazoles steps A: 4-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl)-1,3-thiazoles
To 1,3-thiazoles-(311.4mg is 2.7mmol) at CH for 4-base methyl alcohol
2Cl
2(15mL) add Et in Nei the solution
3N (1.9mL, 13.6mmol).This solution is cooled to-78 ℃, and adding TBSOTf (776 μ L, 3.38mmol).This reaction is warmed to room temperature and stirred 1 hour.Should react dilution then, use saturated NaHCO with EtOAc (75 mL)
3, salt solution, 1N HCl and salt solution (being respectively 20 mL) washing.With the organic layer dried over sodium sulfate, filter, and concentrate.Resistates by fast silica gel chromatogram method purifying (0-15%EtOAc/ hexane), has been obtained 4-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl)-1,3-thiazoles.R
f=0.28 (15%EtOAc/ hexane).
LCMS＝230.1(M+1)
+.
1H NMR(CDCl
3，600MHz)δ8.77(d，J＝2.0Hz，1H)，7.25(m，1H)，4.93(d，J＝1.1Hz，2H)，0.95(s，9H)，0.12(s，6H).
Step B:4-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl)-2-iodo-1,3-thiazoles
To 4-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl)-1,3-thiazoles (106.4mg, 0.465mmol) drip in-78 ℃ of solution in THF (5mL) n-BuLi (solution of 465 μ L 1.6M in hexane, 0.744mmol).This is reflected at-78 ℃ and stirred 30 minutes, then by sleeve pipe iodine (295mg, 1.16mmol) solution in THF (5mL).This reaction is warmed to room temperature kept 15 minutes, pour NaHSO then into
3In the aqueous solution (20mL).This mixture is extracted with EtOAc (60mL).With organic layer salt solution, saturated NaHCO
3And salt solution (being respectively 20mL) washing, with the organic layer dried over sodium sulfate, filter, and concentrate.By purified by flash chromatography (15%EtOAc/ hexane), obtained 4-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl)-2-iodo-1,3-thiazoles.R
f=0.55 (15%EtOAc/ hexane).
LCMS＝356.0(M+1)
+.
1H NMR(CDCl
3，600MHz)δ7.16(s，1H)，4.86(s，2H)，0.93(s，9H)，0.10(s，6H).
Intermediate 8
(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-4-methyl-3-[2-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls)-5-(trifluoromethyl) benzyl]-1,3- azoles alkane-2-ketone
To (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[2-iodo-5-(trifluoromethyl) benzyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone (975 mg, 1.633mmol) add in the solution in DMSO (16mL) two (tetramethyl ethylene ketones), two boron (1.24g, 4.899mmol), complex compound (1: the 1) (133mg of [1,1 '-two (diphenylphosphino)-ferrocene] palladium chloride (II) and methylene dichloride, 0.1633mmol) and KOAc (320mg, 3.266mmol).This mixture is outgased with nitrogen, then 80 ℃ of heating 16 hours.Then this solution is cooled to room temperature, with EtOAc dilution (200 mL) and, use saturated NaHCO
3And salt solution (being respectively 80mL) washing.With the organic layer dried over sodium sulfate, filter via the silicon-dioxide plug, and concentrate.Resistates is passed through reverse-phase chromatography purifying (C-18,10-95%MeCN/ water contains 0.1%TFAA), obtained (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-4-methyl-3-[2-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls)-5-(trifluoromethyl) benzyl]-1,3- azoles alkane-2-ketone.
LCMS＝598.1(M+1)
+.
1H NMR(CDCl
3，500MHz)δ7.98(d，J＝7.8Hz，1H)，7.88(s，1H)，7.78(s，2H)，7.67(s，1H)，7.57(d，J＝7.8Hz，1H)，5.68(d，J＝7.5Hz，1H)，5.01(d，J＝15.6Hz，1H)，4.76(d，J＝15.5Hz，1H)，3.98-3.93(m，1H)，1.35(d，J＝6.9Hz，12H)，0.77(d，J＝6.7Hz，3H).
Embodiment 118
(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-{[3 '-sec.-propyl-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
Xiang Guanzhong adds (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[2-iodo-5-(trifluoromethyl) benzyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone (52.5mg, 0.0879mmol), 3-isopropyl benzene boric acid (17.3mg, 0.106mmol), DME (370[mu] h), EtOH (120 μ L) and 1MNa
2CO
3The aqueous solution (264 μ L, 0.264mmol).This mixture is added Pd (PPh then with the nitrogen degassing
3)
4(10.2mg, 8.8 * 10
-3Mmol), this mixture is outgased with nitrogen once more.With the seal of tube, 100 ℃ of heating 2 hours.Then this solution is cooled to room temperature, with EtOAc (50mL) dilution, water and salt solution (being respectively 15mL) washing.With the organic layer dried over sodium sulfate, filter, and concentrate.By fast silica gel chromatogram method purifying (0-15%EtOAc/ hexane), obtained (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-{[3 '-sec.-propyl-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone.Rf=0.29 (15%EtOAc/ hexane).
LCMS＝590.1(M+1)
+.
1HNMR(CDCl
3，500MHz)δ7.85(s，1H)，7.72(s，1H)，7.68(s，2H)，764(d，J＝8.0Hz，1H)，7.44(d，J＝8.0Hz，1H)，7.39(t，J＝7.6Hz，1H)，7.29(d，J＝7.8Hz，1H)，7.15(bs，1H)，7.11(bd，J＝7.5Hz，1H)，5.46(d，J＝8.0Hz，1H)，4.91(d，J＝15.7Hz，1H)，4.21(d，J＝15.8Hz，1H)，3.69(m，1H)，2.96(m，1H)，1.26-1.28(m，6H)，0.38(d，J＝6.4Hz，3H).
Embodiment 119
(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-{[4 '-fluoro-3 '-pseudoallyl-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
Xiang Guanzhong adds (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-{[3 '-chloro-4 '-fluoro-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone (embodiment 146) (30.2mg, 0.0504mmol), pseudoallyl boric acid (27mg, 0.31mmol), 1,1-two (di-t-butyl phosphino-) ferrocene palladium chloride (5.5mg, 8.4 * 10
-3Mmol), THF (350 μ L) and 1 M K
2CO
3The aqueous solution (350 μ L).With the effective nitrogen degassing, sealing was 100 ℃ of heating 5 hours.Then this solution is cooled to room temperature, with EtOAc (50mL) dilution, water and salt water washing (being respectively 15 mL).With the organic layer dried over sodium sulfate, filter, and concentrate.By fast silica gel chromatogram method purifying (0-15%EtOAc/ hexane), obtained (4S, 5R)-and 5-[3,5-two (trifluoromethyl) phenyl]-3-{[4 '-fluoro-3 '-pseudoallyl-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone.R
f=0.29 (15%EtOAc/ hexane).
LCMS＝606.2(M+1)
+.
1H NMR(CDCl
3，500MHz)δ7.86(s，1H)，7.70(s，3H)，7.64(d，J＝8.0Hz，1H)，7.42(d，J＝8.0Hz，1H)，7.23(dd，J＝7.8，2.0Hz，1H)，7.12-7.17(m，2H)，5.54(d，J＝8.0Hz，1H)，5.28(s，1H)，5.26(s，1H)，4.90(d，J＝15.8Hz，1H)，4.18(d，J＝15.8Hz，1H)，3.78(m，1H)，2.16(s，3H)，0.47 (d，J＝6.7Hz，3H).
Embodiment 120
(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-4-methyl-3-[2-(1H-pyrroles-3-yl)-5-(trifluoromethyl) benzyl]-1,3- azoles alkane-2-ketone
To (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-4-methyl-3-{5-(trifluoromethyl)-2-[1-(triisopropyl silyl)-1H-pyrroles-3-yl] benzyl }-1,3- azoles alkane-2-ketone (embodiment 149) (22.6mg, 0.0326mmol) add in 0 ℃ of solution in THF (2mL) TBAF (solution of 65 μ L 1M in THF, 0.065mmol).After 30 minutes, should react and use saturated NH
4Cl (5mL) handles.This mixture is extracted with EtOAc (35mL), with organic layer water and salt water washing (being respectively 15mL).With the organic layer dried over sodium sulfate, filter, and concentrate.By fast silica gel chromatogram method purifying (25-60%EtOAc/ hexane), obtained (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl l-4-methyl-3-[2-(1H-pyrroles-3-yl)-5-(trifluoromethyl) benzyl]-1,3- azoles alkane-2-ketone.R
f=0.11 (25%EtOAc/ hexane).
LCMS＝537.1(M+1)
+.
1H NMR(CDCl
3，600MHz)δ8.49(s，1H)，7.85(s，1H)，7.71(s，2H)，7.64(s，1H)，7.58(d，J＝S.1Hz，1H)，7.51(d，J＝8.0Hz，1H)，6.88-6.91(m，2H)，6.33(d，J＝1.6Hz，1H)，5.53(d，J＝8.0Hz，1H)，5.02(d，J＝15.7Hz，1H)，4.46(d，J＝156Hz，1H)，3.80(m，1H).0.49(d，J＝6.6Hz，3H).
Embodiment 121
(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[2-(1-sec.-propyl-1H-pyrroles-3-yl)-5-(trifluoromethyl) benzyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
To (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-4-methyl-3-[2-(1H-pyrroles-3-yl)-5-(trifluoromethyl) benzyl]-1,3- azoles alkane-2-ketone (6.8mg, 0.0127mmol) (embodiment 120) in the solution of DMSO (300 μ L), add powder KOH (3.6mg, 0.0643mmol).Stir after 15 minutes, and the adding 2-iodopropane (3.2 μ L, 0.032mmol).After 1.5 hours, add entry (5mL) in stirring at room, this mixture is at first used CH
2Cl
2(EtOAc (2 * 15mL) extractions are used in 2 * 15mL) extractions then.With the organic phase dried over sodium sulfate that merges, filter, and concentrate.By PTLC purifying resistates (25%EtOAc/ hexane), obtained (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[2-(1-sec.-propyl-1H-pyrroles-3-yl)-5-(trifluoromethyl) benzyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone.R
f=0.33 (25%EtOAc/ hexane).
LCMS＝579.2(M+1)
+.
1HNMR(CDCl
3，500MHz)δ 7.85(s，1H)，7.71(s，2H)，7.61(s，1H)，7.56(d，J＝8.0Hz，1H)，7.50(d，J＝8.0Hz，1H)，6.83(t，J＝2.1Hz，lH)，6.79(t，J＝2.5Hz，1H)，6.24(t，J＝2.3Hz，1H)，5.49(d，J＝8.0Hz，1H)，5.04(d，J＝15.5Hz，1H)，4.48(d，J＝15.6Hz，1H)，4.27(m，1H)，3.76(m，1H)，1.48(d，J＝6.6 Hz，6H)，0.49(d，J＝6.6Hz，3H).
Embodiment 122
(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-{[2 '-methoxyl group-5 '-nitro-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
To (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-{[2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, (159.4mg 0.276mmol) adds HNO in the solution in HOAc (5mL) to 3- azoles alkane-2-ketone (embodiment 143)
3(1.5 mL).After 45 minutes, add HNO again
3(1.5mL).After 45 minutes, this reaction is poured in the frozen water (30mL).This mixture with EtOAc (75mL) extraction, is used 1N NaOH, saturated NaHCO
3And salt solution (being respectively 25mL) washing.With the organic layer dried over sodium sulfate, filter, and concentrate.By fast silica gel chromatogram method purifying (8-40%EtOAc/ hexane), obtained (4S, 5R)-and 5-[3,5-two (trifluoromethyl) phenyl]-3-{[2 '-methoxyl group-5 '-nitro-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone.R
f=0.11 (25%EtOAc/ hexane).
LCMS＝623.1(M+1)
+.
1HNMR(CDCl
3，500MHz，rotamers present)δ8.34(m，1H)，8.10(m，1H)，7.85(d，J＝6.9Hz，1H)，7.61-7.71(m，4H)，7.40(m，1H)，7.11(m，1H)，5.66(d，J＝8.0Hz)，5.28(d，J＝8.2Hz)，4.89-4.94(m，1H)，3.74-4.09(m，5H)，0.61(d，J＝6.6Hz)，0.47(d，J＝6.5Hz).
Embodiment 123
(4S, 5R)-3-{[5 '-amino-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-5-[3,5-two (trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
To (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-{[2 '-methoxyl group-5 '-nitro-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, add PtO in the 3- azoles alkane-solution of 2-ketone (embodiment 122) (48.2 mg, 0.077 mmol) in EtOAc (4 mL)
2(12 mg) places (air bag) under the nitrogen atmosphere, vigorous stirring with this reaction.After 45 minutes,, wash with 100%EtOAc by removing by filter catalyzer via silica gel plug.This filtrate is concentrated, obtained (4S, 5R)-3-{[5 '-amino-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-5-[3,5-two (trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone.R
f=0.20 (40%EtOAc/ hexane).LCMS＝593.2(M+1)
+。
1H NMR (CDCl
3, there is rotational isomer in 500MHz)
δ 7.85(s，1H)，7.60-7.70(m，4H)，7.36(d，J＝7.8Hz，1H)，6.74-6.84(m，2H)，6.56(s，1H)，5.45-5.54(m，1H)，4.82-4.87(m，1H)，3.64-4.17(m，2H)，3.70(s，3H)，0.43-0.53(m，3H).
Embodiment 124
(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-{[2 '-methoxyl group-5 '-(methylthio group)-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
To (4S, 5R)-3-{[5 '-amino-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-5-[3,5-two (trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-(40mg is 0.0676mmol) at CHCl for 2-ketone (embodiment 123)
3Add in the solution in (1mL) with the nitrogen degassing methyl disulfide (10 μ L, 0.101mmol) and nitrite tert-butyl (16 μ L, 0.135mmol).This was reflected at stirring at room 30 minutes, and reflux is 2 hours then.This solution is cooled to room temperature, with hexane (3mL) dilution.This solution is directly loaded on the silicagel column, with 25%EtOAc/ hexane wash-out.To contain the level part merging of required product, by silica gel chromatography repurity, with 5-25%EtOAc/ hexane wash-out, obtained (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-{[2 '-methoxyl group-5 '-(methylthio group)-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone.R
f=0.52 (40%EtOAc/ hexane).LCMS＝624.1(M+1)
+。
1H NMR (CDCl
3, there is rotational isomer in 600MHz)
δ6.94-7.85(m，9H)，5.58(d，J＝8.1Hz)5.25(d，J＝7.8Hz)，4.94(d，J＝15.8Hz)，4.85(d，J＝15.7Hz)，3.65-4.12(m，5H)，2.47(s)，2.44(s)，0.54(d，J＝6.6Hz)，0.40(d，J＝6.6Hz).
Embodiment 125
(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-{[2 '-methoxyl group-5 '-(methylsulfinyl)-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
To (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-{[2 '-methoxyl group-5 '-(methylthio group)-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-(32.5mg is 0.0522mmol) at CH for 2-ketone (embodiment 124)
2Cl
2(5mL) add in Nei-60 ℃ of solution m-CPBA (14.6mg, 77% purity, 0.0652mmol).With this sluggish be warmed to-20 ℃, use EtOAc (35mL) dilution then, use NaHSO
3The aqueous solution, salt solution, saturated NaHCO
3And salt solution (being respectively 15mL) washing.With the organic layer dried over sodium sulfate, filter, and concentrate.By fast silica gel chromatogram purifying (20-100%EtOAc/ hexane); obtained (4S; 5R)-and 5-[3,5-two (trifluoromethyl) phenyl]-3-{[2 '-methoxyl group-5 '-(methylsulfinyl)-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone.R
f=0.10 (75%EtOAc/ hexane).
LCMS＝640.1(M+1)
+.
1H NMR(CDCl
3，600MHz)δ7.10-7.86(m，9H)，4.87-5.59(m，2H)，3.56-4.14(m，5H)，2.79(s)，2.75(s)，2.73(s)，0.61(d，J＝6.5Hz)，0.57(d，J＝6.4Hz)，0.46(d，J＝6.4Hz)，0.43(d，J＝6.5Hz).
Embodiment 126
(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-{[2 '-methoxyl group-5 '-(methyl sulphonyl)-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
To (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-{[2 '-methoxyl group-5 '-(methylthio group)-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-(7.8mg is 0.013mmol) at CH for 2-ketone (embodiment 124)
2Cl
2(1mL) add in Nei 0 ℃ of solution m-CPBA (14mg, 77% purity, 0.063mmol).This is reflected at stirring at room 30 minutes, uses EtOAc (35mL) dilution then, use NaHSO
3The aqueous solution, salt solution, saturated NaHCO
3And salt solution (being respectively 15mL) washing.With the organic layer dried over sodium sulfate, filter, and concentrate.By PTLC purifying resistates (50%EtOAc/ hexane); obtained (4S; 5R)-and 5-[3,5-two (trifluoromethyl) phenyl]-3-{[2 '-methoxyl group-5 '-(methyl sulphonyl)-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone.R
f=0.11 (40%EtOAc/ hexane).LCMS＝656.2(M+1)
+。
1H NMR (CDCl
3, there is rotational isomer in 600MHz)
δ7.99-8.02(m，1H)，7.84-7.86(m，1H)，7.75-7.78(m，1H)，7.58-7.72(m，4H)，7.38-7.42(m，1H)，7.15-7.18(m，1H)，5.55(d，J＝8.0Hz)，5.26(d，J＝8.1Hz)，4.91-4.97(m，1H)，3.63-4.03(m，5H)，3.12(s)，3.10(s)，0.62(d，J＝6.6Hz)，0.48(d，J＝6.6Hz)
Embodiment 127
(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[2-(6-pseudoallyl pyridine-2-yl)-5-(trifluoromethyl) benzyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
Steps A: 2-bromo-6-pseudoallyl pyridine
Xiang Guanzhong adds 2, the 6-dibromo pyridine (100mg, 0.422mmol), pseudoallyl boric acid (40mg, 0.464mmol), DME (1.5mL), EtOH (500 μ L) and 1M aqueous sodium carbonate (1mL, 1.0mmol).This mixture is outgased with nitrogen.Add Pd (PPh then
3)
4(37mg 0.032mmol), outgases this mixture once more with nitrogen.With the seal of tube with 100 ℃ of heating 1 hour.Then this solution is cooled to room temperature, with EtOAc (50mL) dilution, water and salt water washing (being respectively 15mL).With the organic layer dried over sodium sulfate, filter, and concentrate.By fast silica gel chromatogram method purifying (5%EtOAc/ hexane), obtained 2-bromo-6-pseudoallyl pyridine.R
f=0.45 (15%EtOAc/ hexane).
LCMS＝200.0(M+1)
+.
1H NMR(CDCl
3，500MHz)δ7.49(t，J＝7.8Hz，1H)，7.39(d，J＝7.8Hz，1H)，7.34(d，J＝8.0Hz，1H)，5.93(s，1H)，5.32(m，1H)，2.17(s，3H).
Step B:(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[2-(6-pseudoallyl pyridine-2-yl)-5-(trifluoromethyl) benzyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
Xiang Guanzhong adds 2-bromo-6-pseudoallyl pyridine (17.5mg, 0.0878mmol), (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-4-methyl-3-[2-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls)-and 5-(trifluoromethyl) benzyl]-1,3- azoles alkane-2-ketone (26.2mg, 0.0439mmol), DME (190 μ L), EtOH (62 μ L) and 1M aqueous sodium carbonate (100 μ L, 0.1mmol).This mixture is outgased with nitrogen.Add Pd (PPh then
3)
4(9mg, 7.8 * 10
-3Mmol), this mixture is outgased with nitrogen once more.With the seal of tube, 100 ℃ of heating 2 hours.Then this solution is cooled to room temperature, with EtOAc (50mL) dilution, water and salt water washing (being respectively 15mL).With the organic layer dried over sodium sulfate, filter, and concentrate.By fast silica gel chromatogram method purifying (5-25%EtOAc/ hexane), obtained (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[2-(6-pseudoallyl pyridine-2-yl)-5-(trifluoromethyl) benzyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone.R
f=0.15 (1 5%EtOAc/ hexane).
LCMS＝589.1(M+1)
+.
1HNMR(CDCl
3，500MHz)δ7.81-7.85(m，2H)，7.74(s，1H)，7.69-7.69(m，3H)，7.58(d，J＝8.0Hz，1H)，7.53(d，J＝7.7Hz，1H)，7.34(d，J＝7.6Hz，1H)，5.94(s，1H)，5.48(d，J＝7.7Hz，1H)，5.36(s，1H)，5.06(d，J＝16.0Hz，1H)，4.47(d，J＝16.1Hz，1H)，3.91(m，1H)，2.23(s，3H)，0.50(d，J＝6.6Hz，3H).
Embodiment 128
(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[2-(3-methoxyl group-6-methyl isophthalic acid-oxo pyridine-2-yl)-5-(trifluoromethyl) benzyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
To (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[2-(3-methoxyl group-6-picoline-2-yl)-5-(trifluoromethyl) benzyl]-the 4-methyl isophthalic acid, 3- azoles alkane-(7.6mg is 0.0128mmol) at CH for 2-ketone (embodiment 174)
2Cl
2(1.3mL) add in Nei 0 ℃ of solution m-CPBA (5.8mg, 77% purity, 0.0256mmol).This is reflected at stirring at room 1 hour, uses CH then
2Cl
2(10mL) NaHSO is used in dilution
3The aqueous solution, saturated K
2CO
3And salt solution (5mL respectively) washing.With the organic layer dried over sodium sulfate, filter, and concentrate.By PTLC purifying resistates (50%Et
2O/CH
2Cl
2), obtained this title compound.
R
f＝0.23(50％Et
2O/CH
2Cl
2)，LCMS＝609.2(M+1)
+.
1H NMR(CDCl
3，500MHz)δ7.85(s，1H)，7.78(d，J＝7.7Hz，1H)，7.70(s，2H)，7.62(s，1H)，7.53(d，J＝7.8Hz，1H)，7.32(d，J＝8.9Hz，1H)，7.04(d，J＝9.2Hz，1H)，5.74(d，J＝8.3Hz，1H)，4.88(d，J＝14.8Hz，1H)，4.11-3.96(m，1H)，3.88(d，J＝14.9Hz，1H)，3.86(s，3H)，2.49(s，3H)，0.65(d，J＝6.6Hz，3H).
Embodiment 129
(4S, 5R)-3-[2-(3-amino-6-isopropyl pyridine-2-yl)-5-(trifluoromethyl) benzyl]-5-[3,5-two (trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
To (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[2-(6-pseudoallyl-3-nitropyridine-2-yl)-5-(trifluoromethyl) benzyl]-the 4-methyl isophthalic acid, (19.3mg 0.0305mmol) adds 10%Pd/C (5mg) in the solution in EtOH (300 μ L) to 3- azoles alkane-2-ketone (embodiment 177).This reaction is placed (air bag) under the nitrogen atmosphere, vigorous stirring with this reaction.After 90 minutes, this mixture is loaded on the PTLC plate, and purifying (30%EtOAc/ hexane, launch twice), obtained (4S, 5R)-3-[2-(3-amino-6-isopropyl pyridine-2-yl)-5-(trifluoromethyl) benzyl]-5-[3,5-two (trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone.R
f=0.63 (the 30%EtOAc/ hexane launches twice).
LCMS＝606.2(M+1)
+.
1H NMR(CDCl
3，500MHz)δ7.84(s，1H)，7.78(8，1H)，7.72(d，J＝8.0Hz，1H)，7.69(s，2H)，7.55(d，J＝8.0Hz，1H)，7.09-7.05(m，2H)，5.53-5.52(m，1H)，4.92(d，J＝5.5Hz，1H)，4.15-4.10(m，1H)，3.89-3.78(m，1H)，3.48(s，2H)，3.00-2.95(m，1H)，1.26-1.23(m，6H)，0.44(d，J＝5.1Hz，3H).
Embodiment 130
(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[2-(3-chloro-6-isopropyl pyridine-2-yl)-5-(trifluoromethyl) benzyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
To CuCl
2(9.3mg) and nitrite tert-butyl (6.6 μ L, 0.0559mmol) be added in (4S among the MeCN (300 μ L) in the solution in MeCN (300 μ L) via sleeve pipe, 5R)-3-[2-(3-amino-6-isopropyl pyridine-2-yl)-5-(trifluoromethyl) benzyl]-5-[3,5-two (trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone (embodiment 129) (16.9mg, 0.0279mmol).This is reflected at 60 ℃ of heating 1 hour, is cooled to room temperature then, with EtOAc (20mL) dilution, water and salt water washing (8mL respectively).With the organic layer dried over sodium sulfate, filter, and concentrate.By PTLC purifying resistates (30%EtOAc/ hexane), obtained (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[2-(3-chloro-6-isopropyl pyridine-2-yl)-5-(trifluoromethyl) benzyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone.R
f=0.56 (30%EtOAc/ hexane).
LCMS＝625.1(M+1)
+.
1H NMR(CDCl
3，500MHz)δ7.85(s，1H)，7.78(d，J＝8.3Hz，1H)，7.73-7.71(m，2H)，7.68(s，2H)，7.53(d，J＝7.8Hz，1H)，7.24(d，J＝8.2Hz，1H)，5.55(d，J＝7.7Hz，1H)，5.05(d，J＝15.4Hz，1H)，3.97(d，J＝15.4Hz，1H)，3.88-3.82(m，1H)，3.17-3.08(m，1H)，1.30-1.32(m，6H)，0.53(d，J＝6.7Hz，3H).
Embodiment 131
(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[2-(2-pseudoallyl-1,3-thiazoles-4-yl)-5-(trifluoromethyl) benzyl 1-4-methyl isophthalic acid, 3- azoles alkane-2-ketone
Steps A: 4-bromo-2-pseudoallyl-1,3-thiazoles
Xiang Guanzhong adds 2,4-two bromo thiazoles (100mg, 0.411mmol), pseudoallyl boric acid (39mg, 0.452mmol), DME (1.625mL), EtOH (563 μ L) and IM aqueous sodium carbonate (1.03mL, 1.03mmol).This mixture is outgased with nitrogen.Add Pd (PPh then
3)
4(24mg 0.0206mmol), outgases this mixture once more with nitrogen.With the seal of tube with 100 ℃ of heating 2 hours.Then this solution is cooled to room temperature, with EtOAc (50mL) dilution and water and salt water washing (being respectively 15mL).With the organic layer dried over sodium sulfate, filter, and concentrate.By fast silica gel chromatogram method purifying (0-15%EtOAc/ hexane), obtained 4-bromo-2-pseudoallyl-1,3-thiazoles; NMR shows the impurity that existence is not removed.R
f=0.53 (15%EtOAc/ hexane).
LCMS＝206.0(M+1)
+.
1H NMR(CDCl
3，500MHz)δ7.13(s，1H)，5.87(s，1H)，5.33(d，J＝1.3Hz，1H)，2.21(s，3H).
Step B:(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[2-(2-pseudoallyl-1,3-thiazoles-4-yl)-5-(trifluoromethyl) benzyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
Xiang Guanzhong adds 4-bromo-2-pseudoallyl-1, the 3-thiazole (20mg, 0.097mmol), (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-4-methyl-3-[2-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls)-and 5-(trifluoromethyl) benzyl]-1,3- azoles alkane-2-ketone (29.4mg, 0.0492mmol), THF (340 μ L), 1M K
2CO
3The aqueous solution (340 μ L) and 1,1-two (di-t-butyl phosphino-) ferrocene palladium chloride (3.2mg, 4.9 * 10
-3Mmol).This mixture is outgased with nitrogen.With the seal of tube, 100 ℃ of heating 1.5 hours.Then this solution is cooled to room temperature, with EtOAc dilution (50mL) and water and salt water washing (being respectively 15mL).With the organic layer dried over sodium sulfate, filter, and concentrate.By fast silica gel chromatogram method purifying (5-25%EtOAc/ hexane), then by PTLC purifying (90%CH
2Cl
2/ hexane), obtained (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[2-(2-and propenyl-1,3-thiazoles-4-yl)-5-(trifluoromethyl) benzyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone.R
f=0.16 (15%EtOAc/ hexane).
LCMS＝595.1(M+1)
+.
1HNMR(CD
2Cl
2，500MHz)δ7.90(s，1H)，7.64-7.76(m，5H)，7.38(s，1H)，5.89(s，1H)，5.60(d，J＝8.1Hz，1H)，5.37(d，J＝1.2Hz，1H)，4.99(d，J＝16.0Hz，1H)，4.66(d，J＝16.0Hz，1H)，3.94(m，1H)，2.25(s，3H)，0.59(d，J＝6.4Hz，3H).
Embodiment 132
(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[2-[4-(hydroxymethyl)-1,3-thiazoles-2-yl]-5-(trifluoromethyl) benzyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
To (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[2-[4-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl)-1, the 3-thiazol-2-yl]-5-(trifluoromethyl) benzyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone (embodiment 178) (54.0mg, 0.0774mmol) add in 0 ℃ of solution in THF (10mL) TBAF (solution of 194 μ L 1M in THF, 0.194mmol).This is reflected at 0 ℃ stirred 30 minutes, pour saturated NH then into
4In the Cl (15mL).This mixture is extracted with EtOAc (60mL), with organic layer water and salt water washing (being respectively 15mL).With the organic layer dried over sodium sulfate, filter, and concentrate.By fast silica gel chromatogram method purifying (60%EtOAc/ hexane), obtained (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[2-[4-(hydroxymethyl)-1,3-thiazoles-2-yl]-5-(trifluoromethyl) benzyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone.R
f=0.11 (40%EtOAc/ hexane).
LCMS＝585.1(M+1)
+.
1H NMR(CDCl
3，500MHz)δ7.85(s，1H)，7.81(d，J＝8.0Hz，1H)，7.70-7.73(m，4H)，7.36(s，1H)，5.52(d，J＝8.0Hz，1H)，5.39(d，J＝15.3Hz，1H)，4.81(s，2H)，4.55(d，J＝15.3Hz，1H)，3.87(m，1H)，0.69(d，J＝6.7Hz，3H).
Embodiment 133
2-[2-((4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-4-methyl-2-oxo-1,3- azoles alkane-3-yl } methyl)-4-(trifluoromethyl) phenyl]-1,3-thiazoles-4-formaldehyde
To (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[2-[4-(hydroxymethyl)-1,3-thiazoles-2-yl]-5-(trifluoromethyl) benzyl]-the 4-methyl isophthalic acid, 3- azoles alkane-(40.9mg is 0.070mmol) at CH for 2-ketone (embodiment 132)
2Cl
2(5mL) add in Nei 0 ℃ of solution DMP (59.4mg, 0.140mmol).This reaction is warmed to room temperature and stirred 45 minutes.Next should react with EtOAc dilution (40mL), and with 1N NaOH (2 * 15mL) and salt solution (2 * 15mL) wash.With the organic layer dried over sodium sulfate, filter, and concentrate.By fast silica gel chromatogram method purifying (50%EtOAc/ hexane), obtained 2-[2-((4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-4-methyl-2-oxo-1,3- azoles alkane-3-yl } methyl)-4-(trifluoromethyl) phenyl]-1,3-thiazoles-4-formaldehyde.R
f=0.24 (40%EtOAc/ hexane).
LCMS＝583.1(M+1)
+.
1H NMR(CDCl
3，500MHz)δ10.09(s，1H)，8.33(s，1H)，7.87(s，2H)，7.82(d，J＝8.2Hz，1H)，7.79(s，2H)，7.72，(d，J＝8.1Hz，1H)，5.70(d，J＝8.0Hz，1H)，5.13(d，J＝16.0Hz，1H，4.83(d，J＝16.0Hz，1H)，4.23(m，1H)，0.75(d，J＝6.6Hz，3H).
Embodiment 134
(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[2-[4-(1-hydroxyethyl)-1,3-thiazoles-2-yl]-5-(trifluoromethyl) benzyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
To 2-[2-((4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-4-methyl-2-oxo-1,3- azoles alkane-3-yl } methyl)-4-(trifluoromethyl) phenyl]-(43.9mg is 0.075mmol) at Et for 1,3-thiazoles-4-formaldehyde (embodiment 133)
2Add in-40 ℃ of solution in the O (7.5mL) MeMgBr (solution of 30 μ L 3M in ether, 0.10mmol).Should react and closely monitor, and drip MeMgBr again and run out of until nearly all raw material aldehyde by TLC.Pour this reaction into saturated NH then
4In the Cl (15mL).This mixture is extracted with EtOAc (50mL), with organic layer water and salt water washing (being respectively 15mL).With the organic layer dried over sodium sulfate, filter, and concentrate.By fast silica gel chromatogram method purifying (5-50%EtOAc/ hexane), obtained (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[2-[4-(1-hydroxyethyl)-1, the 3-thiazol-2-yl]-5-(trifluoromethyl) benzyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone.R
f=0.17 (40%EtOAc/ hexane).
LCMS＝599.1(M+1)
+.
1H NMR(CDCl
3，500MHz)δ7.70-7.86(m，6H)，7.31-7.32(m，1H)，5.53-5.55(m，1H)，5.35-5.41(m，1H)，5.06(m，1H)，4.57-4.62(m，1H)，3.88(m，1H)，1.61-1.63(m，3H)，0.69(d，J＝6.7Hz，3H).
Embodiment 135
(4S, 5R)-3-[2-(4-ethanoyl-1,3-thiazoles-2-yl)-5-(trifluoromethyl) benzyl]-5-[3,5-two (trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
To (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[2-[4-(1-hydroxyethyl)-1,3-thiazoles-2-yl]-5-(trifluoromethyl) benzyl]-the 4-methyl isophthalic acid, 3- azoles alkane-(31.0mg is 0.052mmol) at CH for 2-ketone (embodiment 134)
2Cl
2(6mL) add in Nei 0 ℃ of solution DMP (55mg, 0.130mmol).This reaction is warmed to room temperature and stirred 45 minutes.Should react dilution then, with 1N NaOH (2 * 15mL) and salt solution (2 * 15mL) washings with EtOAc (40mL).With the organic layer dried over sodium sulfate, filter, and concentrate.By fast silica gel chromatogram method purifying (40%EtOAc/ hexane), obtained (4S, 5R)-3-[2-(4-ethanoyl-1,3-thiazoles-2-yl)-5-(trifluoromethyl) benzyl]-5-[3,5-two (trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone.R
f=0.26 (40%EtOAc/ hexane).
LCMS＝597.1(M+1)
+.
1H NMR(CDCl
3，600MHz)δ8.27(s，1H)，7.89(s，1H)，7.77-7.82(m，4H)，7.71(d，J＝7.9Hz，1H)，5.68(d，J＝7.9Hz，1H)，5.22(d，J＝16.3Hz，1H)，4.85(d，J＝16.4Hz，1H)，4.08(m，1H)，2.70(s，3H)，0.71(d，J＝6.6Hz，3H).
Embodiment 136
(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[2-[4-(1-hydroxyl-1-methylethyl)-1,3-thiazoles-2-yl]-5-(trifluoromethyl) benzyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
To (4S; 5R)-3-[2-(4-ethanoyl-1; the 3-thiazol-2-yl)-5-(trifluoromethyl) benzyl]-5-[3; 5-two (trifluoromethyl) phenyl]-the 4-methyl isophthalic acid; 3- azoles alkane-2-ketone (embodiment 135) (38.1mg; 0.064mmol) the THF/ heptane (1: 1,8mL) add in Nei-40 ℃ of solution MeMgBr (solution of 21 μ L 3M in ether, 0.07mmol).Temperature is remained on-40 ℃ to-20 ℃ also, should react and closely monitor, drip MeMgBr again and run out of until nearly all raw ketone by TLC.Pour this reaction into saturated NH then
4In the Cl (15mL).This mixture is extracted with EtOAc (50mL), with organic layer water and salt water washing (being respectively 15mL).With the organic layer dried over sodium sulfate, filter, and concentrate.By fast silica gel chromatogram method purifying (10-60%EtOAc/ hexane), obtained (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[2-[4-(1-hydroxyl-1-methylethyl)-1, the 3-thiazol-2-yl]-5-(trifluoromethyl) benzyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone.R
f=0.20 (40%EtOAc/ hexane).
LCMS＝613(M+1)
+.
1H NMR(CD
2Cl
2，500MHz)δ7.90(s，1H)，7.85(d，J＝8.0Hz，1H)，7.77(s，3H)，7.71(d，J＝8.3Hz，1H)，7.32(s，1H)，5.59(d，J＝8.0Hz，1h)，5.28(d，J＝15.8Hz，1H)，4.74(d，J＝15.8Hz，1H)，3.89(m，1H)，3.01(bs，1H)，1.63(s，3H)，1.62(s，3H)，0.64(d，J＝6.5Hz，3H).
Embodiment 137
(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[2-(4-pseudoallyl-1,3-thiazoles-2-yl)-5-(trifluoromethyl) benzyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
To (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[2-[4-(1-hydroxyl-1-methylethyl)-1, the 3-thiazol-2-yl]-5-(trifluoromethyl) benzyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone (embodiment 136) (9.5mg, 0.015mmol) add in the solution in toluene (4mL) the tosic acid monohydrate (20mg, 0.105mmol).This is reflected at 80 ℃ of heating 30 minutes, is cooled to room temperature then,, use saturated NaHCO with EtOAc (35mL) dilution
3And salt solution (being respectively 15mL) washing.With the organic layer dried over sodium sulfate, filter, and concentrate.By fast silica gel chromatogram method purifying (25%EtOAc/ hexane), obtained (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[2-(4-pseudoallyl-1,3-thiazoles-2-yl)-5-(trifluoromethyl) benzyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone.R
f=0.55 (40%EtOAc/ hexane).
LCMS＝595.1(M+1)
+.
1HNMR(CD
2Cl
2，500MHz)δ7.91(s，1H)，7.78-7.83(m，4H)，7.68(d，J＝8.5Hz，1H)，7.33(s，1H)，5.95(d，J＝0.9Hz，1H)，5.66(d，J＝8.0Hz，1H)，5.24(m，1H)，5.07(d，J＝16.4Hz，1H)，5.00(d，J＝16.3Hz，1H)，4.03(m，1H)，2.17(s，3H)，0.63(d，J＝6.4Hz，3H).
Embodiment 138
(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-{[4 '-fluoro-3 '-sec.-propyl-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
To (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-{[4 '-fluoro-3 '-pseudoallyl-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, (18.8mg 0.031mmol) adds 10%Pd/C (15mg) in the solution in EtOH (4.5mL) to 3- azoles alkane-2-ketone (embodiment 119).This reaction is placed (air bag) under the nitrogen atmosphere, vigorous stirring.After 45 minutes, by removing by filter catalyzer.This filtrate is concentrated, and resistates is passed through fast silica gel chromatogram method purifying, with 15%EtOAc/ hexane wash-out.Be further purified by PTLC, use 75%CH
2Cl
2/ hexane wash-out, obtained (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-{[4 '-fluoro-3 '-sec.-propyl-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone.R
f=0.35 (15%EtOAc/ hexane).
LCMS＝608.2(M+1)
+.
1H NMR(CDCl
3，500MHz)δ7.86(s，1H)，7.71(s，1H)，7.70(s，2H)，7.64(d，J＝8.0Hz，1H)，7.41(d，J＝8.0Hz，1H)，7.15(m，1H)，7.08-7.12(m，2H)，5.52(d，J＝8.0Hz，1H)，4.89(d，J＝15.7Hz，1H)，4.18(d，J＝15.8Hz，1H)，3 76(m，1H)，3.28(m，1H)，1.25-1.29(m，6H)，0.42(d，J＝6.4Hz，3H).
Embodiment 139
(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[2-[5-(1-methoxy ethyl)-1,3-thiazoles-2-yl]-5-(trifluoromethyl) benzyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
To (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[2-[5-(1-hydroxyethyl)-1, the 3-thiazol-2-yl]-5-(trifluoromethyl) benzyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone (embodiment 154) (13.2mg, 0.0221mmol) (solution of 26.5 μ L 1M in THF 0.0265mmol), adds MeI (1) then to add NaHMDS in 0 ℃ of solution in THF (1mL).1.5 after hour, in this reaction, add again NaHMDS (solution of 15 μ L 1M in THF, 0.015mmol) and MeI (1).This reaction is warmed to room temperature kept 20 minutes, pour saturated NH then into
4In the Cl (10mL).This mixture is extracted with EtOAc (35mL), with organic layer water and salt water washing (being respectively 15mL).With the organic layer dried over sodium sulfate, filter, and concentrate.By fast silica gel chromatogram method purifying (15-75%EtOAc/ hexane), obtained (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[2-[5-(1-methoxy ethyl)-1, the 3-thiazol-2-yl]-5-(trifluoromethyl) benzyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone.R
f=0.37 (40%EtOAc/ hexane).
LCMS＝613.0(M+1)
+.
1H NMR(CDCl
3，500MHz)δ7.87(s，1H)，7.74-7.82(m，5H)，7.67(d，J＝8.0Hz，1H)，6.63-5.66(m，1H)，5.08-5.14(m，1H)，4.83-4.88(m，1H)，4.64-4.68(m，1H)，4.01-4.08(m，1H)，3.34(m，3H)，1.60(d，J＝6.4Hz，3H)，0.69(d，J＝6.7Hz，3H).
Embodiment 140 and 141
(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[2-(1,1-titanium dioxide-1-thionaphthene-2-yl)-5-(trifluoromethyl) benzyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone and 2.2mg (15%) (4S, 5R)-and 5-[3,5-two (trifluoromethyl) phenyl]-4-methyl-3-[2-(1-oxidation-1-thionaphthene-2-yl)-5-(trifluoromethyl) benzyl]-1,3- azoles alkane-2-ketone
To (4S, 5R)-3-[2-(1-thionaphthene-2-yl)-5-(trifluoromethyl) benzyl]-5-[3,5-two (trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-(14.5mg is 0.024mmol) at CH for 2-ketone (embodiment 150)
2Cl
2(2mL) add in Nei the solution m-CPBA (16mg, 77% purity, 0.071mmol).This is reflected at stirring at room 3 hours, uses EtOAc (40mL) dilution then, use NaHSO
3The aqueous solution (15mL), saturated NaHCO
3(15mL) and salt solution (15mL) washing.With the organic layer dried over sodium sulfate, filter, and concentrate.By PTLC purifying resistates (25%EtOAc/ hexane, 2 elutriants), obtained (4S, 5R)-and 5-[3,5-two (trifluoromethyl) phenyl]-3-[2-(1,1-titanium dioxide-1-thionaphthene-2-yl)-5-(trifluoromethyl) benzyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone and 2.2mg (15%) (4S, 5R)-and 5-[3,5-two (trifluoromethyl) phenyl]-4-methyl-3-[2-(1-oxidation-1-thionaphthene-2-yl)-5-(trifluoromethyl) benzyl]-1,3- azoles alkane-2-ketone.141 data: R
f=0.09 (25%EtOAc/ hexane).
LCMS＝636.2(M+1)
+.
1H NMR(CDCl
3，500MHz)δ7.96(d，J＝8.0Hz，1H)，7.83(s，1H)，7.68-7.77(m，5H)，7.63(m，1H)，7.57(m，1H)，7.50(d，J＝7.6Hz，1H)，7.28(s，1H)，5.75(d，J＝8.0Hz，1H)，5.21(d，J＝15.8Hz，1H)，4.21(d，J＝15.8Hz，1H)，4.01(m，1H)，0.70(d，J＝6.7Hz，3H).
140 data: R
f=0.06 (25%EtOAc/ hexane).
LCMS＝620.2(M+1)
+.
1H NMR(CDCl
3，500MHz)δ7.15-7.95(m，11H)，5.72-5.75(m，1H)，5.36(d，J＝15.6Hz)，5.07(d，J＝15.8Hz)，4.41(d，J＝16.0Hz)，4.22(d，J＝15.8Hz)，3.88-4.08(m，1H)，0.68(d，J＝6.6Hz)，0.61(d，J＝6.6Hz).
Embodiment 142
(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethoxy) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
Steps A: 2-(brooethyl)-1-nitro-4-(trifluoromethoxy) benzene
Nitrosonitric acid (5mL) is cooled to 0 ℃, and adding 3-(trifluoromethoxy) bromotoluene (1mL, 6.16mmol).After 15 minutes, this reaction is poured in the frozen water (100mL), with EtOAc (200mL) extraction.With organic layer water, saturated NaHCO
3And salt solution (difference 75) washing.With the organic layer dried over sodium sulfate, filter, and concentrate.By fast silica gel chromatogram purifying resistates (0-15%EtOAc/ hexane), obtained 2-(brooethyl)-1-nitro-4-(trifluoromethoxy) benzene.R
f=0.54 (15%EtOAc/ hexane).
1H NMR(CDCl
3，500MHz)δ8.14(d，J＝8.9Hz，1H)，743(m，1H)，731(m，1H)，4.82(s，2H).
Step B:(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-4-methyl-3-[2-nitro-5-(trifluoromethoxy) benzyl]-1,3- azoles alkane-2-ketone
To (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone (840mg, 2.68mmol) add in the solution in DMA (25mL) NaHMDS (solution of 2.68mL1M in THF, 2.68mmol).This was reflected at stirring at room 5 minutes, then by sleeve pipe be added in 2-(brooethyl)-1-nitro-4-(trifluoromethoxy) benzene among the DMA (5mL) (967mg, 3.22mmol).After 15 minutes, pour this reaction into saturated NH
4In the Cl (50mL).This mixture is extracted with EtOAc (150mL), with organic layer water and salt water washing (being respectively 40mL).With the organic layer dried over sodium sulfate, filter, and concentrate.By fast silica gel chromatogram method purifying (5-25%EtOAc/ hexane), obtained (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-4-methyl-3-[2-nitro-5-(trifluoromethoxy) benzyl]-1,3- azoles alkane-2-ketone.R
f=0.10 (15%EtOAc/ hexane).
LCMS＝533.2(M+1)
+.
1H NMR(CDCl
3，500MHz)δ8.16(d，J＝8.9Hz，1H)，7.92(s，1H)，7.80(s，2H)，7.44(s，1H)，7.33(d，J＝8.9Hz，1H)，5.78(d，J＝7.8Hz，1H)，4.94(d，J＝17.0Hz，1H)，4.79(d，J＝16.9Hz，1H)，4.25(m，1H)，0.81(d，J＝6.7Hz，3H).
Step C:(4S, 5R)-3-[2-amino-5-(trifluoromethoxy) benzyl]-5-[3,5-two (trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
To (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-4-methyl-3-[2-nitro-5-(trifluoromethoxy) benzyl]-1, (1.07g 2.01mmol) adds PtO in the solution in EtOAc (30mL) to 3- azoles alkane-2-ketone
2(100mg, 0.44mmol).This reaction is placed (air bag) under the nitrogen atmosphere, vigorous stirring.After 1 hour, by removing by filter catalyzer, and this filtrate concentrated.By purified by flash chromatography (5-40%EtOAc/ hexane), obtained (4S, 5R)-3-[2-amino-5-(trifluoromethoxy) benzyl]-5-[3,5-two (trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone.R
f=0.45 (40%EtOAc/ hexane).
LCMS＝503.2(M+1)
+.
1HNMR(CDCl
3，600MHz)δ7.89(s，1H)，7.75(s，2H)，7.03(dd.J＝8.7，2.0Hz，1H)，6.90(d，J＝2.1Hz，1H)，6.67(d，J＝8.7Hz，1H)，5.67(d，J＝8.5Hz，1H)，4.73(d，J＝15.4Hz，1H)，4.35(bs，2H)，4.09(d，J＝15.4Hz，1H)，4.04(m，1H)，0.78(d，J＝6.6Hz，3H).
Step D:(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[2-iodo-5-(trifluoromethoxy) benzyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
To (4S, 5R)-3-[2-amino-5-(trifluoromethoxy) benzyl]-5-[3,5-two (trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, (582mg is 1.16mmol) at CHCl for 3- azoles alkane-2-ketone
3(35mL) add in Nei the solution nitrite tert-butyl (275 μ L, 2.32mmol).After 10 minutes, add I
2(736mg, 2.9mmol).This was reflected at stirring at room 30 minutes, then 65 ℃ of heating 2 hours.Then this solution is cooled to room temperature,, uses NaHSO with EtOAc (150mL) dilution
3The aqueous solution, water, salt solution, saturated NaHCO
3And salt solution (being respectively 50mL) washing.With the organic layer dried over sodium sulfate, filter, and concentrate.By fast silica gel chromatogram purifying resistates (2-15%EtOAc/ hexane), obtained (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[2-iodo-5-(trifluoromethoxy) benzyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone.R
f=0.30 (15%EtOAc/ hexane).
LCMS＝614.1(M+1)
+.
1H NMR(CDCl
3，500MHz)δ7.89-7.91(m，2H)，7.79(s，2H)，7.23(m，1H)，6.95(m，1H)，5.75(d，J＝8.0Hz，1H)，4.81(d，J＝15.8Hz，1H)，4.32(d，J＝15.8Hz，1H)，4.07(m，1H)，0.78(d，J＝6.6Hz，3H).
Step e: (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethoxy) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
In microwave tube, add (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[2-iodo-5-(trifluoromethoxy) benzyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone (41.6mg, 0.0679mmol), (4-fluoro-5-sec.-propyl-2-p-methoxy-phenyl) boric acid (18mg, 0.085mmol), DME (305 μ L), EtOH (100 μ L) and 1M aqueous sodium carbonate (140 μ L, 0.140mmol).This mixture is outgased with nitrogen.Add Pd (PPh then
3)
4(4mg, 3.4 * 10
-3Mmol), this mixture is outgased with nitrogen once more.With the seal of tube, under microwave, shone 10 minutes with 200W in 150 ℃.Then this solution is cooled to room temperature, with EtOAc (40mL) dilution, water and salt water washing (being respectively 15mL).With the organic layer dried over sodium sulfate, filter, and concentrate.By fast silica gel chromatogram method purifying (2-15%EtOAc/ hexane), obtained (4S, 5R)-and 5-[3,5-two (trifluoromethyl) phenyl]-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethoxy) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone.R
f=0.24 (15%EtOAc/ hexane).LCMS＝654.3(M+1)
+。
1H NMR (CDCl
3, there is rotational isomer in 500MHz)
δ7.85(s，1H)，7.69(s，2H)，7.21-7.30(m，4H)，6.95-7.00(m，1H)，6.65-6.68(m，1H)，5.59(d，J＝8.0Hz)，5.41(d，J＝8.0Hz)，4.74-4.81(m，1H)，3.75-4.09(m，5H)，3.19(m，1H)，1.16-1.27(m，6H)，0.51(d，J＝6.7Hz)，0.36(d，J＝6.6Hz).
Made compound in the table 6 by above-mentioned general method:
Table 6
Made compound in the table 7 by above-mentioned general method:
Table 7
Intermediate 9
4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl alcohol
With [2-iodo-5-(trifluoromethyl) phenyl] methyl alcohol (embodiment 69) (3.09g, 10.2mmol), (4-fluoro-5-sec.-propyl-2-p-methoxy-phenyl) boric acid (4.34g, 20.5mmol), (Ph
3P)
4Pd (1.42g, 1.23mmol) and Na
2CO
3(9.11g is 85.9mmol) at benzene/EtOH/H
2O (7: 1: 3, the 250mL) mixture in reflux 24 hours under nitrogen.After being cooled to room temperature, aqueous phase separation is come out, use CH
2Cl
2(3 * 50mL) extractions.With the organic layer drying (Na that merges
2SO
4) and vacuum concentration, obtained crude product.With it by purified by flash chromatography (Si, 65 * 200mm, the 0-20%EtOAc mixture gradient in hexane), obtained 4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl alcohol.R
f=0.50 (mixture of 20%EtOAc in hexane).
1H NMR(500MHz，CDCl
3)δ7.86(s，1H)，7.59(d，J＝6.7Hz，1H)，7.30(d，J＝7.9Hz，1H)，6.99(d，J＝8.6Hz，1H)，6.68(d，J＝12.0Hz，1H)，4.52(br s，1H)，4.46(br s，1H)，3.73(s，3H)，3.25-3.17(m，1H)，1.82(br s，1H)，1.24(d，J＝6.8Hz，6H).
Intermediate 10
2 '-(brooethyl)-4-fluoro-5-sec.-propyl-2-methoxyl group-4 '-(trifluoromethyl) biphenyl
0 ℃ under nitrogen atmosphere, (3.11g is 11.8mmol) at anhydrous CH with triphenylphosphine by sleeve pipe
2Cl
2(7mL) Nei solution be added to carbon tetrabromide (3.93g, 11.8mmol) and 4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] (3.38g is 9.87mmol) at anhydrous CH for methyl alcohol
2Cl
2(56mL) in Nei the solution that is stirring.This reaction is warmed to room temperature.After 2 hours,, obtained crude product with this reaction mixture vacuum concentration.With it by purified by flash chromatography (Si, 65 * 200mm, the 0-20%EtOAc mixture gradient in hexane), obtained 2 '-(brooethyl)-4-fluoro-5-sec.-propyl-2-methoxyl group-4 '-(trifluoromethyl) biphenyl.
1H NMR(500MHz，CDCl
3)δ7.83(s，1H)，7.61(d，J＝8.0Hz，1H)，7.35(d，J＝8.0Hz，1H)，7.15(d，J＝8.6Hz，1H)，6.72(d，J＝12.0Hz，1H)，4.43(br d，J＝10.0Hz，1H)，4.30(br d，J＝10.2Hz，1H)，3.76(s，3H)，3.30-3.22(m，1H)，1.29(d.J＝6.9Hz，6H).
Intermediate 11
5-[3,5-two (trifluoromethyl) phenyl]-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-4,4-dimethyl-1,3- azoles alkane-2-ketone
Steps A: 2-[methoxyl group (methyl) amino]-1,1-dimethyl-2-oxoethyl } benzyl carbamate
0 ℃ under nitrogen atmosphere, with N-methylmorpholine (682mg, 741 μ L, 6.74mmol) and isobutyl chlorocarbonate ((0.64g is 2.69mmol) at anhydrous CH 3.37mmol) to be added to N-carbobenzoxy-(Cbz)-2-methylalanine successively for 460mg, 441 μ L
2Cl
2In the interior solution that is stirring.The muddy mixture of gained was stirred 90 minutes at 0 ℃.Add N, (316mg 3.24mmol), is warmed to room temperature with this mixture and stirred 3 hours O-dimethyl hydroxyl amine hydrochlorate in batches.Pour this mixture into 1N HCl (30mL), use CH
2Cl
2(3 * 40mL) extractions.The extraction liquid that merges is washed dry (Na with 1N HCl (30mL)
2SO
4) and vacuum concentration, obtained crude product.It is passed through purified by flash chromatography (Si, 40 * 160mm, the 0-80%EtOAc mixture gradient in hexane), obtained 2-[methoxyl group (methyl) amino]-1,1-dimethyl-2-oxoethyl } benzyl carbamate.R
f=0.47 (mixture of 50%EtOAc in hexane).LCMS calculated value=303.1; Measured value=303.2 (M+Na)
+
1H NMR(500MHz，CDCl
3)δ7.37-7.29(m，5H)，5.82(s，1H)，5.09(s，2H)，3.60(s，3H)，3.18(s，3H)，1.60(s，6H).
Step B:(1,1-dimethyl-2-oxoethyl) benzyl carbamate
At-78 ℃ under nitrogen, with diisobutylaluminium hydride (1.77mL, the solution of 1M in toluene, 0.708mmol) add 2-[methoxyl group (methyl) amino]-1,1-dimethyl-2-oxoethyl } (198.5mg is 0.708mmol) in the solution that is stirring in anhydrous THF (7.1mL) for benzyl carbamate.This being reflected at-78 ℃ stirred 4 hours.Add MeOH (100 μ L) and 1N HCl (250 μ L), and this reaction is warmed to room temperature.With this mixture Et
2O (50mL) dilution is with 1N HCl (2 * 50mL), 50% saturated NaHCO
3(50mL) and water (50mL) washing, dry then (MgSO
4) and vacuum concentration, obtained (1,1-dimethyl-2-oxoethyl) benzyl carbamate.R
f=0.40 (mixture of 20%EtOAc in hexane).LCMS calculated value=244.1; Measured value=244.1 (M+Na)
+
1H NMR(500MHz，CDCl
3)δ9.43(s，1H)，7.38-7.30(m，5H)，5.34(s，1H)，5.09(s，2H)，1.37(s，6H).
Step C:{2-[3,5-two (trifluoromethyl) phenyl]-2-hydroxyl-1, the 1-dimethyl ethyl } benzyl carbamate
Under nitrogen, (1.63mL, the 1M solution in THF 1.63mmol) is added drop-wise to 1-iodo-3, and (608mg, 317 μ L are 1.79mmol) in the solution that is stirring in anhydrous THF (1mL) for 5-two (trifluoromethyl) benzene with ethyl-magnesium-bromide in room temperature.And should react and stir 30 minutes.At-20 ℃, (163.5mg is 0.739mmol) in the solution that is stirring in anhydrous THF (1mL) gained solution to be added to (1,1-dimethyl-2-oxoethyl) benzyl carbamate.And should react with being warmed to room temperature in 3 hours.Add saturated NH
4Cl (10mL) and water (10mL), and with this mixture with EtOAc extraction (3 * 20mL).With the extraction liquid drying (Na that merges
2SO
4) and vacuum concentration, obtained crude product.It is passed through purified by flash chromatography (Si, 25 * 160mm, the 0-40%EtOAc mixture gradient in hexane), obtained 2-[3,5-two (trifluoromethyl) phenyl]-2-hydroxyl-1, the 1-dimethyl ethyl } benzyl carbamate.R
f=0.40 (mixture of 20%EtOAc in hexane).LCMS calculated value=436.1; Measured value=436.0 (M+1)
+
1H NMR(600MHz，CDCl
3)δ7.80(s，1H)，7.77(s，2H)，7.39-7.33(m，5H)，5.12-5.08(m，2H)，1.36(s，1H)，4.90(d，J＝4.4Hz，1H)，4.81(s，1H)，1.36(s，3H)，1.23(s，3H).
Intermediate 12
[(1S)-and 2-(4-chloropyridine-2-yl)-1-methyl-2-oxoethyl] benzyl carbamate
With 2-(dimethylamino) ethanol (5.28mmol) solution in anhydrous hexane (3.3mL) is cooled to-5 ℃ for 471mg, 531mL, under nitrogen, drip n-Butyl Lithium (solution of 1.6M in hexane, 6.60mL, 10.6mmol).After 30 minutes, this solution is cooled to-78 ℃ 0 ℃ of maintenance, drips the 4-chloropyridine (by (264mg is 1.76mmol) at CH with corresponding HCl salt by sleeve pipe
2Cl
2The saturated K of solution (20mL)
2CO
3(10mL) CH is used in washing then
2Cl
2(2 * 20mL) strip, and merge organic layer, dry (Na
2SO
4) and vacuum concentration obtain) solution in hexane (3.3mL) is at-78 ℃ after 1 hour, this solution becomes scarlet.By sleeve pipe add electrophilic reagent solution (by-15 ℃ under nitrogen with the isopropylmagnesium chloride (solution of 2M in THF, 1.29mL, 2.59mmol) be added to (1S)-2-[methoxyl group (methyl) amino]-1-methyl-2-oxoethyl benzyl carbamate (702mg, 2.64mmol) in the solution in anhydrous THF (3.5mL) and stirred 15 minutes and prepare).Be warmed to room temperature also keeps spending the night with allowing this sluggish.Add entry (25mL) and saturated NH
4Cl (50mL), and with this mixture EtOAc (3 * 50mL) extractions.With the extraction liquid drying (MgSO that merges
4) and vacuum concentration, obtained crude product.It is passed through purified by flash chromatography (Si, 40 * 160mm, the 0-30%EtOAc mixture gradient in hexane), obtained [(1S)-and 2-(4-chloropyridine-2-yl)-1-methyl-2-oxoethyl] benzyl carbamate.R
f=0.46 (mixture of 20%EtOAc in hexane).LCMS calculated value=319.1; Measured value=319.3 (M+1)
+
1H NMR(500MHz，CDCl
3)δ8.58(d，J＝5.0Hz，1H)，8.04(s，1H)，7.47(dd，J＝5.2，2.0Hz，1H)，7.35-7.30(m，5H)，5.78(s，1H)，5.72(m，1H)，5.11(m，2H)，1.47(d，J＝7.0Hz，3H).
Intermediate 13
[(1S)-and 1-methyl-2-oxo-2-(1,3-thiazoles-2-yl) ethyl] benzyl carbamate
-78 ℃ under nitrogen, ((462mg, 251 μ L 2.82mmol) in the solution that is stirring in anhydrous THF (13mL), stirred 45 minutes 2.83mmol) to be added drop-wise to the 2-bromo thiazole for the solution of 1.6M in hexane, 1.76mL with n-Butyl Lithium.Individually, at-15 ℃ under nitrogen, with the isopropylmagnesium chloride (solution of 2M in THF, 0.94mL, 1.99mmol) be added to (1S)-2-[methoxyl group (methyl) amino]-1-methyl-2-oxoethyl } (500mg is 1.88mmol) in the solution that is stirring in anhydrous THF (4mL) for benzyl carbamate.This solution was stirred 15 minutes at-15 ℃, be added drop-wise in the above-mentioned 2-lithiumation thiazole solution at-78 ℃.This reaction is warmed to ambient temperature overnight, adds saturated NH
4Cl (20mL) and water (10mL), and with this mixture EtOAc (3 * 30mL) extractions.With the extraction liquid salt water washing that merges, dry (Na
2SO
4) and vacuum concentration, obtained crude product.It is passed through purified by flash chromatography (Si, 25 * 160mm, the 0-50%EtOAc mixture gradient in hexane), obtained [(1S)-and 1-methyl-2-oxo-2-(1,3-thiazoles-2-yl) ethyl] benzyl carbamate.R
f=0.28 (mixture of 20%EtOAc in hexane).LCMS calculated value=291.1; Measured value=291.3 (M+1)
+
1H NMR(600MHz，CDCl
3)δ8.03(s，1H)，7.70(d，J＝3.1Hz，1H)，7.34-7.29(m，5H)，5.79(d，J＝6.6Hz，1H)，5.53-5.49(m，1H)，5.14-5.08(m，2H)，1.55(d，J＝6.4Hz，3H).
Intermediate 14
[(1S)-and 1-methyl-2-(1-methyl isophthalic acid H-imidazol-4 yl)-2-oxoethyl] benzyl carbamate
Will (1S)-2-[methoxyl group (methyl) amino]-1-methyl-2-oxoethyl } (64mg is 0.24mmol) at CH for benzyl carbamate
2Cl
2Solution (1mL) is cooled to-20 ℃ under nitrogen, drip isopropylmagnesium chloride (solution of 120 μ L 2.0M in THF).This mixture was stirred 20 minutes at-20 ℃.In an independent flask, (109mg is 0.48mmol) at anhydrous CH in room temperature ethylmagnesium bromide (solution of 480 μ L2.0M in ether) to be added to 4-iodo-1-methyl isophthalic acid-H-imidazoles
2Cl
2(1.5mL) in Nei the solution.The gained mixture was stirred 20 minutes, add above-mentioned solution lentamente by sleeve pipe then.The gained solution stirring is spent the night.With saturated NH
4Cl adds in this reaction soln, with this mixture dilute with water, with water CH
2Cl
2(2 * 25mL) extractions.With the organic extract liquid drying (Na that merges
2SO
4) and vacuum concentration.By the purified by flash chromatography resistates, obtained [(1S)-and 1-methyl-2-(1-methyl isophthalic acid H-imidazol-4 yl)-2-oxoethyl] benzyl carbamate.LCMS calculated value=288.14; Measured value=288.3 (M+1)
+
1H NMR(500MHz，CDCl
3)δ7.65(s，1H)；7.47(s，1H)；7.35-7.28(m，5H)；5.93(d，J＝6.9Hz，1H)；5.29-5.25(m，1H)；5.13(s，2H)；3.73(s，3H)；1.26(d，J＝7.1Hz，3H).
Intermediate 15
((1S)-2-{1-[(benzyloxy) methyl]-1H-imidazoles-2-yl }-1-methyl-2-oxoethyl) benzyl carbamate
Steps A: the methyl 1-[(benzyloxy)]-the 1H-imidazoles
With monochloromethyl-ether (4.3mL, 29mmol) and imidazoles (6g, 58mmol) mixture heating up in acetonitrile (200mL) refluxed 3.5 hours.Solvent removed in vacuo.Gained oily resistates at CH
2Cl
2(300mL) and between the water (150mL) distribute.Then with organic extract liquid water (2 * 150mL) washings, dry (Na
2SO
4) and vacuum concentration, obtained the 1-[(benzyloxy) methyl]-the 1H-imidazoles, need not be further purified and directly use.LCMS calculated value=189.10; Measured value=189.1 (M+1)
+
1H NMR(500MHz，CDCl
3)δ7.63(s，1H)；7.40-7.30(m，5H)；7.16(t，J＝6.5Hz，1H)；7.09(t，J＝10.6Hz，1H)；5.34(s，2H)；4.45(s，2H).
Step B:((1S)-and the 2-{1-[(benzyloxy) methyl]-1H-imidazoles-2-yl }-1-methyl-2-oxoethyl) benzyl carbamate
At-78 ℃ under nitrogen, to the 1-[(benzyloxy) methyl]-(706mg 3.75mmol) adds n-Butyl Lithium (solution of 2.3mL1.6M in hexane) to the 1H-imidazoles in the solution in THF (4mL).This mixture was stirred 30 minutes at-78 ℃.-15 ℃ under nitrogen, to (1S)-2-[methoxyl group (methyl) amino]-1-methyl-2-oxoethyl (200mg 0.75mmol) adds isopropylmagnesium chloride (solution of 375 μ L2.0M in THF) to benzyl carbamate in the solution in THF (2mL).The gained mixture was stirred 15 minutes at-15 ℃.At-78 ℃, this mixture is added in the above-mentioned solution by sleeve pipe.This mixture-78 ℃ of stir abouts 3 hours, is warmed to room temperature then gradually, and stirring is spent the night.With the saturated NH of this mixture
4Cl handles.With water layer CH
2Cl
2(3 * 25mL) extractions.Organic layer is merged dry (Na
2SO
4) and vacuum concentration.Resistates is passed through purified by flash chromatography, obtained ((1S)-2-{1-[(benzyloxy) methyl]-1H-imidazoles-2-yl-1-methyl-2-oxoethyl) benzyl carbamate, contain the 30% unreacted raw material of having an appointment (1S)-2-[methoxyl group (methyl) amino]-1-methyl-2-oxoethyl benzyl carbamate.This mixture need not be further purified be directly used in next step.LCMS calculated value=394.18; Measured value=394.2 (M+1)
+
Intermediate 16
2-bromo-4,5-two chloro-1-methyl isophthalic acid H-imidazoles
With 2-bromo-4, the 5-dichloro-imidazole (1g, 4.6mmol), methyl-iodide (346 μ L, 5.56mmol), salt of wormwood (1.27g, 9.2mmol) and Tetrabutylammonium bromide (148mg, 0.46mmol) mixture in acetonitrile (2mL) was 70-80 ℃ of vigorous stirring 1.0 hours.After being cooled to room temperature, filter out inorganic salt, wash with acetonitrile.Pass through purified by flash chromatography (Si) with the filtrate evaporation and with resistates, obtained 2-bromo-4,5-two chloro-1-methyl isophthalic acid H-imidazoles are white solid.LCMS calculated value=230.89; Measured value=230.9 (M+1)
+
1H NMR(500MHz，CDCl
3)δ3.61(s，3H).
Intermediate 17
4-iodo-1-methyl isophthalic acid H-pyrazoles
(132mg is 0.5mmol) at Et to 18-hat-6 under nitrogen
2Add in the solution in the O (8mL) potassium tert.-butoxide (616mg, 5.5mmol).This mixture is stirred, the disposable adding 4-of room temperature iodine pyrazoles (1g, 5mmol).This reaction is cooled to 0 ℃, and (342 μ L are 5.5mmol) at Et to drip methyl iodide at 0 ℃
2Solution in the O (2mL).The gained mixture is warmed to room temperature, and stirring is spent the night.With this solution with water dilution, use Et then
2O (2 * 50mL) extractions.The organic layer that merges is washed with salt solution (45mL), with anhydrous sodium sulfate drying and vacuum concentration.By purified by flash chromatography, obtained 4-iodo-1-methyl isophthalic acid H-pyrazoles.LCMS calculated value=208.96; Measured value=209.0 (M+1)
+
1H NMR(500MHz，CDCl
3)δ 7.52(s，1H)；7.43(s，1H)；3.95 (s，3H).
Intermediate 18
3-iodo-1-methyl isophthalic acid H-pyrazoles
(250mg is 2.57mmol) with nitrite tert-butyl (336 μ L, 2.83mmol) reflux 3 hours in methylene iodide (5mL) with 1-methyl isophthalic acid-H-pyrazoles-3-amine.Solvent removed in vacuo and volatile matter by purified by flash chromatography gained resistates (Si), have obtained 3-iodo-1-methyl isophthalic acid H-pyrazoles.LCMS calculated value=208.96; Measured value=209.0 (M+1)
+
1H NMR(500MHz，CDCl
3)δ7.21(d，J＝2.1Hz，1H)；6.42(d，J＝2.2Hz，1H)；3.94(s，3H).
Intermediate 19,20
(4S, 5S)-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-4-methyl-5-(1-methyl isophthalic acid H-tetrazolium-5-yl)-1,3- azoles alkane-2-ketone and (4S, 5S)-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-4-methyl-5-(2-methyl-2H-tetrazolium-5-yl)-1,3- azoles alkane-2-ketone
Steps A: [(1S, 2S)-the 2-{[tertiary butyl (dimethyl) silyl] the oxygen base-1-methyl-2-(1H-tetrazolium-5-yl) ethyl] benzyl carbamate and [1S, 2S)-the 2-{[tertiary butyl (dimethyl) silyl] the oxygen base-1-methyl-2-(2H-tetrazolium-5-yl) ethyl] benzyl carbamate
With ((1S, 2S)-and the 2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-2-cyano group-1-methylethyl) benzyl carbamate (106.6mg, 0.306mmol), triethylamine hydrochloride (211mg, 1.53mmol) and sodiumazide (99.4mg, 1.56mmol) mixture in dry toluene (6mL) reflux 20 hours under nitrogen, kept 2 days in room temperature.Should react dilution, with EtOAc (3 * 20mL) extractions with 1N HCl (20mL).With the extraction liquid drying (Na that merges
2SO
4) and vacuum concentration, obtained crude product.It need not be further purified direct use.LCMS calculated value=392.2; Measured value=392.1 (M+1)
+
Step B:[(1S, 2S)-the 2-{[tertiary butyl (dimethyl) silyl] the oxygen base-1-methyl-2-(1-methyl isophthalic acid H-tetrazolium-5-yl) ethyl] benzyl carbamate and [(1S, 2S)-the 2-{[tertiary butyl (dimethyl) silyl] the oxygen base-1-methyl-2-(2-methyl-2H-tetrazolium-5-yl) ethyl] benzyl carbamate
In room temperature under nitrogen, with (trimethyl silyl) diazomethane (solution of 2M in hexane, 459 μ L, 0.918mmol) be added drop-wise to [(1S, 2S)-and the 2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-1-methyl-2-(1H-tetrazolium-5-yl) ethyl] benzyl carbamate and [{ 1S, 2S)-the 2-{[tertiary butyl (dimethyl) silyl] the oxygen base-1-methyl-2-(2H-tetrazolium-5-yl) ethyl] the benzyl carbamate crude product methylene chloride (3: 2,5mL) in Nei the solution.After 15 minutes, gas release stops, and with this reaction mixture vacuum concentration, has obtained crude product.It is passed through purified by flash chromatography (Si, 12 * 160mm, the mixture gradient of 0-70%EtOAc in hexane), obtained [(1S, 2S)-and the 2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-1-methyl-2-(1-methyl isophthalic acid H-tetrazolium-5-yl) ethyl] benzyl carbamate and [(1S, 2S)-and the 2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-1-methyl-2-(2-methyl-2H-tetrazolium-5-yl) ethyl] benzyl carbamate, be 2: 1 mixtures of regional isomer.LCMS calculated value=406.2; Measured value=406.2 (M+1)
+
Step C:[(1S, 2S)-2-hydroxyl-1-methyl-2-(2-methyl-2H-tetrazolium-5-yl) ethyl] benzyl carbamate and [(1S, 2S)-2-hydroxyl-1-methyl-2-(1-methyl isophthalic acid H-tetrazolium-5-yl) ethyl] benzyl carbamate.
At 0 ℃, with tetrabutylammonium (1M, solution in THF, 177 μ L, 0.177mmol) be added drop-wise to [(1S, 2S)-and the 2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-1-methyl-2-(1-methyl isophthalic acid H-tetrazolium-5-yl) ethyl] benzyl carbamate and [(1S, 2S)-and the 2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-1-methyl-2-(2-methyl-2H-tetrazolium-5-yl) ethyl] benzyl carbamate (2: 1 mixtures of regional isomer, 65.2mg, 0.161mmol) in the solution that is stirring in THF (2mL).This is reflected at 0 ℃ stirred 2 hours, use saturated NH
4Cl (10mL) dilution is with EtOAc (3 * 30mL) extractions.With the extraction liquid drying (Na that merges
2SO
4) and vacuum concentration, obtained crude product.It is passed through purified by flash chromatography (Si, 12 * 160mm, the mixture gradient of 0-80%EtOAc in hexane), obtained [(1S, 2S)-2-hydroxyl-1-methyl-2-(2-methyl-2H-tetrazolium-5-yl) ethyl] benzyl carbamate and [(1S, 2S)-2-hydroxyl-1-methyl-2-(1-methyl isophthalic acid H-tetrazolium-5-yl) ethyl] benzyl carbamate.2-methyl isomer (intermediate 20): LCMS calculated value=292.1; Measured value=292.1 (M+1)
+
1H NMR(500MHz，CDCl
3)δ7.33-7.29(m，5H)，5.59(d，J＝8.5Hz，1H)，5.09-5.00(m，5H)，4.49(m，1H)，4.26(s，3H)，1.07(d，J＝6.9Hz，3H).
1-methyl isomer (intermediate 19): LCMS calculated value=292.1; Measured value=292.1 (M+1)
+
1H NMR(500MHz，CDCl
3)δ7.33-7.29(m，5H)，5.72(s，1H)，5.07(m，3H)，4.99(m，2H)，4.18(m，1H)，4.10(s，3H)，1.24(d，J＝6.7Hz，3H).
Embodiment 196
(4S, 5R)-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-4-methyl-5-pyridin-4-yl-1,3- azoles alkane-2-ketone
Steps A: [(1S)-and 1-methyl-2-oxo-2-pyridin-4-yl ethyl] benzyl carbamate
At-15 ℃ under nitrogen, with isopropylmagnesium chloride (1.6mL, the solution of 1M in THF, 3.23mmol) be added drop-wise to (1S)-2-[methoxyl group (methyl) amino]-1-methyl-2-oxoethyl } (embodiment 17 for benzyl carbamate, (879mg is 3.30mmol) in the solution that is stirring in anhydrous THF (4.2mL) for step 1).This being reflected at-15 ℃ stirred 30 minutes, then by by drip the solution of 4-pyridyl magnesium bromide in anhydrous THF (by room temperature under nitrogen with ethylmagnesium bromide (6mL, the solution of 2M in THF, 6.00mmol) be added to the 4-iodine pyridine (1.35g, 6.60mmol) in the solution that is stirring in anhydrous THF (45mL) and stir made in 30 minutes).This reaction is warmed to room temperature and stirred 5 hours.Add 1N HCl (15mL) with stopped reaction, use saturated NaHCO
3This mixture is adjusted to alkaline pH.With this mixture with EtOAc (2 * 50mL) and CH
2Cl
2(3 * 50mL) extractions.With EtOAc and CH
2Cl
2Extraction liquid is used the salt water washing respectively, dry (Na
2SO
4), merging, vacuum concentration has obtained crude product.It is passed through purified by flash chromatography (Si, 40 * 160mm, the 0-100%EtOAc mixture gradient in hexane), obtained [(2R)-and 1-methyl-2-oxo-2-pyridin-4-yl ethyl] benzyl carbamate, be colorless solid.R
f=0.33 (50%EtOAc/ hexane).LCMS calculated value=285.1; Measured value=285.3 (M+1)
+
1H NMR(500MHz，CDCl
3)δ8.85(d，J＝3.3Hz，2H)，7.76(d，J＝5.5Hz，2H)，7.36-7.32(m，5H)，5.70(d，J＝6.8Hz，1H)，5.31-5.25(m，1H)，5.13(s，2H)，1.43(s，3H).
Step B:[(1S, 2R)-2-hydroxyl-1-methyl-2-pyridin-4-yl ethyl] benzyl carbamate
-78 ℃ under nitrogen, (964mg, (539.1mg is 1.90mmol) in the solution in anhydrous EtOH (40mL) for benzyl carbamate 3.79mmol) to be added to [(2R)-1-methyl-2-oxo-2-pyridin-4-yl ethyl] with three tert.-butoxy lithium aluminium hydride.This being reflected at-78 ℃ stirred 2 hours.Add 2% acetic acid aqueous solution with stopped reaction, use saturated NaHCO
3(about 50mL) is adjusted to alkaline pH with this mixture.(3 * 100mL) extractions are washed the extraction liquid that merges with salt solution (50mL), dry (Na with EtOAc with this mixture
2SO
4) and vacuum concentration, obtained crude product.It is passed through purified by flash chromatography (Si, 40 * 160mm, the 0-100%EtOAc mixture gradient in hexane), obtained [(1S, 2R)-2-hydroxyl-1-methyl-2-pyridin-4-yl ethyl] benzyl carbamate, be colorless solid.R
f＝0.49(EtOAc)。LCMS calculated value=287.1; Measured value=287.3 (M+1)
+
1H NMR(500MHz，CDCl
3)δ8.41(d，J＝5.7Hz，2H)，7.36-7.32(m，7H)，5.27(d，J＝7.4Hz，1H)，5.10(s，2H)，4.89(s，1H)，4.02(br s，1H)，0.96(d，J＝6.7Hz，3H).
Step C:(4S, 5R)-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-4-methyl-5-pyridin-4-yl-1,3- azoles alkane-2-ketone
In room temperature under nitrogen, with sodium hydride (52.4mg, 60% dispersion liquid in mineral oil 1.31mmol) is added to [(1S, 2R)-and 2-hydroxyl-1-methyl-2-pyridin-4-yl ethyl] (150mg is 0.524mmol) in the solution in anhydrous THF (6mL) for benzyl carbamate.In stirring at room after 30 minutes, by sleeve pipe add 2-(brooethyl)-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl (255mg, 0.629mmol) solution in anhydrous THF (3mL).With this reaction mixture in stirred overnight at room temperature.Add saturated NH
4Cl (10mL), (3 * 20mL) extract with EtOAc with this mixture.With the extraction liquid drying (Na that merges
2SO
4) and vacuum concentration, obtained crude product.It is passed through purified by flash chromatography (Si, 25 * 160mm, the mixture gradient of 0-70%EtOAc in hexane), obtained (4S, 5R)-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-4-methyl-5-pyridin-4-yl-1,3- azoles alkane-2-ketone is colorless oil.R
f＝0.49(EtOAc)。LCMS calculated value=503.2; Measured value=503.3 (M+1)
+ 1H NMR (600MHz, CDCl
3, 1: 1 mixture of atropisomer)
δ8.61(d，J＝4.1Hz，2H)，7.68(s，0.5H)，7.61(s，1H)，7.60(s，0.5H)，7.33(dd，J＝7.4，3.8，Hz 1H)，7.16(br s，2H)，6.97(dd，J＝17.8，8.4Hz，1H)，6.67(dd，J＝12.0，3.4Hz，1H)，5.44(d，J＝8.2Hz，0.5H)，5.28(d，J＝8.0Hz，0.5H)，4.79(d，J＝15.8Hz，0.5H)，4.76(d，J＝15.8Hz，0.5H)，4.15-4.09(m，1H)，3.88(d，J＝15.8Hz，0.5H)，3.79-3.70(m，0.5H)，3.74(s，3H)，3.23-3.17(m，1H)，1.26-1.16(m，6H)，0.52(d，J＝6.5Hz，1.5H)，0.38(d，J＝6.5Hz，1.5H).
Embodiment 197
(4S, 5S)-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-4-methyl-5-(4-methyl isophthalic acid, 3-thiazol-2-yl)-1,3- azoles alkane-2-ketone
Steps A: [(1S)-and 1-methyl-2-oxoethyl] benzyl carbamate
-78 ℃ under nitrogen, ((790mg, 543 μ L are 6.23mmol) at anhydrous CH 12.9mmol) to be added drop-wise to oxalyl chloride for 1.01g, 918 μ L with dimethyl sulfoxide (DMSO)
2Cl
2(12.6mL) in Nei the solution that is stirring, should react and stir 15 minutes.(965mg is 4.61mmol) at anhydrous CH for carbamate to drip [(1S)-2-hydroxyl-1-methylethyl] by sleeve pipe
2Cl
2(12.6mL) Nei solution stirs this mixture 30 minutes at-78 ℃.(1.34g, 1.85mL 13.2mmol), are warmed to room temperature with this reaction and stirred 2 hours to add triethylamine.Add entry (15mL), isolate water, use CH
2Cl
2(3 * 15mL) extractions.With the saturated NaHCO of organic extract liquid that merges
3With the salt water washing, dry then (MgSO
4) and vacuum concentration, obtained [(1S)-and 1-methyl-2-oxoethyl] benzyl carbamate, be colorless oil.R
f=0.75 (mixture of 50%EtOAc in hexane).
1H NMR(500MHz，CDCl
3)δ9.58(s，1H)，7.39-7.35(m，5H)，5.39(br s，1H)，5.15(s，2H)，4.33(m，1H)，1.40(d，J＝7.1Hz，3H).
Step B:[(1, S)-2-cyano-2-hydroxy--1-methylethyl] benzyl carbamate
At-78 ℃ under nitrogen, with diethyl cyaniding aluminium (4.53mL, the solution of 1M in toluene, 4.53mmol) be added drop-wise to [(1S)-and 1-methyl-2-oxoethyl] (0.853g is 4.12mmol) in the solution that is stirring in dry toluene (33mL) for benzyl carbamate.This mixture was stirred 6 hours at-78 ℃, be warmed to ambient temperature overnight then.Add saturated NH
4Cl (20mL) and water (10mL), (3 * 50mL) extract with EtOAc with this mixture then.With the extraction liquid drying (Na that merges
2SO
4) and vacuum concentration, obtained crude product.It is passed through purified by flash chromatography (Si, 40 * 160mm, the 0-40%EtOAc mixture gradient in hexane), obtained [(1, S)-2-cyano-2-hydroxy--1-methylethyl] benzyl carbamate, be 3: 1 mixtures of diastereomer.R
f=0.63 (mixture of 50%EtOAc in hexane).LCMS calculated value=257.1; Measured value=257.1 (M+1)
+ 1H NMR (500MHz, CDCl
3) main diastereomer:
δ7.39-7.31(m，5H)，5.11(m，2H)，4.60br(s，1H)，3.96(m，1H)，1.34(d，J＝6.7Hz，3H)，
Less important diastereomer:
δ7.39-7.31(m，5H)，5.14(m，2H)，4.50br(s，1H)，4.10(m，1H)，1.30(d，J＝7.0Hz，3H).
Step C:((1S, 2S)-the 2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-2-cyano group-1-methylethyl) benzyl carbamate
In room temperature under nitrogen, tert-butyldimethylsilyl chloride (471mg, 3.12mmol) and imidazoles (483mg, (665mg is 2.84mmol) at anhydrous CH for benzyl carbamate 7.10mmol) to be added to [(1S)-2-cyano-2-hydroxy--1-methylethyl] successively
2Cl
2(13mL) in Nei the solution that is stirring.This mixture stirring is spent the night.Add entry (30mL), with this mixture Et
2O (3 * 30mL) extractions.With the extraction liquid drying (MgSO that merges
4) and vacuum concentration, obtained crude product.It is passed through purified by flash chromatography (Si, 40 * 160mm, the mixture gradient of 0-15%EtOAc in hexane), obtained ((1S, 2R)-the 2-{[tertiary butyl (dimethyl) silyl] the oxygen base-2-cyano group-1-methylethyl) benzyl carbamate and ((1S, 2S)-the 2-{[tertiary butyl (dimethyl) silyl] the oxygen base-2-cyano group-1-methylethyl) benzyl carbamate.(1S, 2R)-diastereomer: R
f=0.29 (mixture of 10%EtOAc in hexane).LCMS calculated value=349.2; Measured value=349.1 (M+1)
+
1H NMR(500MHz，CDCl
3)δ7.39-7.33(m，5H)，5.16(d，J＝12.1Hz，1H)，5.07(d，J＝12.1Hz，1H)，4.89(brd，J＝6.6Hz，1H)，4.68(br，d，3.6Hz，1H)，3.92(m，1H)，1.31(d，J＝6.7Hz，3H)，0.91(s，9H)，0.21(s，3H)，0.17(s，3H).
(1S, 2S)-diastereomer: R
f=0.24 (mixture of 10%EtOAc in hexane).LCMS calculated value=349.2; Measured value=349.1 (M+1)
+
1H NMR(500MHz，CDCl
3)δ7.38-7.32(m，5H)，5.10(s，2H)，4.76(br d，J＝6.9Hz，1H)，4.63(br s，1H)，4.00(m，1H)，1.31(d，J＝6.8Hz，3H)，0.90(d，J＝2.9Hz，9H)，0.17(s，3H)，0.08(s，3H).
Step D:((1S, 2S)-the 3-amino-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-1-methyl-3-sulfo-propyl group) benzyl carbamate
Will ((1S, 2S)-the 2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-2-cyano group-1-methylethyl) and benzyl carbamate (115.6mg, 0.287mmol), the mixture of phosphorodithioic acid diethyl ester (1mL) and water (3) is in stirred overnight at room temperature.With this reaction mixture at saturated NaHCO
3(40mL) and between the EtOAc (40mL) distribute.Isolate water layer, with EtOAc (2 * 40mL) extractions.With the extraction liquid drying (Na that merges
2SO
4) and vacuum concentration, obtained crude product.It is passed through purified by flash chromatography (Si, 12 * 160mm, the 0-40%EtOAc mixture gradient in hexane), obtained ((1S, 2S)-and the 3-amino-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-1-methyl-3-sulfo-propyl group) benzyl carbamate, be colorless oil.R
f=0.30 (mixture of 20%EtOAc in hexane).LCMS calculated value=383.2; Measured value=383.1 (M+1)
+
1H NMR(500MHz，CDCl
3)δ8.36(s，1H)，7.87(s，1H)，7.37-7.29(m，5H)，5.13(m，2H)，4.85(d，J＝8.2Hz，1H)，4.72(s，1H)，4.47(m，1H)，1.05(d，J＝6.7Hz，3H)，0.96(s，9H)、0.08(s，3H)，0.07(s，3H).
Step e: [(1S, 2S)-2-hydroxyl-1-methyl-2-(4-methyl isophthalic acid, 3-thiazol-2-yl) ethyl] benzyl carbamate
With ((1S, 2S)-and the 3-amino-2-{[tertiary butyl (dimethyl) silyl] the oxygen base }-1-methyl-3-sulfo-propyl group) benzyl carbamate (96.8mg, 0.253mmol) and monochloroacetone (117mg, 101 μ L, 1.27mmol) solution in anhydrous EtOH (5mL) reflux 20 hours under nitrogen, then stirring at room 2 days.With this reaction mixture vacuum concentration, obtained crude product.It is passed through purified by flash chromatography (Si, 12 * 160mm, the 0-100%EtOAc mixture gradient in hexane), obtained [(1S, 2S)-2-hydroxyl-1-methyl-2-(4-methyl isophthalic acid, 3-thiazol-2-yl) ethyl] benzyl carbamate.R
f=0.44 (mixture of 50%EtOAc in hexane).LCMS calculated value=307.1; Measured value=307.1 (M+1)
+
1H NMR(500MHz，CDCl
3)δ7.31(m，5H)，6.80(s，1H)，5.49(br s，1H)，5.06(m，3H)，4.26-4.18(m，1H)，2.38(s，3H)，1.09(d，J＝6.5Hz，3H).
Step F: (4S, 5S)-4-methyl-5-(4-methyl isophthalic acid, 3-thiazol-2-yl)-1,3- azoles alkane-2-ketone
Will [(1S, 2S)-2-hydroxyl-1-methyl-2-(4-methyl isophthalic acid, 3-thiazol-2-yl) ethyl] (53.4mg, 0.174mmol) solution in the 7.5N KOH aqueous solution (1mL), MeOH (2mL) and THF (4mL) is in stirred overnight at room temperature for benzyl carbamate.This reaction mixture with 3N HCl acidifying, is used EtOAc (3 * 20mL) extractions.With the extraction liquid salt water washing that merges, dry (Na
2SO
4) and vacuum concentration, obtained product.LCMS calculated value=199.1; Measured value=199.1 (M+1)
+
1H NMR(500MHz，CDCl
3)δ6.92(s，1H)，6.82(s，1H)，5.91(d，J＝8.2Hz，1H)，4.39-4.35(m，1H)，2.44(s，3H)，0.95(d，J＝6.4Hz，3H).
Step G:(4S, 5S)-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-4-methyl-5-(4-methyl isophthalic acid, 3-thiazol-2-yl)-1,3- azoles alkane-2-ketone
In room temperature under nitrogen, with sodium hydride (60% dispersion liquid in mineral oil, 8.1mg, 0.202mmol) be added to (4S, 5S)-4-methyl-5-(4-methyl isophthalic acid, 3-thiazol-2-yl)-1, (33.4mg is 0.168mmol) in the solution that is stirring in anhydrous THF (1mL) for 3- azoles alkane-2-ketone.Should react and stir 15 minutes, then by sleeve pipe add 2 '-(brooethyl)-4-fluoro-5-sec.-propyl-2-methoxyl group-4 '-(81.0mg is 0.202mmol) in the solution in anhydrous THF (2mL) for (trifluoromethyl) biphenyl.This is reflected at stirred overnight at room temperature.Add saturated NH
4Cl (10mL), (3 * 20mL) extract with EtOAc with this mixture.With the extraction liquid drying (Na that merges
2SO
4) and vacuum concentration, obtained crude product.It is passed through flash chromatography (Si, 25 * 160mm, the mixture gradient of 0-70%EtOAc in hexane) and chirality HPLC (IA post, 20 * 250mm, the mixture of 5%i-PrOH in heptane) purifying, obtained (4S, 5S)-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-4-methyl-5-(4-methyl isophthalic acid, the 3-thiazol-2-yl)-1,3- azoles alkane-2-ketone.R
f=0.18 (mixture of 20%EtOAc in hexane).LCMS calculated value=523.2; Measured value=523.1 (M+1)
+ 1H NMR (500MHz, CDCl
3, 1: 1 mixture of atropisomer)
δ7.68(s，0.5H)，7.63(s，0.5H)，7.59(d，J＝8.0Hz，1H)，7.32(d，J＝7.9Hz，1H)，6.99(d，J＝8.5Hz，0.5H)，6.95(d，J＝8.5Hz，0.5H)，6.88(s，1H)，6.68(d，J＝5.0Hz，0.5H)，6.66(d，J＝4.9Hz，0.5H)，5.70(d，J＝8.3Hz，0.5H)，5.55(d，J＝8.2Hz，0.5H)，4.72(d，J＝15.9Hz，0.5H)，4.64(d，J＝15.9Hz，0.5H)，4.20(d，J＝15.9Hz，0.5H)，3.95(d，J＝15.9Hz，0.5H)，3.91-3.83(m，1H)，3.75(s，1.5H)，3.74(s，1.5H)，3.23-3.15(m，1H)，2.40(s，3H)，1.26-1.18(m，6H)，0.65(d，J＝6.5Hz，1.5H)，0.55(d，J＝6.5Hz，1.5H).
According to above-mentioned general method, made the compound in the table 8.Preparation embodiment 198 is as reference compound.
Table 8
Embodiment 253,254
(4S; 5R)-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-4-methyl-5-[3-(methylsulfinyl) phenyl]-1; 3- azoles alkane-2-ketone (embodiment 253) (45; 5R)-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group 4-(trifluoromethyl) biphenyl-2-yl] methyl }-4-methyl-5-[3-(methyl sulphonyl) phenyl]-1,3- azoles alkane-2-ketone (embodiment 254)
Under nitrogen in 0 ℃, to (4S, 5R)-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-4-methyl-5-[3-(methylthio group) phenyl]-1,3- azoles alkane-2-ketone (embodiment 208) (25mg, 0.0457mmol) drip 3-chlorine peroxybenzoic acid (77% in the solution in anhydrous methylene chloride (1.5mL), 26mg is 0.114mmol) at CH
2Cl
2Solution (0.5mL).After the adding, this mixture is warmed to room temperature and stirred 2 hours.With the saturated Na of this reaction mixture
2SO
3(15mL) handle.With water layer Et
2O (3 * 20mL) extractions.With the saturated NaHCO of organic extract liquid that merges
3Washing, dry (Na
2SO
4) and vacuum concentration.By purified by flash chromatography crude product (Si; 12 * 160mm; the mixture gradient of 0-60%EtOAc in hexane); obtained (4S; 5R)-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-4-methyl-5-[3-(methylsulfinyl) phenyl]-1; 3- azoles alkane-2-ketone and (45; 5R)-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-4-methyl-5-[3-(methyl sulphonyl) phenyl]-1,3- azoles alkane-2-ketone.Embodiment 253:LCMS calculated value=564.19; Measured value=564.3 (M+1)
+ 1HNMR (500MHz, CDCl
3, 1: 1 mixture of atropisomer)
δ7.73(8，0.5H)；7.66-7.52(m，4.5H)；7.42(s，0.5H)；7.40(s，0.5H)；7.37(d，J＝3.4Hz，0.5H)；7.36(d，J＝3.5Hz，0.5H)；7.02(d，J＝8.4Hz，0.5H)；6.99(d，J＝8.4Hz，0.5H)；6.71(d，J＝3.1Hz，0.5H)；6.69(d，J＝2.9Hz，0.5H)；5.59(d，J＝5.9Hz，0.5H)；5.57(d，J＝5.9Hz，0.5H)；5.42(t，J＝8.4Hz，1H)；4.85(d，J＝3.4Hz，0.5H)；4.82(d，J＝3.4Hz，0.5H)；4.80(d，J＝7.8Hz，0.5H)；4.77(d，J＝7.7Hz，0.5H)；4.16(d，J＝15.8Hz，0.5H)；3.92(d，J＝15.8Hz，0.5H)；3.76(s，3H)；3.85-3.72(m，1H)；3.26-3.19(m，1H)；2.73(d，J＝4.7Hz，3H)；1.30-1.26(m，4.5H)；1.20(d，J＝6.9Hz，1.5H)；0.55(d，J＝6.7Hz，0.75H)；0.52(d，J＝6.7Hz，0.75H)；0.41(d，J＝4.0Hz，0.75H)；0.39(d，J＝4.1Hz，0.75H).
Embodiment 254:LCMS calculated value=580.17; Measured value=580.3 (M+1)
+ 1H NMR (500MHz, CDCl
3, 1: 1 mixture of atropisomer)
δ7.95(s，0.5H)；7.94(s，0.5H)；7.81(s，0.5H)；7.80(s，0.5H)；7.73(s，0.5H)；7.65-7.58(m，3H)；7.57(s，0.5H)；7.38(d，J＝3.5Hz，0.5H)；7.36(d，J＝3.8Hz，0.5H)；7.02(d，J＝8.4Hz，0.5H)；6.99(d，J＝8.4Hz，0.5H)；6.72(s，0.5H)；6.69(s，0.5H)；5.58(d，J＝8.1Hz，0.5H)；5.42(d，J＝8.0Hz，0.5H)；4.86(d，J＝15.9Hz，0.5H)；4.81(d，J＝15.9Hz，0.5H)；4.17(d，J＝15.8Hz，0.5H)；3.91(d，J＝15.8Hz，0.5H)；3.81-3.75(m，1H)；3.78(s，3H)；3.27-3.19(m，1H)；3.07(s，3H)；1.30-1.26(m，4.5H)；1.21(t，J＝8.7Hz，1.5H)；0.53(d，J＝6.5Hz，1.5H)；0.39(d，J＝65Hz，1.5H).
Embodiment 255
3-((4S, 5R)-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-4-methyl-2-oxo-1,3- azoles alkane-5-yl) phenyl aldehyde
With (4S, 5R)-5-[3-(1,3-dioxane-2-yl) phenyl]-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone (embodiment 210) (380mg, 0.647mmol) at THF and 1N HCl (3: the 1) solution in (4mL) stirring at room 2 hours.This reaction mixture is diluted with EtOAc, with sodium bicarbonate and salt water washing.Dry and the vacuum concentration with organic layer.By purified by flash chromatography crude product (Si), obtained 3-((4S, 5R)-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl)-4-methyl-2-oxo-1,3- azoles alkane-5-yl) phenyl aldehyde.LCMS calculated value=530.19; Measured value=530.4 (M+1)
+ 1H NMR (500MHz, CDCl
3, 1: 1 mixture of atropisomer)
δ10.03(s，1H)；7.88(s，0.5H)；7.87(s，0.5H)；7.77-7.52(m，5H)；7.37(d，J＝3.5Hz，0.5H)；7.36(d，J＝3.4Hz，0.5H)；7.02(d，J＝8.4Hz，0.5H)；6.99(d，J＝8.4Hz，0.5H)；6.71(d，J＝3.5Hz，0.5H)； 6.69(d，J＝3.4Hz，0.5H)；4.17(d，J＝15.8Hz，0.5H)；6.98(d，J＝15.8Hz，0.5H)；3.78(s，3H)；3.85-3.71(m，1H)；3.26-3.19(m，1H)；1.30-1.26(m，4.5H)；1.19(d，J＝6.9Hz，1.5H)；0.53(d，J＝6.6Hz，1.5H)；0.40(d，J＝6.6Hz，1.5H).
Embodiment 256
(4S, 5R)-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-5-[3-(hydroxyl)-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-5-[3-(hydroxyl
At 0 ℃ under nitrogen atmosphere, to 3-((4S, 5R)-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-4-methyl-2-oxo-1,3- azoles alkane-5-yl) (12mg 0.023mmol) adds NaBH in the solution in anhydrous EtOH (1mL) to phenyl aldehyde
4Powder (4.5mg, 0.119mmol).This solution is warmed to room temperature and stirred 1 hour.This mixture is handled dilute with water with 2%HOAc.Water layer is extracted (3 * 10mL) with EtOAc.With the saturated NaHCO of organic extract liquid that merges
3(12mL) and salt solution (12mL) washing, dry (Na
2SO
4) and vacuum concentration.By the purified by flash chromatography crude product, obtained (4S, 5R)-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-5-[3-(hydroxyl)-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-5-[3-(hydroxyl.LCMS calculated value=532.0; Measured value=532.4 (M+1)
+ 1H NMR (500MHz, CDCl
3, 1: 1 mixture of atropisomer)
δ7.73(s，0.5H)；7.67(s，0.5H)；7.64(s，0.5H)；7.62(s，0.5H)；7.42-7.32(m，3H)；7.24(s，1H)；7.15(s，0.5H)；7.14(s，0.5H)；7.01(d，J＝8.4Hz，0.5H)；6.98(d，J＝8.5Hz，0.5H)；6.71(s，0.5H)；6.68(s，0.5H)；5.51(d，J＝8.1Hz，0.5H)；5.37(d，J＝8.0Hz，0.5H)；4.81(d，J＝15.9Hz，0.5H)；4.74(d，J＝16Hz，0.5H)；4.73(s，2H)；4.15(d，J＝15.9Hz，1H)；3.92(d，J＝15.9Hz，1H)；3.77(s，3.0H)；3.79-3.74(H，0.5H)；3.74-3.68(m，0.5H)；3.25-3.18(m，1H)；1.29-1.25(m，4.5H)；1.19(d，J＝6.9Hz，1.5H)；0.53(d，J＝6.4Hz，1.5H)；0.40(d，J＝6.4Hz，1.5H).
Embodiment 257
(4S, 5R)-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-5-[3-(1-hydroxyethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
At-78 ℃ under nitrogen, to 3-((4S, 5R)-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-4-methyl-2-oxo-1,3- azoles alkane-5-yl) (11mg 0.021mmol) adds methyl-magnesium-bromide (solution of 30 μ L3.0M in ether) to phenyl aldehyde in the solution in THF (1mL).This mixture was stirred 2 hours at-78 ℃.With the saturated NH of this mixture
4Cl (10mL) handles.(3 * 10mL) extract with EtOAc with water layer.The organic layer that merges is washed dry (Na with salt solution (15mL)
2SO
4) and vacuum concentration, obtained crude product.It is passed through purified by flash chromatography (Si), obtained (4S, 5R)-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-5-[3-(1-hydroxyethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone.LCMS calculated value=546,22; Measured value=546.4 (M+1)
+ 1H NMR (500MHz, CDCl
3, 1: 1 mixture of atropisomer)
δ7.74(s，0.5H)；7.67(s，0.5H)；7.64(s，0.5H)；7.63(s，0.5H)；7.36(m，3H)；7.24(s，1H)；7.15(s，0.5H)；7.14(s，0.5H)；7.01(d，J＝8.5Hz，0.5H)；6.99(d，J＝8.5Hz，0.5H)；6.71(s，0.5H)；6.68(s，0.5H)；5.52(d，J＝8.0Hz，0.5H)；5.36(d，J＝7.9Hz，0.5H)；4.92(q，J＝6.4Hz，1H)；4.83(d，J＝15.7，0.5H)；4.77(d，J＝16.0，0.5H)；4.16(d，J＝15.5Hz，0.5H)；3.92(d，J＝15.5Hz，0.5H)；3.77(d，J＝7.1Hz，3H)；3.81-3.68(m，1H)；3.25-3.18(m，1H)；1.64(br，s，1H)；1.49(d，J＝6.4Hz，3H)；1.30-1.26(m，4.5H)；1.19(d，J＝6.9Hz，1.5H)；0.53(d，J＝6.5Hz，1.5H)；0.40(d，J＝6.5Hz，1.5H).
According to above-mentioned general method, make the compound in the table 9:
Table 9
| Embodiment | R | LCMS(M+1) + |
| 258 | Et | 560.4 |
| 259 | n-Pr | 574.4 |
Embodiment 260
(4S, 5R)-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-4-methyl-5-{3-[(methylamino) methyl] phenyl }-1,3- azoles alkane-2-ketone
To 3-((4S, 5R)-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-4-methyl-2-oxo-1,3- azoles alkane-5-yl) phenyl aldehyde (15mg, 0.028mmol) 1, add methylamine (solution of 1mL 2.0M in THF) in the solution in the 2-ethylene dichloride (1mL).With the gained mixture with sodium triacetoxy borohydride (34.8mg, 0.16mmol) and AcOH (0.05mL) processing.With this mixture under nitrogen in stirring at room 5 days.This reaction mixture is handled with 1N NaOH, and (3 * 15mL) extract with ether with water layer.With ether extraction liquid salt water washing, dry (Na
2SO
4) and vacuum concentration.Resistates is passed through purified by flash chromatography (Si), obtained (4S, 5R)-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-4-methyl-5-{3-[(methylamino) methyl] phenyl }-1,3- azoles alkane-2-ketone.LCMS calculated value=545.23; Measured value=545.4 (M+1)
+ 1H NMR (500MHz, CDCl
3, 1: 1 mixture of atropisomer)
δ7.74(s，0.5H)；7.67(s，0.5H)；7.64(s，0.5H)；7.62(s，0.5H)；7.33(m，3H)；7.20(s，1H)；7.13(s，0.5H)；7.12(s，0.5H)；7.01(d，J＝8.4Hz，0.5H)；6.98(d，J＝8.5Hz，0.5H)；6.71(d，J＝2.9Hz，0.5H)；6.68(d，J＝2.8Hz，0.5H)；5.51(d，J＝8.1Hz，0.5H)；5.37(d，J＝8.0Hz，0.5H)；4.82(d，J＝15.9Hz，0.5H)；4.75(d，J＝15.9Hz，0.5H)；4.16(d，J＝15.9Hz，0.5H)；3.92(d，J＝15.9Hz，0.5H)；3.77(m，5.5H)；3.70(t，J＝6.6Hz，0.5H)；3 25-3.18(m，1H)；2.45(s，3H)；1.93(br，s，1H)；1.27(m，4.5H)；1.19(d，J＝6.9Hz，1.5H)；0.53(d，J＝6.5Hz，1.5H)；0.40(d，J＝6.5Hz，1.5H).
Embodiment 261
(4S, 5R)-the 5-{3-[(dimethylamino) methyl] phenyl }-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
To 3-((4S, 5R)-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-4-methyl-2-oxo-1,3- azoles alkane-5-yl) phenyl aldehyde (15mg, 0.028mmol) add in the solution in EtOH (1mL) dimethyl amine (solution of 140 μ L 2.0M in MeOH) and titanium isopropylate (79 μ L, 0.28mmol).The stirring of gained white suspension is spent the night.(7.1mg 0.188mmol), spends the night this mixture stirring to add sodium borohydride.By being poured in the 2N ammoniacal liquor (2mL), this mixture comes stopped reaction.Filter out the gained inorganic precipitation, use washed with dichloromethane.The filtrate that merges is used methylene dichloride (2 * 15mL) extractions.With extraction liquid drying (Na
2SO
4) and vacuum concentration.Resistates is passed through purified by flash chromatography (Si), obtained (4S, 5R)-and the 5-{3-[(dimethylamino) methyl] phenyl }-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone.LCMS calculated value=559.25; Measured value=559.4 (M+1)
+ 1H NMR (500MHz, CDCl
3, 1: 1 mixture of atropisomer)
δ7.74(s，0.5H)；7.67(s，0.5H)；7.64(s，0.5H)；7.62(s，0.5H)；7.37-7.29(m，3H)；7.18(s，1H)；7.16(s，0.5H)；7.13(s，0.5H)；7.01(d，J＝8.4Hz，0.5H)；6.99(d，J＝8.5Hz，0.5H)；6.71(d，J＝3.0Hz，0.5H)；6.68(d，J＝2.9Hz，0.5H)；5.52(d，J＝8.1Hz，0.5H)；5.37(d，J＝8.0Hz，0.5H)；4.82(d，J＝15.9Hz，0.5H)；4.77(d，J＝16.0Hz，0.5H)；4.15(d，J＝16.0Hz，0.5H)；3.91(d，J＝15.9Hz，0.5H)；3.76(s，3H)；3.80-3.73(m，0.5H)；3.72-3.68(m，0.5H)；3.43(s，2H)；3.25-3.18(m，1H)；2.23(s，6H)；1.27(m，4.5H)；1.19(d，J＝6.9Hz，1.5H)；0.53 (d，J＝6.5Hz，1.5H)；0.39(d，J＝6.6Hz，1.5H).
Embodiment 262
(4S, 5R)-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-5-(1H-imidazoles-2-yl)-4-methyl isophthalic acid, 3- azoles alkane-2-ketone
With (4S, 5S)-and the 5-{1-[(benzyloxy) methyl]-1H-imidazoles-2-yl }-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone (embodiment 244) (16.9mg, 0.028mmol), 20% palladium hydroxide/carbon (8.3mg) and the mixture of 1N HCl (28uL) in MeOH (1mL) stir down at hydrogen (air bag) and spend the night, then with this mixture via diatomite filtration, and vacuum concentration.By the purified by flash chromatography crude product, obtained (4S, 5R)-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-5-(1H-imidazoles-2-yl)-4-methyl isophthalic acid, 3- azoles alkane-2-ketone.LCMS calculated value=492.18; Measured value=492.2 (M+1)
+ 1H NMR (500MHz, CDCl
3, 1: 1 mixture of atropisomer)
δ7.71(s，0.5H)；7.67(s，0.5H)；7.65(s，0.5H)；7.64(s，0.5H)；7.37(d，J＝3.2Hz，0.5H)；7.35(d，J＝3.3Hz，0.5H)；7.09(d，2H)；7.02(d，J＝8.4Hz，0.5H)；6.99(d，J＝8.5Hz.0.5H)；6.72(d，J＝4.3Hz，0.5H)；6.69(d，J＝4.2Hz，0.5H)；5.76(d，J＝8.3Hz，0.5H)；5.64(d，J＝8.7Hz，0.5H)；4.72(d，J＝15.8Hz，0.5H)；4.68(d，J＝15.8Hz，0.5H)；4.20(d，J＝15.7Hz，0.5H)；4.01(d，J＝15.7Hz，0.5H)；3.90(br，s，1H)；3.79-3.72(m，4H)；3.25-3.18(m，1H)；1.28-1.22(m，6H)；0.67(d，J＝6.5Hz，1.5H)；0.59(d，J＝6.5Hz，1.5H).
Embodiment 263
(4S, 5R)-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-4-methyl-5-(1-pyridine oxide-4-yl)-1,3- azoles alkane-2-ketone
At 0 ℃ with m-chlorobenzoic acid (77%, 47.9mg, 0.214mmol) be added to (4S, 5R)-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-4-methyl-5-pyridin-4-yl-1,3- azoles alkane-2-ketone (53.7,0.107mmol) at anhydrous CH
2Cl
2(10.8mL) in Nei the solution.After 15 minutes, this was reflected at stirring at room 3 hours 0 ℃ of maintenance.With this reaction CH
2Cl
2(40mL) saturated Na is used in dilution
2SO
3(20mL) with saturated K
2CO
3(2 * 20mL) washings.With organic layer drying (Na
2SO
4) and vacuum concentration, obtained (4S, 5R)-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-4-methyl-5-(1-pyridine oxide-4-yl)-1,3- azoles alkane-2-ketone is oily matter.LCMS calculated value=519.2; Measured value=519.3 (M+1)
+
Embodiment 264
4-((4S, 5R)-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-4-methyl-2-oxo-1,3- azoles alkane-5-yl) pyridine-2-formonitrile HCN
In room temperature under nitrogen, with trimethylsilyl cyanide (39.9mg, 54 μ L, 0.402mmol) be added to (4S, 5R)-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-4-methyl-5-(1-pyridine oxide-4-yl)-1, (37.9mg is 0.0732mmol) at anhydrous CH for 3- azoles alkane-2-ketone
2Cl
2(2mL) in Nei the solution that is stirring.Should react and stir 5 minutes, and the adding Benzoyl chloride (20.5mg, 17 μ L, 0.146mmol).This is reflected at stirred overnight at room temperature.Add 50% saturated K
2CO
3(10mL), with this mixture CH
2Cl
2(20mL) dilution.Isolate water layer and use CH
2Cl
2(2 * 10mL) extractions.With the organic extract liquid drying (K that merges
2CO
3) and vacuum concentration, obtained crude product.It by purified by flash chromatography (Si, 12 * 160mm, the 0-70%EtOAc mixture gradient in hexane), is obtained product (11.6mg, 30%), be colorless oil.By chirality HPLC (AD post, 20 * 250mm, the mixture of 10%i-PrOH in heptane) product is split into its enantiomorph, obtained 4-((4S, 5R)-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-4-methyl-2-oxo-1,3- azoles alkane-5-yl) pyridine-2-formonitrile HCN and 4-((4R, 5S)-3-{[4 '-fluoro-51-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-4-methyl-2-oxo-1,3- azoles alkane-5-yl) pyridine-2-formonitrile HCN.R
f=0.72 (mixture of 50%EtOAc in hexane).LCMS calculated value=528.2; Measured value=528.3 (M+1)
+ 1H NMR (500MHz, CDCl
3, 1: 1 mixture of atropisomer)
δ8.73(s，1H)，7.67-7.59(m，2H)，7.55(d，J＝3.3Hz，1H)，7.40(d，J＝4.2Hz，1H)，7.35(dd，J＝7.8，3.3Hz，1H)，6.99(d，J＝8.4Hz，1H)，6.95(d，J＝8.4Hz，1H)，6.69(d，J＝3.1Hz，1H)，6.67(d，J＝3.1Hz，1H)，5.47(d，J＝8.1Hz，0.5H)，5.30(d，J＝8.1Hz，0.5H)，4.81(t，J＝15.1Hz，1H)，4.11(d，J＝15.8Hz，0.5H)，3.89(d，J＝15.8Hz，0.5H)，3.83-3.73(m，1H)，3.76(s，3H)，3.24-3.16(m，1H)，1.27-1.17(m，6H)，0.54(d，J＝6.5Hz，1.5H)，0.39(d，J＝6.5Hz，1.5H).
Embodiment 265
(4S, 5R)-5-(2-chloropyridine-4-yl)-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
With (4S, 5R)-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-4-methyl-5-(1-pyridine oxide-4-yl)-1,3- azoles alkane-2-ketone (53.7mg, 0.104mmol) reflux 2 hours under nitrogen of the solution in phosphoryl chloride (4mL).This reaction mixture is cooled to room temperature, and vacuum concentration with EtOAc (20mL) and water (5mL) dilution, is used saturated NaHCO then
3(10mL) washing.(2 * 20mL) extract with EtOAc with water layer.With the organic layer drying (Na that merges
2SO
4) and vacuum concentration, obtained crude product.It by purified by flash chromatography (Si, 12 * 160mm, the 0-70%EtOAc mixture gradient in hexane), is obtained product, be colorless oil.Product is split into its enantiomorph chirality HPLC (AD post, 20 * 250mm, the mixture of 5%i-PrOH in heptane), obtained (4S, 5R)-5-(2-chloropyridine-4-yl)-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone.R
f=0.17 (mixture of 20%EtOAc in hexane).LCMS calculated value=537.2; Measured value=537.3 (M+1)
+ 1HNMR (500MHz, CDCl
3, 1: 1 mixture of atropisomer)
δ8.40(br s，1H)，7.70(s，0.5H)，7.63(s，1.5H)，7 37(m，1H)，7.24(brs，1H)，7.10(br s，1H)，7.01(d，J＝8.2Hz，0.5H)，6.98(d，J＝8.2Hz，0.5H)，6.72-6.68(m，1H)，5.44(d，J＝8.1Hz，0.5H)，5.29(d，J＝8.1Hz，0.5H)，4.81(t，J＝16.9Hz，1H)，4.14(d，J＝15.9Hz，0.5H)，3.91(d，J＝15.9Hz，0.5H)，3.81-3.71(m，1H)，3.76(s，3H)，3.27-3.19(m，1H)，1.29-1.19(m，6H)，0.58(d，J＝6.5Hz，1.5H)，0.44(d，J＝6.5Hz，1.5H).
Embodiment 266
(4S, 5R)-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-4-methyl-5-(2-picoline-4-yl)-1,3- azoles alkane-2-ketone
With (4S, 5R)-5-(2-chloropyridine-4-yl)-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, and 3- azoles alkane-2-ketone (20.9mg, 0.0389mmol), trimethylboroxin (14.7mg, 16 μ L, 0.116mmol) Cs
2CO
3(38.0mg is 0.117mmol) with (Ph
3P)
4Pd (9.0mg, 0.00778mmol) anhydrous 1, spend the night by the vlil in the 4-dioxane (1mL).This reaction mixture is filtered via plug of celite, wash with EtOAc.With this filtrate vacuum concentration, obtained crude product.It by purified by flash chromatography (Si, 12 * 160mm, the 0-70%EtOAc mixture gradient in hexane), is obtained product, be colorless oil.By chirality BDPLC (AD post, 20 * 250mm, the mixture of 10%i-PrOH in heptane) product is split into its enantiomorph, obtained (4S, 5R)-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-4-methyl-5-(2-picoline-4-yl)-1,3- azoles alkane-2-ketone and (4R, 5S)-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-4-methyl-5-(2-picoline-4-yl)-1,3- azoles alkane-2-ketone.R
f=0.22 (mixture of 50%EtOAc in hexane).LCMS calculated value=517.2; Measured value=517.1 (M+1)
+ 1H NMR (500MHz, CDCl
3, 1: 1 mixture of atropisomer)
δ8.48(d，J＝4.9Hz，1H)，7.69(s，0.5H)，7.61(s，1H)，7.60(s，0.5H)，7.33(m，1H)，7.05(s，1H)，6.99-6.93(m，2H)，6.69(d，J＝3.2Hz，1H)，6.66(d，J＝3.2Hz，1H)，5.40(d，J＝8.1Hz，0.5H)，5.24(d，J＝8.1Hz，0.5H)，4.79(d，J＝15.9Hz，0.5H)，4.74(d，J＝15.9Hz，0.5H)，4.13(d，J＝15.9Hz，0.5H)，3.89(d，J＝15.9Hz，0.5H)，3.78-3.66(m，1H)，3.75(s，3H)，3.23-3.17(m，1H)，2.56(s，3H)，1.25-1.17(m，6H)，0.53(d，J＝6.5Hz，1.5H)，0.39(d，J＝6.5Hz，1.5H).
Made compound in table 10 according to above-mentioned general method:
Table 10
Made compound in table 11 according to above-mentioned general method:
Table 11
Made compound in table 12 according to above-mentioned general method:
Table 12
Embodiment 281
(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-{[4 '-fluoro-2 '-hydroxyl-5 '-sec.-propyl-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
Steps A: 4-fluoro-2 '-(iodomethyl)-5-sec.-propyl-4 '-(trifluoromethyl) biphenyl-2-alcohol
In sealed tube, will [4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl alcohol (71.5mg, 0.209mmol) and iodine (610mg, 2.40mmol) solution in phenyl trimethyl silyl (877 μ L) is in 110 ℃ of heated overnight.This reaction is cooled to room temperature, with 1N HCl (10mL) dilution, with EtOAc (3 * 20mL) extractions.With the extraction liquid 10%Na that merges
2S
2O
3(20mL) washing, dry (Na
2SO
4) and vacuum concentration, obtained crude product.With it by purified by flash chromatography (Si, 12 * 160mm, the 0-20%EtOAc mixture gradient in hexane), obtained 4-fluoro-2 '-(iodomethyl)-5-sec.-propyl-4 '-(trifluoromethyl) biphenyl-2-alcohol.R
f=0.65 (mixture of 20%EtOAc in hexane).
1H NMR(500MHz，CDCl
3)δ7.81(s，1H)，7.60(d，J＝7.9Hz，1H)，7.34(d，J＝7.9Hz，1H)，7.10(d，J＝8.3Hz，1H)，6.69(d，J＝11.1Hz，1H)，4.82(s，1H)，4.41(d，J＝9.4Hz，1H)，4.23(d，J＝9.3Hz，1H)，3.27-3.19(m，1H)，1.27(br s，6H).
Step B:2-{[4-fluoro-2 '-(iodomethyl)-5-sec.-propyl-4 '-(trifluoromethyl) biphenyl-2-yl] the oxygen base } tetrahydrochysene-2H-pyrans
In room temperature under nitrogen, with tosic acid (2.8mg, 0.0145mmol) be added to 4-fluoro-2 '-(iodomethyl)-5-sec.-propyl-4 '-(trifluoromethyl) biphenyl-2-alcohol (63.4mg, 0.145mmol) and 3, (60.8mg, 66 μ L are 0.723mmol) at anhydrous CH for 4-dihydro-2H-pyrans
2Cl
2(7.2mL) in Nei the solution, should react and stir 3 days.With the saturated NaHCO of this reaction mixture
3(20mL) dilution, and use CH
2Cl
2(3 * 20mL) extractions.With the extraction liquid drying (Na that merges
2SO
4) and vacuum concentration, obtained crude product.With it by purified by flash chromatography (Si, 12 * 160mm, the 0-20%EtOAc mixture gradient in hexane), obtained 2-{[4-fluoro-2 '-(iodomethyl)-5-sec.-propyl-4 '-(trifluoromethyl) biphenyl-2-yl] the oxygen base tetrahydrochysene-2H-pyrans.R
f=0.74 (mixture of 10%EtOAc in hexane).
1H NMR(500MHz，CDCl
3)δ.75(s，1H)，7.62(d，J＝8.3Hz，0.5H)，7.59(d，J＝8.3Hz，0.5H)，7.53(t，J＝7.3Hz，0.5H)，7.41(s，0.5H)，7.32(d，J＝7.9Hz，0.5H)，7.25(d，J＝7.9Hz，0.5H)，7.15(t，J＝9.4Hz，0.5H)，6.99(d，J＝12.2Hz，0.5H)，6.94(d，J＝12.2Hz，0.5H)，6.69(d，J＝11.0Hz，0.5H)，5.37(s，0.5H)，5.23(s，0.5H)，5.13(s，1H)，4.45(d，J＝9.6Hz，0.5H)，4.40(d，J＝9.6Hz，0.5H)，4.31(d，J＝9.6Hz，0.5H)，4.23(d，J＝9.6Hz，0.5H)3.76(m，0.5H)，3.66-3.54(m，1.5H)，3.29-3.21(m，1H)，1.68-1.44(m，4H)1.32-1.26(m，6H).
Step C:(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-{[4 '-fluoro-2 '-hydroxyl-5 '-sec.-propyl-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
With sodium hydride (60% dispersion liquid in mineral oil, 1.9mg 0.0485mmol) be added to (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, in the 3- azoles alkane-solution that is stirring of 2-ketone in dry DMF (1mL).Should react and stir 30 minutes, by sleeve pipe add 2-{[4-fluoro-2 '-(iodomethyl)-5-sec.-propyl-4 '-(trifluoromethyl) biphenyl-2-yl] the oxygen base tetrahydrochysene-2H-pyrans (16.9mg, 0.324mmol) solution in dry DMF (1mL), and this is reflected at stirred overnight at room temperature.Should react and use saturated NH
4Cl (10mL) and water (5mL) dilution are with EtOAc (3 * 20mL) extractions.With the extraction liquid drying (Na that merges
2SO
4) and vacuum concentration, obtained crude product.(0.6mg, 0.00324mmol) solution in MeOH (5mL) is in stirred overnight at room temperature with crude product and tosic acid.With this reaction mixture vacuum concentration, obtained crude product.It is passed through purified by flash chromatography (Si, 12 * 160mm, the mixture gradient of 0-35%EtOAc in hexane), obtained (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-{[4 '-fluoro-2 '-hydroxyl-5 '-sec.-propyl-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone.R
f=0.33 (mixture of 20%EtOAc in hexane).LCMS calculated value=624.2; Measured value=624.3 (M+1)
+ 1H NMR (500 MHz, CDCl
3, 1: 1 mixture of atropisomer)
δ7.86(s，1H)，7.67(m，4H)，7.42(d，J＝7.1Hz，0.5H)，7.41(d，J＝7.1Hz，0.5H)，6.95(d，J＝7.3Hz，0.5H)，6.94(d，J＝7.3Hz，0.5H)，6.70(d，J＝5.6Hz，0.5H)，6.68(d，J＝5.6Hz，0.5H)，5.66(d，J＝8.0Hz，0.5H)，5.36(d，J＝8.1Hz，0.5H)，4.93(d，J＝15.8Hz，0.5H)，4.88(d，J＝15.8Hz，0.5H)，4.18(d，J＝15.8Hz，0.5H)，4.00(d，J＝15.8Hz，0.5H)，3.87-3.83(m，0.5H)，3.77-3.71(m，0.5H)，3.22-3.14(m，1H)，1.77(br s，1H)，1.27-1.17(m，6H)，0.57(d，J＝6.5Hz，1.5H)，0.45(d，J＝6.5Hz，1.5H).
Made compound in table 13 according to above-mentioned general method:
Table 13
Embodiment 283
(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-{[4 '-fluoro-3 '-hydroxyl-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
Steps A: the tertiary butyl [4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methoxyl group } dimethylsilane
In room temperature under nitrogen, with tert-butyldimethylsilyl chloride (0.48g, 3.21mmol) and imidazoles (0.50g, 7.30mmol) be added to successively [4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] (1.00g is 2.93mmol) at anhydrous CH for methyl alcohol
2Cl
2(13.4mL) in Nei the solution that is stirring, and should react to stir and spend the night.Add entry (50mL), and (3 * 50mL) extract with EtOAc with this mixture.With the extraction liquid drying (MgSO that merges
4) and vacuum concentration, obtained crude product.It is passed through purified by flash chromatography (Si, 25 * 160mm, the mixture of 1%EtOAc in hexane), obtained the tertiary butyl [4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methoxyl group dimethylsilane, be colorless oil.R
f=0.16 (mixture of 1%EtOAc in hexane).LCMS calculated value=457.2; Measured value=457.2 (M+1)
+
1H NMR(500MHz，CDCl
3)δ7.94(s，1H)，7.57(d，J＝7.8Hz，1H)，7.29(d，J＝7.6Hz，1H)，7.00(d，J＝8.6Hz，1H)，6.69(d，J＝12.1Hz，1H)，4.63(br s，1H)，4.50(br s，1H)，3.75(s，3H)，3.29-3.21(m，1H)，1.28(d，J＝6.9Hz，6H)，0.93(s，9H)，0.03(s，6H).
Step B:2 '-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl]-4-fluoro-5-sec.-propyl-2-methoxyl group-4 '-(trifluoromethyl) biphenyl-3-alcohol
At-78 ℃ under nitrogen, with the n-Butyl Lithium (solution of 1.6M in hexane, 261 μ L, 0.417mmol) via syringe pump be added drop-wise in 30-45 minute the tertiary butyl [4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methoxyl group (200mg is 0.438mmol) in the solution that is stirring in anhydrous THF (0.5mL) for dimethylsilane.After adding is finished, this is reflected at-78 ℃ and stirred 2 hours, obtained purple solution.(43.4mg, 47 μ L 0.417mmol), and are reflected at-78 ℃ with this and stirred 3 hours to drip trimethyl borate.This reaction mixture is warmed to 0 ℃, add rapidly acetate (25.1mg, 24 μ L, 0.626mmol), drip then 30% aqueous hydrogen peroxide solution (52 μ L, 0.459mmol).This is reflected at stirred overnight at room temperature, and dilute with water (10mL) is also used Et
2O (3 * 20mL) extractions.With the extraction liquid that merges with 50% saturated FeSO
4(20mL) washing, dry (Na
2SO
4) and vacuum concentration, obtained crude product.It is passed through purified by flash chromatography (Si, 12 * 160mm, the mixture gradient of 0-100%EtOAc in hexane), obtained 2 '-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl)-4-fluoro-5-sec.-propyl-2-methoxyl group-4 '-(trifluoromethyl) biphenyl-3-alcohol.R
f=0.32 (mixture of 10%EtOAc in hexane).LCMS calculated value=473.1; Measured value=473.2 (M+1)
+
1H NMR(600MHz，CDCl
3)δ7.95(s，1H)，7.56(d，J＝7.8Hz，1H)，7.35(d，J＝7.9Hz，1H)，6.53(d，J＝7.8Hz，1H)，5.65(s，1H)，4.68(br s，1H)，4.54(br s，1H)，3.42(s，3H)，3.26-3.20(m，1H)，1.25(d，J＝6.9Hz，6H)，0.90(s，9H)，0.02(s，6H)
Step C:4-fluoro-2 '-(hydroxymethyl)-5-sec.-propyl-2-methoxyl group-4 '-(trifluoromethyl) biphenyl-3-alcohol
At 0 ℃, to fluoridize the tertiary butyl ammonium (solution of 1M in THF, 179 μ L, 0.179mmol) be added drop-wise to 2 '-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl)-4-fluoro-5-sec.-propyl-2-methoxyl group-4 '-(trifluoromethyl) biphenyl-3-alcohol (76.8mg, 0.163mmol) in the solution that is stirring in THF (2mL), and this reaction is warmed to ambient temperature overnight.Add saturated NH
4Cl (10mL), (3 * 20mL) extract with EtOAc with this mixture.With the extraction liquid drying (Na that merges
2SO
4) and vacuum concentration, obtained crude product.With it by purified by flash chromatography (Si, 12 * 160mm, the 0-40%EtOAc mixture gradient in hexane), obtained 4-fluoro-2 '-(hydroxymethyl)-5-sec.-propyl-2-methoxyl group-4 '-(trifluoromethyl) biphenyl-3-alcohol.R
f=0.26 (mixture of 20%EtOAc in hexane).
1HNMR(600MHz，CDCl
3)δ7.85(s，1H)，7.63(d，J＝7.9Hz，1H)，7.41(d，J＝8.0Hz，1H)，6.53(d，J＝7.7Hz，1H)，4.50(br s，1H)，4.47(s，1H)，3.42(s，3H)，3.25-3.19(m，1H)，1.24(br s，6H).
Step D:2 '-(brooethyl)-4-fluoro-5-sec.-propyl-2-methoxyl group-4 '-(trifluoromethyl) biphenyl-3-alcohol
0 ℃ under nitrogen, (102.8mg is 0.392mmol) at anhydrous CH with triphenylphosphine
2Cl
2In the solution (2mL) by sleeve pipe be added to carbon tetrabromide (130mg, 0.392mmol) and 4-fluoro-2 '-(hydroxymethyl)-5-sec.-propyl-2-methoxyl group-4 '-(58.5mg is 0.163mmol) at anhydrous CH for (trifluoromethyl) biphenyl-3-alcohol
2Cl
2(2mL) in Nei the solution that is stirring, and this is reflected at stirred overnight at room temperature.With this reaction mixture vacuum concentration, obtained crude product.With it by purified by flash chromatography (Si, 12 * 160mm, the 0-40%EtOAc mixture gradient in hexane), obtained 2 '-(brooethyl)-4-fluoro-5-sec.-propyl-2-methoxyl group-4 '-(trifluoromethyl) biphenyl-3-alcohol.R
f=0.55 (mixture of 20%EtOAc in hexane).
1H NMR(600MHz，CDCl
3)δ7.84(s，1H)，7.61(d，J＝7.9Hz，1H)，7.42(d，J＝8.0Hz，1H)，6.69(d，J＝7.8Hz，1H)，5.59(s，1H)，4.50(d，J＝9.6Hz，1H)，4.39(d，J＝9.7Hz，1H)，3.47(s，3H)，3.29-3.23(m，1H)，1.27(d，J＝6.9Hz，6H).
Step e: 2-{[2 '-(brooethyl)-4-fluoro-5-sec.-propyl-2-methoxyl group-4 '-(trifluoromethyl) biphenyl-3-yl] the oxygen base } tetrahydrochysene-2H-pyrans
In room temperature under nitrogen, with 3,4-dihydro-2H-pyrans (51.9mg, 56 μ L, 0.617mmol) be added to tosic acid (2.3mg, 0.0123mmol) and 2 '-(brooethyl)-4-fluoro-5-sec.-propyl-2-methoxyl group-4 '-(52.0mg is 0.123mmol) at anhydrous CH for (trifluoromethyl) biphenyl-3-alcohol
2Cl
2(6.1mL) in Nei the solution that is stirring, and should react to stir and spend the night.With this reaction mixture CH
2Cl
2(45mL) saturated NaHCO is used in dilution
3(5mL) with 30% saturated Na
2SO
3(5mL) washing, dry (Na
2SO
4) and vacuum concentration, obtained crude product.It is passed through purified by flash chromatography (Si, 12 * 160mm, the mixture gradient of 0-40%EtOAc in hexane), obtained 2-{[2 '-(brooethyl)-4-fluoro-5-sec.-propyl-2-methoxyl group-4 '-(trifluoromethyl) biphenyl-3-yl] the oxygen base tetrahydrochysene-2H-pyrans.R
f=0.59 (mixture of 20%EtOAc in hexane).
1H NMR(600MHz，CDCl
3)δ7.82(s，1H)，7.60(d，J＝7.0Hz，1H)，7.41(d，J＝8.0Hz，1H)，6.67(d，J＝7.8Hz，1H)，5.77(s，1H)，4.97(dd，J＝4.9，2.9Hz，1H)，4.49(d，J＝9.8Hz，1H)，4.37(d，J＝9.8Hz，1H)，3.89-3.87(m，1H)，3.61-3.49(m，1H)，3.46(s，3H)，3.27-3.21(m，1H)，1.89-1.83(m，1H)，1.78-1.70(m，1H)1.64-1.48(m，3H)，1.26(d，J＝6.8Hz，6H).
Step F: (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-{[4 '-fluoro-3 '-hydroxyl-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
Room temperature with sodium hydride (60% dispersion liquid in mineral oil, 14.7mg 0.368mmol) is added to (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, (57.7mg is 0.184mmol) in the solution that is stirring in anhydrous THF (2mL) for 3- azoles alkane-2-ketone.After 30 minutes, by sleeve pipe add 2 '-(brooethyl)-4-fluoro-5-sec.-propyl-2-methoxyl group-4 '-(trifluoromethyl) biphenyl-3-alcohol (62.0mg, the 0.123mmol) solution in anhydrous THF (2mL), and this reaction mixture stirred spend the night.Add saturated NH
4Cl (10mL), (3 * 20mL) extract with EtOAc with this mixture.With the extraction liquid drying (Na that merges
2SO
4) and vacuum concentration, obtained crude product.It is passed through purified by flash chromatography (Si, 12 * 160mm, the mixture gradient of 0-40%EtOAc in hexane), obtained (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-{[4 '-fluoro-3 '-hydroxyl-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone.R
f=0.25 (mixture of 20%EtOAc in hexane).LCMS calculated value=654.2; Measured value=654.2 (M+1)
+ 1H NMR (500 MHz, CDCl
3, 1: 1 mixture of atropisomer)
δ7.86(m，1H)，7.73-7.63(m，4H)7.44(m，1H)，6.55(d，J＝7.6Hz，0.5H)，6.52(d，J＝7.7Hz，0.5H)，5.71(br s，1H)，5.60(d，J＝8.0Hz，0.5H)，5.54(d，J＝8.0Hz，0.5H)，4.87(d，J＝16.0Hz，0.5H)，4.72(d，J＝16.1Hz，0.5H)，4.23(d，J＝16.1Hz，0.5H)，3.98(d，J＝15.9Hz，0.5H)，3.93-3.85(m，0.5H)，3 .77-3.71(m，0.5H)，3.51(s，1.5H)，3 47(s，1.5H)，3.25-3.17(m，1H)，1.26-1.18(m，6H)，0.58(d，J＝6.5Hz，1.5H)，0.38(d，J＝6.6Hz，1.5H).
Embodiment 284
(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-{[4 '-fluoro-2 ', 3 '-dihydroxyl-5 '-sec.-propyl-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
At-78 ℃ under nitrogen, with boron tribromide (17.4mg, 6.6 μ L, 0.0692mmol) be added to (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-{[4 '-fluoro-3 '-hydroxyl-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl)-the 4-methyl isophthalic acid, (22.6mg is 0.0346mmol) at anhydrous CH for 3- azoles alkane-2-ketone
2Cl
2(1mL) in Nei the solution that is stirring, and should react and stir 8 hours.Should react water (5mL) dilution and (3 * 20mL) extract with EtOAc.With the extraction liquid drying (Na that merges
2SO
4) and vacuum concentration, obtained crude product.It is passed through chirality HPLC purifying (IA post, 20 * 250mm, the mixture of 15%i-PrOH in heptane), obtained (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-{[4 '-fluoro-2 ', 3 '-dihydroxyl-5 '-sec.-propyl-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone.R
f=0.24 (mixture of 20%EtOAc in hexane).LCMS calculated value=640.2; Measured value=640.2 (M+1)
+ 1H NMR (600MHz, CDCl
3, 1: 1 mixture of atropisomer)
δ7.85(s，1H)，7.70-7.62(m，4H)，7.41(m，1H)，6.52(s，0.5H)，6.51(s，0.5H)，6.20(br s，2H)，5.65(d，J＝7.9Hz，0.5H)，5.38(d，J＝8.0Hz，0.5H)，5.00(d，J＝15.5Hz，0.5H)，4.92(d，J＝15.6Hz，0.5H，4.15(d，J＝15.5Hz，0.5H)，4.02(d，J＝15.6Hz，0.5H)，3.88(t，J＝6.7Hz，0.5H)，3.77(t，J＝6.7Hz，0.5H)，3.19-3.13(m，1H)，1.26-1.17(m，6H)，0.59(d，J＝6.1Hz，1.5H)，0.48(d，J＝6.2Hz，1.5H).
Intermediate 20
Steps A: 2-(2-fluoro-3,4-Dimethoxyphenyl) propan-2-ol
At-20 ℃ under nitrogen, with the methylmagnesium-chloride (solution of 3M in THF, 1.74mL, 5.22mmol) be added drop-wise to 1-(2-fluoro-3, the 4-Dimethoxyphenyl) ethyl ketone (J.Chem.Soc.Perkin Trans.2 1994,547-555) (646mg is 3.26mmol) in the solution that is stirring in heptane (3.1mL) and THF (1.4mL).This reaction is warmed to room temperature, stirred 4 hours.Add 50% saturated NH
4Cl (20mL), (3 * 20mL) extract with EtOAc with this mixture.With the extraction liquid drying (Na that merges
2SO
4) and vacuum concentration, obtained 2-(2-fluoro-3,4-Dimethoxyphenyl) propan-2-ol, be colorless oil.LCMS calculated value=197.1; Measured value=197.1 (M-OH)
+
1H NMR(600MHz，CDCl
3)δ7.14(t，J＝8.8Hz，1H)，6.61(dd，J＝8.8，1.4Hz，1H)，3.86(s，3H)，3.83(s，3H)，2.56-2.25(br s，1H)，1.58(s，6H).
Step B:2-fluoro-1-sec.-propyl-3, the 4-dimethoxy benzene
With 10% palladium on carbon (69.8mg) 2-(2-fluoro-3,4-Dimethoxyphenyl) propan-2-ol (698mg, 3.26mmol) suspension in the solution in 5N HCl (0.7mL) and EtOH (5.6mL) in room temperature in H
2(15psi) stirring is spent the night down.This mixture filtered via plug of celite and with EtOAc (～75mL) wash.Filtrate is washed dry (MgSO with 50% saturated brine (10mL)
4) and vacuum concentration, obtained 2-fluoro-1-sec.-propyl-3, the 4-dimethoxy benzene.
1H NMR(500MHz，CDCl
3)δ6.86(t，J＝8.3Hz，1H)，6.63(dd，J＝8.7，1.5Hz，1H)，3.89(s，3H)，3.84(s，3H)，3.19-3.11(m，1H)，1.22(d，J＝6.8Hz，6H).
Step C:1-bromo-3-fluoro-2-sec.-propyl-4, the 5-dimethoxy benzene
Room temperature with bromine (80.6mg, 26 μ L 0.504mmol) are added to 2-fluoro-1-sec.-propyl-3, the 4-dimethoxy benzene (50.0mg, 0.252mmol) and potassium acetate (49.5mg 0.504mmol) in the solution in acetate (1mL), and should react to stir and spent the night.Should react water (10mL) and saturated Na
2SO
3(10mL) dilution, any with EtOAc (3 * 20mL) extractions.With the saturated NaHCO of extraction liquid that merges
3(2 * 10mL) washings, dry (MgSO
4) and vacuum concentration, obtained 1-bromo-3-fluoro-2-sec.-propyl-4, the 5-dimethoxy benzene.
1HNMR(600MHz，CDCl
3)δ6.86(d，J＝2.0Hz，1H，3.87(s，3H)，3.81(s，3H)，3.43-3.34(m，1H)，1.31-1.29(dd，J＝7.1，1.4Hz，6H).
Made compound in table 14 according to above-mentioned general method:
Table 14
Embodiment 289
5-[3,5-two (trifluoromethyl) phenyl]-3-{[5 '-(difluoromethyl)-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-1,3- azoles alkane-2-ketone
Steps A: 2 '-(5-[3,5-two (trifluoromethyl) phenyl]-2-oxo-1,3- azoles alkane-3-yl } methyl)-6-methoxyl group-4 '-(trifluoromethyl) biphenyl-3-formaldehyde
With 5-[3,5-two (trifluoromethyl) phenyl]-3-[2-iodo-5-(trifluoromethyl) benzyl]-1,3- azoles alkane-(embodiment 66,50mg for 2-ketone; 0.0858mmol), 5-formyl radical-2-anisole ylboronic acid (46mg; 0.257mmol), tetrakis triphenylphosphine palladium (0) (12mg; 0.0103mmol) and the mixture heating up of yellow soda ash (74mg) in benzene/ethanol/water (2.8/0.4/1.2mL) refluxed 60 hours.Should react dilution, use H successively with EtOAc (30mL)
2Dried over mgso is used in O (10mL) and salt solution (10mL) washing, filters, and vacuum concentration.Crude product is by fast silica gel chromatogram purifying (0-50%EtOAc/ hexane gradient), obtained 2 '-({ 5-[3,5-two (trifluoromethyl) phenyl]-2-oxo-1,3- azoles alkane-3-yl } methyl)-6-methoxyl group-4 '-(trifluoromethyl) biphenyl-3-formaldehyde, be yellow oil.LCMS＝592.1(M+1)
+。
1H NMR (CDCl
3, 500MHz, atropisomer mixture):
δ9.98(s，1H)，7.99-7.96(m，1H)，7.90(s，1H)，7.75(s，2H)，7.69-7.64(m，2Hz)，7.53(s，1H)，7.41-7.38(m，1H)，7.17-7.14(m，1H)，5.37(t，J＝8.2Hz，1H)，4.59(d，J＝15.3Hz，1H)，4.37(d，J＝15.6Hz，1H)，3.92(s，3H)，3.67-3.64(m，1Hz)，3.19-3.16(m，1H).
Step B:5-[3,5-two (trifluoromethyl) phenyl]-3-{[5 '-(difluoromethyl)-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-1,3- azoles alkane-2-ketone
At 0 ℃, with three fluoridize diethylamino sulphur (22 μ L, 0.1675mmol) be added drop-wise to 2 '-({ 5-[3,5-two (trifluoromethyl) phenyl]-2-oxo-1,3- azoles alkane-3-yl } methyl)-6-methoxyl group-4 '-(steps A, 50mg is 0.0838mmol) at CH for (trifluoromethyl) biphenyl-3-formaldehyde
2Cl
2(1mL) in Nei the solution that is stirring.This was reflected at stirring at room 14 hours.Should react at 0 ℃ and to use water treatment, use CH
2Cl
2(10mL) H is used in dilution
2Dried over sodium sulfate is used in O (10mL) and salt solution (10mL) washing, filters, and vacuum concentration.Crude product is by fast silica gel chromatogram purifying (0-25%EtOAc/ hexane gradient), obtained 5-[3,5-two (trifluoromethyl) phenyl]-3-{[5 '-(difluoromethyl)-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-1,3- azoles alkane-2-ketone is fining glass shape thing.LCMS＝594.2(M-19)
+。
1H NMR (benzene-d
6, 500MHz, atropisomer mixture):
δ7.64(s，1H)，7.38-7.36(m，2H)，7.30-7.26(m，2H)，7.14-7.11(m，2H)，6.85(d，J＝8Hz，1H)，6.45(d，J＝8.5Hz，1H)，6.37-6.13(m，1H)，4.46-4.38(m，2H)，3.79-3.76(m，1H)，3.21(s，3H)，2.36(t，J＝8.7Hz，1H)，2.05(t，J＝8.4Hz，1H).
Use chirality HPLC (15%IPA/ heptane, the AS post) this compound separation is become its enantiomorph (5S)-5-[3,5-two (trifluoromethyl) phenyl]-3-{[5 '-(difluoromethyl)-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-1,3- azoles alkane-2-ketone and (5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-{[5 '-(difluoromethyl)-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-1,3- azoles alkane-2-ketone.
Embodiment 290
5-[3,5-two (trifluoromethyl) phenyl]-3-{[2 '-methoxyl group-4,5 '-two (trifluoromethyl)-biphenyl-2-yl] methyl }-1,3- azoles alkane-2-ketone
Steps A: 2-iodo-1-methoxyl group-4-(trifluoromethyl) benzene
(500mg is 2.62mmol) at CH to 2-methoxyl group-5-(trifluoromethyl) aniline
2Cl
2Stirring in (10mL) add in the solution nitrite tert-butyl (467 μ L, 3.93mmol).Should react and stir 5 minutes, (1.3g 5.24mmol), heated 2 hours at 70 ℃ to add iodine then.Should react cooling, use CH
2Cl
2(10mL) dilute, use saturated Na
2S
2O
3(10mL) and salt solution (10mL) washing, use dried over sodium sulfate, filter also vacuum concentration.Crude product has obtained 2-iodo-1-methoxyl group-4-(trifluoromethyl) benzene by fast silica gel chromatogram purifying (hexane), is light yellow solid.
1H NMR(CDCl
3，500MHz)：δ8.05(d，J＝2Hz，1H)，7.61(dd，J＝8.7，1.8Hz，1H)，6.89(d，J＝8.7Hz，1H)，3.97(s，3H).
Step B:[2-methoxyl group-5-(trifluoromethyl) phenyl] boric acid
-78 ℃ under nitrogen with n-Butyl Lithium (solution of 1.6M in hexane, 456 μ L, 0.729mmol) be added drop-wise to 2-iodo-1-methoxyl group-4-(trifluoromethyl) benzene (steps A, 200mg, 0.662mmol) THF (1,5mL) in Nei the solution that is stirring.This is reflected at-78 ℃ and stirred 30 minutes, add then triisopropyl borate ester (458 μ L, 1.986mmol).This is reflected at-78 ℃ of restir 2 hours, uses saturated NH
4The Cl stopped reaction.With this mixture CH
2Cl
2Extraction is with organic phase NaHCO
3(15mL) and salt solution (15mL) washing, dry (Na
2SO
4), filter, vacuum concentration, it directly uses without purifying to have obtained [2-methoxyl group-5-(trifluoromethyl) phenyl] boric acid.
Step C:5-[3,5-two (trifluoromethyl) phenyl]-3-{[2 '-methoxyl group-4,5 ' two (trifluoromethyl)-biphenyl-2-yl] methyl }-1,3- azoles alkane-2-ketone
With 5-[3,5-two (trifluoromethyl) phenyl]-3-[2-iodo-5-(trifluoromethyl) benzyl]-1,3- azoles alkane-(embodiment 66,100mg for 2-ketone; 0.171mmol) usefulness [2-methoxyl group-5-(trifluoromethyl) phenyl] boric acid (step B, 113mg; 0.514mmol), tetrakis triphenylphosphine palladium (0) (24mg; 0.0206mmol) and yellow soda ash (148mg) as described in embodiment 291, handle, obtained 5-[3,5-two (trifluoromethyl) phenyl]-3-{[2 '-methoxyl group-4,5 '-two (trifluoromethyl)-biphenyl-2-yl] methyl }-1,3- azoles alkane-2-ketone is fining glass shape thing.LCMS＝612.1(M-19)
+。
1HNMR (benzene-d
6, 500MHz, atropisomer mixture):
δ7.61(s，1H)，7.40-7.36(m，1H)，7.31(s，1H)，7.27-7.23(m，4H)，6.74-6.72(m，1H)，6.35(d，J＝8.7Hz，1H)，4.42-4.32(m，2H)，3.70(d，J＝15.8Hz，1H)，3.14(s，3H)，2.28(t，J＝8.7Hz，1H)，1.98(t，J＝8.2Hz，1H)
Use chirality HPLC (5%EtOH/ heptane, the AS post) this compound separation is become its enantiomorph (5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-{[2 '-methoxyl group-4,5 '-two (trifluoromethyls)-biphenyl-2-yl] methyl }-1,3- azoles alkane-2-ketone and (55)-5-[3,5-two (trifluoromethyl) phenyl]-3-{[2 '-methoxyl group-4,5 '-two (trifluoromethyl)-biphenyl-2-yl] methyl }-1,3- azoles alkane-2-ketone.
Intermediate 21
(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[2-iodo-5-(trifluoromethyl) benzyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
With (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone (400mg, 1.28mmol) with NaH (60% dispersion liquid in oil, 128mg, 3.2mmol) and 2-(brooethyl)-(embodiment 70,466mg, 1 for 1-iodo-4-(trifluoromethyl) benzene, 28mmol) as described in embodiment 66, handle, obtained (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[2-iodo-5-(trifluoromethyl) benzyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone is white solid.
LCMS＝598.0(M+1)
+.
1H NMR(CDCl
3，500MHz)：δ8.06(d，J＝8.2Hz，1H)，7.93(s，1H)，7.82(s，2H)，7.61(s，1H)，7.33(dd，J＝8.2，1.4Hz，1H)，5.79(d，J＝7.8hz，1H)，4.91(d，J＝16Hz，1H)，4.40(d，J＝16Hz，1H)，4.16-4.06(m，1H)，0.83(d，J＝6.4Hz，3H).
Embodiment 291
(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[2-(2-methoxyl group-5-methyl-3-thienyl)-5-(trifluoromethyl) benzyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
Steps A: 3,5-two bromo-2-methoxythiophene
At 0 ℃, (1g is 8.76mmol) at CH to the 2-methoxythiophene
2Cl
2(18mL) add lentamente in Nei the solution that is stirring N-bromine succinimide (3.12g, 17.52mmol).This reaction is warmed to room temperature and stirred 14 hours.This is reflected at cooling and filtration in the ice bath.Filtrate is used saturated NaHCO
3(2 * 25mL) washings.With water layer with 1N HCl neutralization and use CHCl
3(3 * 25mL) extractions.The organic layer that merges is washed dry (Na with salt solution (25mL)
2SO
4), filter and vacuum concentration.Crude product has obtained 3 by fast silica gel chromatogram purifying (hexane), and 5-two bromo-2-methoxythiophene are baby pink oily matter.LCMS＝272.9(M+)
+。
Step B:3-bromo-2-methoxyl group-5-thiotolene
-78 ℃ under nitrogen with n-Butyl Lithium (solution of 2.0M in pentane, 0.97mL 1.93mmol) is added to 3, (steps A, 500mg is 1.84mmol) in the solution that is stirring in THF (5mL) for 5-two bromo-2-methoxythiophene.This is reflected at-78 ℃ and stirred 1 hour, add then methyl-iodide (114 μ L, 1.84mmol).This reaction is warmed to room temperature and stirred 20 hours.Removal of solvent under reduced pressure, with resistates at EtOAc (15mL) and H
2Distribute between the O (15mL).Water layer is used again (2 * 15mL) extractions are with the organic layer H that merges
2O (15mL) and salt solution (15mL) washing, dry (MgSO
4), filter and vacuum concentration.Crude product has obtained 3-bromo-2-methoxyl group-5-thiotolene by fast silica gel chromatogram purifying (hexane), is yellow oil.
1HNMR(CDCl
3，500MHz)：δ6.44(s，1H)，3.95(s，3H)，2.41(s，3H).
Step C:(2-methoxyl group-5-methyl-3-thienyl) boric acid
Under nitrogen, with 3-bromo-2-methoxyl group-5-thiotolene (step B, 296mg, 1.43mmol) and triisopropyl borate ester (396 μ L, 2.15mmol) mixture that is stirring in toluene/THF (2.3/0.6mL) is cooled to-70 ℃.By syringe pump with dripped in 1 hour n-Butyl Lithium (solution of 2.0M in pentane, 1.07mL, 2.15mmol).This reaction is stirred in-70 ℃ of restir 40 minutes, uses 2N HC.(2mL) in-20 ℃ of processing.This is reflected at EtOAc (15mL) and H
2Distribute between the O (15mL).Water layer is extracted with EtOAc (10mL); The organic layer that merges is washed dry (Na with salt solution (15mL)
2SO
4), filter, and vacuum concentration has obtained (2-methoxyl group-5-methyl-3-thienyl) boric acid, is yellow oil.Product need not be further purified direct use.
Step D:(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[2-(2-methoxyl group-5-methyl-3-thienyl)-5-(trifluoromethyl) benzyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
Will (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[2-iodo-5-(trifluoromethyl) benzyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone (intermediate 21,13mg; 0.0219mmol) usefulness (2-methoxyl group-5-methyl-3-thienyl) boric acid (step C, 10.4mg; 0.0657mmol), tetrakis triphenylphosphine palladium (0) (3mg; 0.0026mmol) and yellow soda ash (20mg) as described in embodiment 291, handle, obtained (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[2-(2-methoxyl group-5-methyl-3-thienyl)-5-(trifluoromethyl) benzyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone is yellow glass shape thing.
LCMS＝598.2(M+1)
+.
1H NMR(benzene-d
6，500MHz)：δ7.75(s，1H)，7.57(s，1H)，7.31-29(m，1H)，7.24(s，2H)，7.12-7.10(m，1H)，6.14(s，1H)，4.96(d，J＝16Hz，1H)，4.57(d， J＝8Hz，1H)，3.99(d，J＝15.8Hz，1H)，3.30(s，3H)，2.95-2.92(m，1H)，2.05(s，3H)，-0.28(d，J＝6.7Hz，3H).
Made compound in table 15 according to above-mentioned general method:
Table 15
Embodiment 298
(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-{[4 '-fluoro-2 '-methoxyl group-5 '-(2-methyl isophthalic acid, 3-dioxolane-2-yl)-4-(trifluoromethyl) biphenyl-2-yl] methyl }-4-1,3- azoles alkane-2-ketone
With (4S, 5S)-5-[3,5-two (trifluoromethyl) phenyl]-3-[2-iodo-5-(trifluoromethyl) benzyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone (intermediate 21,7.34g, 12.29mol), [4-fluoro-2-methoxyl group-5-(2-methyl isophthalic acid, 3-dioxolane-2-yl) phenyl] boric acid (5.5g, 21.48mol), tetrakis triphenylphosphine palladium (0) (1.7g; 1.47mol) and yellow soda ash (10g) at benzene/EtOH/H
2Mixture heating up among the O (203/29/86mL) refluxed 14 hours.With this reaction H
2O handles, at EtOAc (250mL) and H
2Distribute between 0 (75mL).Water layer is used EtOAc (3 * 200mL) extractions again.The extraction liquid that merges is washed dry (MgSO with salt solution (100mL)
4), filter, and vacuum concentration.Crude product is by fast silica gel chromatogram purifying (0-25%EtOAc/ hexane gradient), obtained (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-{[4 '-fluoro-2 '-methoxyl group-5 '-(2-methyl isophthalic acid, 3-dioxolane-2-yl)-and 4-(trifluoromethyl) biphenyl-2-yl] methyl }-4-1,3- azoles alkane-2-ketone is amorphous solid.LCMS＝682.2(M+1)
+。
1H NMR (CDCl
3, 500MHz, atropisomer mixture):
δ7.86(s，1H)，7.71(S，3H)，7.65-7.61(m，1H)，7.37-7.34(m，1H)，7.32-7.28(m，1H)，6.75(dd，J＝12.4，3.6Hz，1H)，5.58(d，J＝8.1Hz，1H)，4.89(d，J＝15.8Hz，1H)，4.08-4.04(m，2H)，3.91-3.76(m，7H)，1.73(d，J＝10.5Hz，3H)，0.4(d，J＝6.5Hz，3H).
Embodiment 299
(4S, 5R)-3-{[5 '-ethanoyl-4 '-fluoro-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-5-[3,5-two (trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
To (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-{[4 '-fluoro-2 '-methoxyl group-5 '-(2-methyl isophthalic acid, 3-dioxolane-2-yl)-and 4-(trifluoromethyl) biphenyl-2-yl] methyl }-4-1,3- azoles alkane-2-ketone (8g, 0.0118mol) add in the solution in acetone (400mL) the tosic acid monohydrate (670mg, 0.0035mol).This was reflected at stirring at room 14 hours.This is reflected at EtOAc (250mL) and saturated NaHCO
3Distribute (250mL).With water layer again with EtOAc extraction (3 * 250mL), with the organic layer that merges with salt solution (200mL) washing, dry (MgSO
4), filter, and vacuum concentration.Crude product is by fast silica gel chromatogram purifying (0-25%EtOAc/ hexane gradient); obtained (4S; 5R)-3-{[5 '-ethanoyl-4 '-fluoro-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-5-[3; 5-two (trifluoromethyl) phenyl]-the 4-methyl isophthalic acid; 3- azoles alkane-2-ketone is yellow solid.LCMS＝638.2(M+1)
+。
1H NMR (CDCl
3, 500MHz, atropisomer mixture):
δ7.87(8，1H)，7.81-7.79(m，1H)，7.74(s，1H)，7.70(s，2H)，7.59(s，1H)，7.39(d，J＝8Hz，1H)，6.80(d，J＝12.8Hz，1H)，5.27(d，J＝8.2Hz，1H)，4.97(d，J＝15.3Hz，1H)，4.04(d，J＝15.5Hz，1H)，3.94(s，3H)，3.72-3.66(m，1H)，2.67-2.64(m，3H)，0.62(d，J＝6.4Hz，3H).
Embodiment 300
(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-{[4 '-fluoro-5 '-pseudoallyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
In room temperature with methyl magnesium iodide (29 μ L; 0.085mmol) be added drop-wise to (4S; 5R)-3-{[5 '-ethanoyl-4 '-fluoro-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-5-[3; 5-two (trifluoromethyl) phenyl]-the 4-methyl isophthalic acid; (30mg is 0.047mmol) in the solution in ether (2mL) for 3- azoles alkane-2-ketone.This was reacted carefully reflux 4 hours.(63 μ L 0.19mmol) and ether (1mL), should react backflow 3 hours adding the methyl magnesium iodide.Should react and use saturated NH
4Cl handles and (3 * 25mL) extract with EtOAc.With the extraction liquid that merges salt solution (25mL) washing, dry (Na
2SO
4), filter and vacuum concentration.Crude product is by fast silica gel chromatogram purifying (0-25%EtOAc/ hexane gradient), obtained (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-{[4 '-fluoro-5 '-pseudoallyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone is fining glass shape thing.LCMS＝636.3(M+1)
+。
1H NMR (benzene-d
6, 500MHz, atropisomer mixture):
δ7.59(s，1H)，7.55(s，1H)，7.35(d，J＝8Hz，1H)，7.30-7.27(m，2H)，6.99-6.96(m，2H)，6.45(d，J＝12.9Hz，1H)，5.32(d，J＝16.9Hz，1H)，5.16-5.15(m，1H)，4.90(d，J＝16.3Hz，1H)，4.48(d，J＝7.7Hz，1H)，3.70(d，J＝6.4Hz，1H)，3.16(s，3H)，2.85-2.79(m，1H)，2.12(s，3H)，-0.025(d，J＝6.5Hz，3H).
Embodiment 301
(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-([4 '-fluoro-2 '-hydroxyl-5 '-pseudoallyl-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
To (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-{[4 '-fluoro-5 '-pseudoallyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-(embodiment 300 for 2-ketone, 50mg, 0.078mmol) add in the solution that is stirring in DMF (450 μ L) lithium chloride (13.4mg, 0.315mmol).Bottle is sealed, and this is reflected at 160 ℃ of heating 14 hours.Add 10%NaOH (10mL), (3 * 10mL) extract with ether with gained solution.Water layer is acidified to pH～3 with 3N HCl, with ether (3 * 25mL) extractions again.With the organic extract liquid that merges salt solution (25mL) washing, dry (MgSO
4), filter and vacuum concentration.Crude product is by fast silica gel chromatogram purifying (0-25%EtOAc/ hexane gradient), obtained (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-{[4 '-fluoro-2 '-hydroxyl-5 '-pseudoallyl-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone is fining glass shape thing.LCMS＝622.1(M+1)
+。
1H NMR (CDCl
3, 500MHz, atropisomer mixture):
δ7.90(s，1H)，7.76-7.70(m，4H)，7.48-7.45(m，1H)，7.11-7.07(m，1H)，6.75(d，J＝11.7Hz，1H)，5.71(d，J＝7.8Hz，1H)，5.59-5.56(m，1H)，5.25-5.21(m，2H)，4.81(d，J＝15.4Hz，1H)，4.04(d，J＝15.6Hz，1H)，3.97-3.92(m，1H)，2.13(s，3H)，0.58(d，J＝6.6Hz，3H).
Embodiment 302
(4S)-4-benzyl-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-1,3- azoles alkane-2-ketone
0 ℃ under nitrogen, (0.926mmol) (33mg 0.185mmol) handles the suspension that is stirring in THF (1mL) with being dissolved in (S)-4-benzyl-2- oxazolidone among the THF (1mL) for 60% dispersion liquid in oil, 37mg with sodium hydride.Should react and stir 20 minutes, dropping 2 '-(brooethyl)-4-fluoro-5-sec.-propyl-2-methoxyl group-4 '-(trifluoromethyl) biphenyl (intermediate 10,50mg, 0.124mmol) solution in THF (1mL).This was reflected at stirring at room 60 hours.With this reaction H
2O (1mL) handles, at EtOAc (25mL) and H
2Distribute between the O (10mL).Water is used EtOAc again, and (3 * 15mL) extractions are with the organic extract liquid that merges salt solution (25mL) washing, dry (MgSO
4) and vacuum concentration, obtained crude product.By fast silica gel chromatogram purifying (0-25%EtOAc/ hexane gradient), obtained (4S)-4-benzyl-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl-1,3- azoles alkane-2-ketone is fining glass shape thing.LCMS＝502.3(M+1)
+。
1H NMR (CDCl
3, 500MHz, atropisomer mixture)
δ7.69-7.64(m，1H)，7.58(s，1H)，7.39-7.36(m，1H)，7.29-7.24(m，3H)，7.06(d，J＝8.5Hz，1H)，6.97-6.91(m，2H)，6.73(d，J＝11.7，1H)，4.79(d，J＝15.8Hz，1H)，4.30(d，J＝15.8Hz，1H)，4.08-4.05(m，1H)，3.99-3.97(m，1H)，3.76(s，3H)，3.65-3.58(m，1H)，3.27-3.17(m，1H)，2.81(dd，J＝13.5，4.1Hz，1H)，2.45-2.40(m，1H)，1.30-1.4(m，6H).
Embodiment 303
(4S)-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-4-(4-methyl-benzyl)-1,3- azoles alkane-2-ketone
Steps A: (2S)-2-amino-3-(4-aminomethyl phenyl) third-1-alcohol
(254mg, 6.696mmol) mixture heating up in THF (20mL) refluxed 1 hour, cooled off in ice bath then with lithium aluminium hydride.Add (S)-4-aminomethyl phenyl L-Ala (500mg 2.79mmol), will make mixture heating up reflux 14 hours in batches.With excessive lithium aluminium hydride by adding H successively
2O (1mL), the 10%NaOH aqueous solution (10mL) and H
2O (2.5mL) decomposes.This mixture is filtered, wash solid with THF.Be dissolved in CHCl with this filtrate vacuum concentration with resistates
3(50mL), with the 5%NaOH aqueous solution (25mL), H
2O (25mL) and salt solution (25mL) washing, dry (MgSO
4), filter, and vacuum concentration, obtained (25)-2-amino-3-(4-aminomethyl phenyl) third-1-alcohol, be pale solid.
1H NMR(CD
3OD，500MHz)δ7.13-7.09(m，4H)，3.52(dd，J＝10.7，4.6Hz，1H)，3.36(dd，J＝10.7，6.9Hz，1H)，3.04-2.99(m，1H)，2.73(dd，J＝13.5，6.2Hz，1H)，2.53(dd，J＝13.5，7.7Hz，1H)，2.30(s，3H).
Step B:(4S)-and 4-(4-methyl-benzyl)-1,3- azoles alkane-2-ketone
0 ℃ under nitrogen, (steps A, 460mg is 2.79mmol) at CH with (2S)-2-amino-3-(4-aminomethyl phenyl) third-1-alcohol
2Cl
2The solution that is stirring (20mL) with diisopropylethylamine (2.92mL, 16.74mmol) and triphosgene (414mg, 1.39mmol) processing.This is reflected at 0 ℃ stirred 3 hours.Should react and use saturated NaHCO
3(10mL) handle and (4 * 20mL) extract with EtOAc.With the organic layer that merges salt solution (25mL) washing, dry (MgSO
4), filter and vacuum concentration.Crude product has obtained (4S)-4-(4-methyl-benzyl)-1 by fast silica gel chromatogram purifying (0-70%EtOAc/ hexane gradient), and 3- azoles alkane-2-ketone is white solid.
LCMS＝192.2(M+1)
+.
1H NMR(CDCl
3，500MHz)δ7.17(d，J＝8Hz，2H)，7.09(d，J＝7.7Hz，2H)，5.39(br s，1H)，4.48(t，J＝8.4Hz，1H)，4.37(dd，J＝8.6，5.6Hz，1H)，4.11-4.06(m，1H)，2.86(d，J＝7.1Hz，2H)，2.36(s，3H).
Step C:(4S)-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-4-(4-methyl-benzyl)-1,3- azoles alkane-2-ketone
With (4S)-4-(4-methyl-benzyl)-1,3- azoles alkane-2-ketone (step B, 14mg, 0.074mmol) with sodium hydride (60% dispersion liquid in oil, 6.2mg, 0.154mmol) and 2 '-(brooethyl)-4-fluoro-5-sec.-propyl-2-methoxyl group-4 '-(trifluoromethyl) biphenyl (intermediate 10,25mg, 0.062mmol) described in embodiment 305, handle, obtained (4S)-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl-4-(4-methyl-benzyl)-1,3- azoles alkane-2-ketone is the clarification gum.LCMS＝516.4(M+1)
+。1H NMR (CDCl
3, 500MHz, atropisomer mixture)
δ7.65-7.60(m，1H)，7.53(s，1H)，7.35-7.32(m，1H)，7.06-7.20(m，2H)，6.82-6.75(m，2H)，6.69(d，J＝11.7Hz，1H)，4.67(d，J＝15.8Hz，1H)，4.06(d，J＝15.8Hz，1H)，4.04-4.00(m，1H)，3.96-3.93(m，1H)，3.73(s，3H)，3.55-3.48(m，1H)，3.23-3.15(m，1H)，2.63(dd，J＝13.5，3.6Hz，1H)，2.35(d，J＝13.5Hz，1H)，2.29(s，3H)，1.25-1.13(m，6H).
Made compound in table 16 according to above-mentioned general method:
Table 16
Embodiment 317
(4S, 5S)-4-benzyl-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 5-methyl isophthalic acid, 3- azoles alkane-2-ketone
Steps A: [1 (S)-1-benzyl-2-oxopropyl] t-butyl carbamate
-15 ℃ under nitrogen, (500mg, 1.62mmol) (540 μ L 1.62mmol) handle the solution that is stirring in THF (3mL) with methyl-magnesium-bromide with N-(tert-butoxycarbonyl)-N-methoxyl group-N-methyl isophthalic acid-phenyl alanimamides.This is reflected at-15 ℃ and stirred 15 minutes, drip then methyl-magnesium-bromide (1.08mL, 3.24mmol).This reaction was stirred in stirring at room 14 hours, handles with 1N HCl (5mL).With this mixture at H
2Distribute between O (15mL) and the EtOAc (20mL), water layer is used EtOAc (2 * 20mL) extractions again.With the organic layer H that merges
2O (20mL) and salt solution (20mL) washing, dry (Na
2SO
4), filter and vacuum concentration.Crude product has obtained [1 (S)-1-benzyl-2-oxopropyl] t-butyl carbamate by fast silica gel chromatogram method purifying, is white solid.
LCMS＝164.2(M-BOC)
+.
1H NMR(CDCl
3，500MHz)δ7.34-7.26(m，3H)，7.18(d，J＝7.1Hz，2H)，5.15(br s，1H)，4.59-4.56(m，1H)，3.14-2.99(m，2H)，2.16(s，3H)，1.44(s，9H).
Step B:[(1S)-and 1-benzyl-2-hydroxypropyl] t-butyl carbamate
At-20 ℃, (0.57mmol) (44.2mg 1.169mmol) handles the solution that is stirring in anhydrous MeOH (5mL) with sodium borohydride for steps A, 150mg with [1 (S)-1-benzyl-2-oxopropyl] t-butyl carbamate.This reaction is stirred in-20 ℃ stirred 1 hour, use H
2O (1mL) handles and vacuum concentration.Resistates is dissolved among the EtOAc (25mL), uses H successively
2O (15mL) and salt solution (15mL) washing, dry (Na
2SO
4), filter and vacuum concentration.Crude product is by the preparative thin layer chromatography purifying, with 15% acetone/hexane wash-out, obtained [(1S, 2R)-1-benzyl-2-hydroxypropyl] t-butyl carbamate (45mg) and [(1S, 2S)-and 1-benzyl-2-hydroxypropyl] t-butyl carbamate, be white solid.[(1S, 2R)-1-benzyl-2-hydroxypropyl] t-butyl carbamate:
LCMS＝166.2(M-BOC)
+.
1H NMR(CDCl
3，500MHz)δ7.34-7.31(m，2H)，7.26-7.23(m，3H)，4.81(br s，1H)，3.83(dq，J＝6.4，2.7Hz，1H)，3.71-3.69(m，1H)，2.90(d，J＝7.3Hz，2H)，1.43(s，9H)，1.22(d，J＝6.5Hz，3H).
[(1S, 2S)-1-benzyl-2-hydroxypropyl] t-butyl carbamate
LCMS＝166.2(M-BOC)
+.
1H NMR(CDCl
3，500MHz)δ7.34-7.31(m，2H)，7.26-7.23(m，3H)，4.58(br s，1H)，3.3.93-3.85(m，2H)，2.90(dd，J＝14.2，5Hz，1H)，2.82-2.73(m，1H)，1.40(s，9H)，1.25(d，J＝6.4Hz，3H).
Step C:(4S, 5S)-4-benzyl-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 5-methyl isophthalic acid, 3- azoles alkane-2-ketone
With [(1S, 2S)-and 1-benzyl-2-hydroxypropyl] t-butyl carbamate (step B, 39mg, 0.148mmol) with sodium hydride (60% dispersion liquid in oil, 12mg, 0.309mmol) and 2 '-(brooethyl)-4-fluoro-5-sec.-propyl-2-methoxyl group-4 '-(trifluoromethyl) biphenyl (intermediate 10,50mg, 0.123mmol) as described in embodiment 305, handle, obtained (4S, 5S)-4-benzyl-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 5-methyl isophthalic acid, 3- azoles alkane-2-ketone is fining glass shape thing.LCMS＝516.4(M+1)
+。
1H NMR (CDCl
3, 500MHz, atropisomer mixture)
δ7.68(d，J＝11.5Hz，1H)，7.66-7.63(m，1H)，7.39-7.36(m，1H)，7.28-7.23(m，3H)，7.07(d，J＝8.5Hz，1H)，6.94(d，J＝6.9Hz，2H)，6.73(d，J＝4.8Hz，1H)，4.81(d，J＝16Hz，1H)4.38(d，J＝16.1Hz，1H)，4.28-4.23(m，1H)，3.78(s，3H)，3.29-3.17(m，2H)，2.81(dd，J＝13.3，3.9Hz，1H)，2.38-2.28(m，1H)，1.29-1.13(m，6H)，0.98(d，J＝6.2Hz，3H).
Embodiment 318
(4S, 5R)-4-benzyl-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 5-methyl isophthalic acid, 3- azoles alkane-2-ketone
With [(15,25)-and 1-benzyl-2-hydroxypropyl] (embodiment 317 for t-butyl carbamate, step B, 39mg, 0.148mmol) with sodium hydride (60% dispersion liquid in oil, 12mg, 0.309mmol) and 2 '-(brooethyl)-4-fluoro-5-sec.-propyl-2-methoxyl group-4 '-(trifluoromethyl) biphenyl (intermediate 10,50mg 0.123mmol) handles as described in embodiment 305, has obtained (4S, 5R)-4-benzyl-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 5-methyl isophthalic acid, 3- azoles alkane-2-ketone is fining glass shape thing, LCMS=516.4 (M+1)
+ 1H NMR (CDCl
3, 500MHz, atropisomer mixture)
δ7.64-759(m，2H)，7.33-7.30(m，1H)，7.28-7.21(m，2H)，7.16(s，1H)，7.00-6.91(m，3H)，6.67(d，J＝3Hz，1H)，4.70(d，J＝2.7Hz，1H)，4.52-4.47(m，1H)，3.95(d，J＝15.8Hz，1H)，3.70(s，3H)，3.68-3.62(m，1H)，3.24-3.18(m，1H)，2.72-2.53(m，2H)，1.28-1.21(m，6H)，1.19(d，J＝6.8Hz，3H).
Embodiment 319
(4R)-4-benzyl-3-{[5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-1,3- azoles alkane-2-ketone
This title compound is by (R)-4-benzyl-2- oxazolidone (49mg according to the method for describing among the embodiment 67,0.27mmol) and 2-(brooethyl)-1-iodo-4-(trifluoromethyl) benzene (100mg, 0.27mmol) make, obtained this title compound, be colorless oil.R
f=0.35 (15%EtOAc/ hexane).LCMS 484(M+1)
+。
1H NMR (CDCl
3, 500MHz) (have atropisomer)
δ7.72(br s 1H)，7.65(br s，1H)，7.42(m，1H)，7.32-7.22(m，3H)，7.08(m，1H)，6.90-6.84(m，3H)，4.81(d，J＝15.8Hz，1H)，4.35(d，J＝15.8Hz)，4.28(t，J＝8.7Hz，1H)，3.96-3.92(m，3H)，3.78(s，3H)，3.62-3.52(m，1H)，2.94-2.86(m，1H)，2.82(dd，J＝9.4，3.9Hz，1H)，2.42(dd，J＝9.6，3.9Hz)，1.26(s，3H)，1.10(s，3H).
Embodiment 320
Embodiment 322 is by (S)-4-benzyl-5 according to the method for describing among the embodiment 14,5-dimethyl-2- oxazolidone (10mg, 0.05mmol) and 2-(brooethyl)-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl (20mg, 0.05mmol) make, obtain this title compound, be colorless oil.LCMS 512(M+1)
+。
1H NMR (CDCl
3, 500MHz) (have atropisomer)
δ7.72(br s 1H)，7.31(br s，1H)，7.12-7.02(m，2H)，6.85-6.82(m，3H)，6.45-6.35(m，4H)，4.61(d，J＝15.8Hz，1H)，4.21(d，J＝15.8Hz)，3.21(s，2H)，3 16(s，3H)，2.62-2.52(m，1H)，2.42-2.18(m，1H)，1.98(m，2H)，1.22(d，J＝7.1Hz)，1.05(d，J＝7.1Hz)，0.98(s，3H)，0.88(s，3H).
Embodiment 321
(4R, 5S)-4-[3,5-two (trifluoromethyl) phenyl]-1-{[4 '-fluoro-5 '-sec.-propyl]-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-5-methyl-pyrrolidin-2-one
Steps A: 3-[3,5-two (trifluoromethyl) phenyl] ethyl propenoate
0 ℃ under nitrogen to NaH (60% suspension in oil, 168mg, 4.96mmol) add in the solution in THF (3mL) the phosphonoacetic acid triethyl (0.5mL, 2.52mmol).This is reflected at 0 ℃ stirred 30 minutes, add 3, and 5-two (trifluoromethyl) phenyl aldehyde (609mg, 2.52mmol).This reaction is warmed to room temperature, restir 2 hours, vacuum concentration then.Resistates with EtOAc (20mL) dilution, is used H
2Dried over mgso is used in O, salt water washing, concentrates, and by purified by flash chromatography, with 10%EtOAc/ hexane wash-out, has obtained this title compound, is white solid.LCMS 313(M+1)
+。
Step B.3-[3,5-two (trifluoromethyl) phenyl]-4-nitro methyl valerate
With 3-[3,5-two (trifluoromethyl) phenyl] ethyl propenoate (170mg, 0.54mmol) and Nitromethane 99Min. (736uL, 10.29mmol) the usefulness TBAH solution (solution of 1.0M in MeOH, 1.5mL) handle, this mixture heating up was refluxed 3 hours, and (4 * 30mL) extract with 10% aqueous ammonium chloride solution (10mL) dilution and with EtOAc.The organic extract liquid that merges is washed with 10% ammonium chloride (20mL), use dried over mgso, vacuum concentration has obtained crude product.It by purified by flash chromatography, is used 10%EtOAC/ hexane wash-out, has obtained 3-[3,5-two (trifluoromethyl) phenyl]-4-nitro methyl valerate, be colorless oil.
1HNMR(CDCl
3，500MHz)δ7.82(br s 1H)，7.64(br s，2H)，4.91(m，1H)，3.91(m，1H)，3.61(s，3H)，2.82(m，2H)，1.42(d，J＝6.7Hz，3H).
Step C:4-[3,5-two (trifluoromethyl) phenyl]-5-methylpyrrolidin-2-ketone
With the suspension of Raney nickel (slurries of 50%w/v in water 200mg) add 3-[3,5-two (trifluoromethyl) phenyl]-solution of 4-nitro methyl valerate in anhydrous EtOH (5mL) in, the gained mixture stirred under the hydrogen capsule in room temperature spends the night.With this reaction mixture via diatomite filtration and with this filtrate vacuum concentration to remove EtOH.Resistates is passed through purified by flash chromatography, use 75%EtOAC/ hexane wash-out, obtained Soviet Union-4-[3,5-two (trifluoromethyl) phenyl]-5-methylpyrrolidin-2-ketone and red-4-[3,5-two (trifluoromethyl) phenyl]-5-methylpyrrolidin-2-ketone, be white solid.Threo form-diastereomer:
LCMS 353(M+1)
+.
1H NMR(CDCl
3，500MHz)δ7.82(br s 1H)，7.64(br s，2H)，5.72(br s，1H)，3.85(m，1H)，3.31(dd，J＝8.9，8.2Hz，1H)，2.61(dd，J＝8.9，8.2Hz，1H)，1.34(d，J＝6.1Hz，3H).
Erythro-diastereomer:
LCMS 353(M+1)
+.
1H NMR(CDCl
3，500MHz)δ7.82(br s 1H)，7.64(br s，2H)，5.76(br s，1H)，4.20(m，1H)，3.90(m，1H)，2.81(dd，J＝8.5，8.2Hz，1H)，2.73(dd，J＝8.5，8.2Hz，1H)，0.88(d，J＝6.7Hz，3H).
Step D:(4R, 5S)-4-[3,5-two (trifluoromethyl) phenyl]-1-{[4 '-fluoro-5 '-sec.-propyl]-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-5-methyl-pyrrolidin-2-one
At 0 ℃ under nitrogen, (60% dispersion liquid in oil, 4.4mg 0.11mmol) add red-4-[3 in the suspension that is stirring in THF (3mL) to NaH, 5-two (trifluoromethyl) phenyl]-5-methylpyrrolidin-2-ketone (16mg, 0.051mmol) solution in THF (1mL).The gained mixture was stirred 30 minutes at 0 ℃, add 2 then '-(brooethyl)-4-fluoro-5-sec.-propyl-2-methoxyl group-4 '-(trifluoromethyl) biphenyl (16mg, 0.051mmol).After 3 hours, should react with 15mL EtOAc and 5mL H
2The O dilution.Separate each layer and with organic phase H
2O, salt water washing, dry (MgSO
4) and concentrate.Resistates by purified by flash chromatography, is used 10%EtOAC/ hexane wash-out, obtained this title compound, be colorless oil.LCMS 636(M+1)
+。
1H NMR (CDCl
3, 500MHz) (have atropisomer)
1H NMRδ7.82(br s1H)，7.80(br s，1H)，7.45-7.36(m，3H)，7.32-7.22(m，3H)，7.08(d，J＝10.1Hz，1H)，6.60(m，1H)，5.05(m，1H)，4.01(d，J＝15.5Hz)，3.78(s，3H)，3.71-3.52(m，2H)，3.24(m，1H)，1.32-1.20(m，6H)，0.56(d，J＝6.4Hz，3H).
Use chirality HPLC (IA post, 20 * 250mm, the mixture of 3%i-PrOH in heptane) this compound separation is become its two kinds of enantiomorph (4R, 5S)-4-[3,5-two (trifluoromethyl) phenyl]-1-{[4 '-fluoro-5 '-sec.-propyl]-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-5-methyl-pyrrolidin-2-one and (4S, 5R)-and 4-[3,5-two (trifluoromethyl) phenyl]-1-{[4 '-fluoro-5 '-sec.-propyl]-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-5-methyl-pyrrolidin-2-one.
Made compound in table 17 according to above-mentioned general method:
Table 17
Embodiment 327
(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-6-methyl-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
Steps A: [2,6-dimethyl-4-(trifluoromethyl) phenyl] amine
With 2,6-two bromo-4-5-trifluoromethylanilines (1.00g, 3.14mmol), trimethylboroxin (1.16ml, 1.04g, 8.33mmol), salt of wormwood (1.15g, 8.33mmol) and catalytic amount (10%) Pd (PPh
3)
4Mixture in DMF (5ml) was 90 ℃ of heating 14 hours.Add entry (10ml).(3 * 20ml) extract with ethyl acetate with this mixture.With the EtOAc layer that merges with the salt water washing and use dried over sodium sulfate.By quick column purification, use EtOAc: hexane (1: 9) obtains this title compound as eluent, is colorless oil.
1H NMR(CDCl
3，500MHz)：δ7.28(s，1H)，7.22(s，1H)，3.88(br s，2H)，2.21(s，6H).
Step B:2-iodo-1,3-dimethyl-5-(trifluoromethyl) benzene
With derive from steps A title compound (0.27g, 1.43mmol), n-amyl nitrite (0.50g, 2.86mmol) and I
2(0.72g, 2.86mmol) mixture in chloroform (10ml) refluxed 1 hour.With this mixture with methylene dichloride (20ml) dilution and with saturated sodium thiosulfate solution and salt water washing.With the organic layer dried over sodium sulfate.By quick column purification, use the hexane wash-out, obtain this title compound, be light yellow liquid.
1H NMR(CDCl
3，500MHz)δ7.31(s，2H)，2.58(s，6H).
Step C:1-(brooethyl)-2-iodo-3-methyl-5-(trifluoromethyl) benzene
With derive from step B title compound (0.26g, 0.87mmol), NBS (0.154g, CCl 0.87mmol) and among the AEBN of catalytic amount
4In mixture refluxed 6 hours.TLC (hexane) shows and has raw mix and new point.After adding AIBN again, should react and reflux 2 hours again.Do not observe variation.This reaction mixture is cooled to room temperature, removes and desolvate.By preparation TLC purifying, use hexane as eluent, obtain this title compound, be white solid, and raw material.
1H NMR(CDCl
3，500MHz)：δ7.54(s，1H)，7.42(s，1H)，4.67(s，2H)，2.60(s，3H)
Step D. (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[2-iodo-3-methyl-5-(trifluoromethyl) benzyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
At 0 ℃, (0.058g 0.186mmol) adds NaH in the solution in THF (5ml) to the oxazolidone that derives from embodiment xx step xx.This mixture was stirred 30 minutes at 0 ℃.Add bromotoluene (0.064g, 0.169mmol) solution in THF (5mL) that derives from step C by syringe.Then with this mixture stirring at room 12 hours.Should react and handle with saturated ammonium chloride solution.(3 * 15ml) extract with ethyl acetate with this mixture.With the EtOAc layer that merges with the salt water washing and use dried over sodium sulfate.By preparation TLC plate purifying, use EtOAc: hexane=1: 9 obtains this title compound as eluent.
1HNMR(CDCl
3，500MHz)：δ7.92(s，1H)，7.82(s，2H)，7.49(s，1H)，7.38(s，1H)，5.77(d，J＝8Hz，1H)，4.93(d，J＝16Hz，1H)，4.45(d，J＝16Hz，1H)，4.05(m，1H)，2.60(s，3H)，0.81(d，J＝6.5Hz，3H).
Step e: (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-6-methyl-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
With derive from step D title compound (0.07g, 0.11mmol), 2-methoxyl group-4-fluoro-5-isopropyl benzene ylboronic acid (0.036g, 0.17mmol), yellow soda ash (0.024g, 0.23mmol) and the Pd (PPh of catalytic amount
3)
4At 2: 1: 4 EtOH/H
2Mixture heating up in the O/ toluene mixture refluxed 3 hours.Remove and desolvate, (3 * 20ml) extract with methylene dichloride with water layer.With the dichloromethane layer salt water washing that merges, and use dried over sodium sulfate.By preparation TLC plate purifying, use EtOAc: hexane=1: 9 obtains this title compound as eluent.By chirality OD post, use the EtOH/n-heptane to separate two kinds of non-mapping atropisomers of this title compound as eluent.Isomer A (comparatively fast eluting):
1H NMR(CDCl
3，500MHz)：δ7.89(s，1H)，7.75(s，2H)，7.52(s，2H)，6.85(d，J＝8.5Hz，1H)，6.71(d，J＝12Hz，1H)，5.63(d，J＝8Hz，1H)，4.71(d，J＝16Hz，1H)，3.93(m，1H)，3.87(d，J＝16Hz，1H)，3.72(s，3H)，3.22(m，1H)，2.09(s，3H)，1.26(m，6H)，0.53(d，J＝6.5Hz，3H)；LC-MS(M+1)：652.3.
Isomer B (eluting more slowly):
1H NMR(CDCl
3，500MHz)：δ7.89(s，1H)，7.73 (s，2H)，7.53(s，2H)，6.90(d，J＝8.5Hz，1H)，6.73(d，J＝12Hz，1H)，5.60(d，J＝8Hz，1H)，4.69(d，J＝15.5Hz，1H)，3.88(m，1H)，3.86(d，J＝15.5Hz，1H)，3.76(s，3H)，3.22(m，1H)，2.11(s，3H)，1.23(m，6H)，0.48(d，J＝6.5Hz，3H)；LC-MS(M+1)：652.3.
Embodiment 328
(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-{[6-chloro-4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
Steps A .[2-chloro-6-methyl-4-(trifluoromethyl) phenyl] amine
With 2-bromo-6-chloro-4-5-trifluoromethylaniline (1.00g, 3.64mmol), front three basic ring boron oxygen (0.66ml, 0.59g, 4.47mmol), salt of wormwood (1.00g, 7.30mmol) and the Pd (PPh of catalytic amount (10%)
3)
4Mixture in DMF (5ml) was 90 ℃ of heating 14 hours.Add entry (20ml).(3 * 50ml) extract with ethyl acetate with this mixture.With the EtOAc layer that merges with the salt water washing and use dried over sodium sulfate.By quick column purification, use EtOAc: hexane (1: 9) obtains this title compound as eluent, is colorless oil.
1H NMR(CDCl
3，500MHz)：δ7.43(s，1H)，7.24(s，1H)，4.38(br s，2H)，2.22(s，3H).
Step B[2-chloro-6-(iodomethyl) 4-(trifluoromethyl) phenyl] amine
With derive from steps A title compound (0.67g, 3.20mmol), n-amyl nitrite (0.75g, 6.41mmol) and I2 (1.05g, 4.17mmol) mixture in chloroform (10ml) refluxed 1 hour.With this mixture with methylene dichloride (20ml) dilution and with saturated sodium thiosulfate solution and salt water washing.With the organic layer dried over sodium sulfate.By quick column purification, use hexane as eluent, obtain 2-iodo-3-chloro-4-trifluoromethyl benzyl iodine.
1H NMR(CDCl
3，500MHz)：δ7.60(s，2H)，4.65(s，2H).
Step C. (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[3-chloro-2-iodo-5-(trifluoromethyl) benzyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
At 0 ℃, (0.058g 0.186mmol) enters NaH in the solution in THF (5ml) to the oxazolidone that derives from embodiment xx step xx.This mixture was stirred 30 minutes at 0 ℃.Add 2-iodo-3-chloro-4-trifluoromethyl benzyl iodine (0.226g, 0.51mmol) solution in THF (5mL) that derives from step B by syringe.With this mixture stirring at room 3 hours.Should react with saturated ammonium chloride solution and handle, (3 * 20ml) extract with ethyl acetate with this mixture.With the EtOAc layer that merges with the salt water washing and use dried over sodium sulfate.By quick column purification, use EtOAc: hexane=1: 9 obtains this title compound as eluent.LC-MS(M+1)：432.0。
Step D:(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-{[6-chloro-4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
With derive from step C title compound (0.10g, 0.16mmol), 2-methoxyl group-4-fruoro-5-isopropyl benzene ylboronic acid (0.067g, 0.32mmol), yellow soda ash (0.034g, 0.32mmol) and the Pd (PPh of catalytic amount
3)
4At 2: 1: 4 EtOH/H
2Mixture heating up in the O/ toluene mixture refluxed 4 hours.Remove and desolvate, (3 * 15ml) extract with methyl chloride with water layer.With the dichloromethane layer salt water washing that merges, and use dried over sodium sulfate.By preparation TLC plate purifying, use EtOAc: hexane=1: 9 obtains this title compound as eluent.By chirality AD post, use the i-PrOH/n-heptane to separate two kinds of non-mapping atropisomers of this title compound.Isomer A (comparatively fast eluting):
1H NMR(CDCl
3，500MHz)：δ7.91(s，1H)，7.75(s，3H)，7.61(s，1H)，6.92(d，J＝8.5Hz，1H)，6.73(d，J＝12Hz，1H)，5.64(d，J＝8Hz，1H)，4.72(d，J＝16Hz，1H)，3.95(d，J＝16Hz，1H)，3.93(m，1H)，3.78(s，3H)，3.22(m，1H)，1.23(m，6H)，0.55(d，J＝7Hz，3H)；LC-MS(M+1)：672.1.
Isomer B (eluting more slowly):
1H NMR(CDCl
3，500MHz)：δ7.89(s，1H)，7.75(s，1H)，7.73(s，2H)，7.62(s，1H)，6.98(d，J＝8.5Hz，1H)，6.74(d，J＝12Hz，1H)，5.61(d，J＝8.5Hz，1H)，4.72(d，J＝16Hz，1H)，3.91(d，J＝16Hz，1H)，3.87(m，1H)，3.79(s，3H)，3.22(m，1H)，1.22(m，6H)，0.48(d，J＝6.5Hz，3H)；LC-MS(M+1)：672.1.
Intermediate 22
(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-(2-bromo-5-luorobenzyl)-4-methyl isophthalic acid, 3- azoles alkane-2-ketone
At 0 ℃, to (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone (2.0g, 6.39mmol) disposable adding NaH (285mg in the solution in THF (40mL), the suspension of 60w/w% in mineral oil, 7.13mmol, 1.1eq.).The gained foam mixture is stirred in ice bath.THF (50mL) is added in this reaction.This mixture was stirred 30 minutes at 0 ℃.Add 2-bromo-5-fluoro benzyl bromide (1.712g, 6.39mmol) solution in THF (20mL).The gained mixture is stirred cooling 30 minutes, be warmed to room temperature then.This is reflected at 3 hours fully.Monitor by LC-MS.Should react with saturated aqueous ammonium chloride and handle (80mL).Vacuum is removed volatile constituent.Crude mixture is extracted with EtOAc, and use dried over sodium sulfate.Gained classifying gel shape thing is passed through silicon-dioxide purifying (Biotage40+M cartridge, EtOAc/ hexane, gradient).Obtain this title compound, be clarification oily matter.
LC-MS：500.09(M+1)
+.
1H NMR(CDCl
3，500MHz)δ7.88(s，1H)，7.79(s，2H)，7.55(dd，J＝8.8，5.2Hz，1H)，7.17(dd，J＝8.7，4.5Hz，1H)，6.95(m，1H)，5.74(d，J＝8.0Hz，1H)，4.83(d，J＝15.8，1H)，4.54(d，J＝16.0Hz，1H)，4.11(m，1H)，0.80(d，J＝6.6Hz，3H)
Embodiment 329
(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[(4,4 '-two fluoro-5 '-sec.-propyl-2 '-methoxyl biphenyl-2-yl) methyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
To (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-(2-bromo-5-luorobenzyl)-4-methyl isophthalic acid, (1.0g is 2.0mmol) 1 for 3- azoles alkane-2-ketone, add (4-fluoro-5-sec.-propyl-2-p-methoxy-phenyl) boric acid (509mg in the solution in the 4-dioxane (6mL), 2.4mmol), [1,1 '-two (diphenylphosphino)-ferrocene] palladium chloride (II) (82mg, 5mol%) and potassium hydroxide aqueous solution (1.3mL, 3M, 2eq.).With this reaction mixture nitrogen purging, in microwave container, seal then.This reaction vessel was carried out microwave irradiation 40 minutes at 150 ℃.With the aftertreatment of crude mixture water.With volatile matter is evaporated.The gained mixture is extracted with EtOAc.With the extraction liquid dried over sodium sulfate that merges.(Biotage 40+M tube is with EtOAc/ hexane wash-out, gradient by the silicon-dioxide purifying for gained purple resistates; 5%-25%).Obtain this title compound, be the clarification solid.LC-MS：588.23 (M+1)
+。
1H NMR (CDCl
3, 500MHz) 6: 4 mixtures of rotational isomer
δ7.85(s，1H)，7.69(s，2H)，7.16-7.21(m，1.5H)，7.04-7.13(m，1.5H)，6.96(dd，J＝14.3，8.80Hz，1H)，6.65(d，J＝10.0Hz，1H)，5.59(d，J＝8.0Hz，0.6H)，5.43(d，J＝8.0Hz，0.4H)，4.85(d，J＝15.8Hz，0.6H)，4.82(d，J＝15.8Hz，0.4H)，4.02(d，J＝15.8Hz，0.6H)，3.85(m，0.6H)，3.76-3.81(m，0.8H)，3.75(s，1.8H)，3.73(s，1.2H)，3.19(m，1H)，1.14-1.26(m，6H)，0.56(d，J＝6.6Hz，1.2H)，0.38(d，J＝6.6Hz，1.8H)
Intermediate 23
(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-(2-chloro-4-luorobenzyl)-4-methyl isophthalic acid, 3- azoles alkane-2-ketone
At 0 ℃, to (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone (1.0g, 3.19mmol)/THF (40mL) solution in disposable adding NaH (153mg, the suspension of 60w/w% in mineral oil, 3.83mmol, 1.2eq.).The gained foam mixture was stirred in ice bath 30 minutes, add then 2-chloro-4-fluorobenzyl chloride (572mg, 3.19mmol).The gained mixture was stirred 30 minutes at 0 ℃, be warmed to ambient temperature overnight.This is reflected at room temperature can not carry out, with its in 60 ℃ of oil baths warm 20 hours.Sample aliquot shows this is reacted completely.It is used NH
4The Cl aqueous solution (50mL) is handled.Volatile matter is evaporated.The gained mixture is extracted with EtOA.With the extraction liquid dried over sodium sulfate that merges, filtration and vacuum concentration are to yellow oil.(Biotage 40+M tube is with EtOAc/ hexane wash-out, gradient by the silicon-dioxide purifying for oily matter; 5%-40%).Obtain this title compound, be flint glass shape thing.
LC-MS：456.12(M+1)
+.
1H MR(CDCl
3，500MHz)δ7.89(s，1H)，7.77(s，2H)，7.46(dd，J＝8.7，6.0Hz，1H)，7.17(dd，J＝8.4，2.5Hz，1H)，7.03(m，1H)，5.68(d，J＝8.2Hz，1H)，4.83(d，J＝15.6，1H)，4.36(d，J＝15.3Hz，1H)，4.06(m，1H)，0.79(d，J＝6.4Hz，3H).
Embodiment 330
(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[(4 ', 5-two fluoro-5 '-sec.-propyl-2 '-methoxyl biphenyl-2-yl) methyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
To (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-(2-chloro-4-luorobenzyl)-4-methyl isophthalic acid, 3- azoles alkane-2-ketone (100mg, 0.22mmol) 1, add (4-fluoro-5-sec.-propyl-2-p-methoxy-phenyl) boric acid (55.8mg in the solution in the 4-dioxane (1mL), 0.26mmol), acid chloride (II) (10mg, 20mol%), potassium hydroxide aqueous solution (147 μ L, 3M is 2eq.) with three-tertiary butyl phosphine (13.4mg, 0.066mmol, 30mol%, the 10%w/w hexane solution).With this reaction mixture nitrogen purging, in microwave container, seal.This reaction vessel was carried out microwave irradiation 40 minutes at 140 ℃.LC-MS shows and has formed required product.Its water (50mL) is handled.Volatile matter is evaporated.The gained mixture is extracted with EtOAc.With the extraction liquid dried over sodium sulfate that merges, filtration and vacuum concentration are to oily matter.After adopting silica gel to carry out carrying out twice purifying, obtain this title compound LC-MS:588.25 (M+1) with an anti-phase prep-HPLC
+
Intermediate 24
(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-(2-chloro-6-luorobenzyl)-4-methyl isophthalic acid, 3- azoles alkane-2-ketone
At 0 ℃, to (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone (1.0g, 3.19mmol) disposable adding NaH (153mg in the solution in THF (40mL), the suspension of 60w/w% in mineral oil, 3.83mmol, 1.2eq.).The gained foam mixture was stirred in ice bath 30 minutes, add then benzyl chloride (572mg, 3.19mmol).The gained mixture was stirred 30 minutes at 0 ℃, be warmed to 60 ℃ then and kept 30 hours.Sample aliquot show residue about 10% initial (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone.Should react cooling, use saturated NH
4Cl (50mL) handles.Volatile matter is evaporated.The gained mixture is extracted with EtOAc.With the extraction liquid dried over sodium sulfate that merges, filtration and vacuum concentration are to yellow oil.Pass through SiO
2(Biotage 40+M is with EtOAc/ hexane wash-out, gradient for purifying; 5%-40%), obtain this title compound, be flint glass shape thing.
LC-MS：456.11(M+1)
+.
1H NMR(CDCl
3，500MHz)δ7.87(s，1H)，7.77(s，2H)，7.22-7.34(m，2H)，7.01-7.09(m，1H)，5.62(d，J＝8.2Hz，1H)，5.01(dd，J＝14.8，2.0Hz，1H)，4.45(d，J＝14.6Hz，1H)，3.91(m，1H)，0.81(d，J＝6.4Hz，3H).
Embodiment 331
(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[(3,4 '-two fluoro-5 '-sec.-propyl-2 '-methoxyl biphenyl-2-yl) methyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
To (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-(2-chloro-6-luorobenzyl)-4-methyl isophthalic acid, 3- azoles alkane-2-ketone (327mg, 0.72mmol) 1, add in the solution in the 4-dioxane (4mL) (4-fluoro-5-sec.-propyl-2-p-methoxy-phenyl) boric acid (228mg, 1.08mmol), acid chloride (II) (33mg, 20mol%), potassium hydroxide (588 μ L, 3M is 2.5eq.) with three-tertiary butyl phosphine (44mg, 0.22mmol, 30mol%, the 10%w/w hexane solution).With gained reaction mixture nitrogen purging, in microwave container, seal.This reaction vessel was carried out microwave irradiation 50 minutes at 135 ℃.LC-MS shows that the feed/product ratio is about 55: 45.Apply reaction conditions (135 ℃ of μ w 50 minutes) once more for reaction mixture.LC-MS microdetermination shows from generation progress of irradiation reaction for the second time.In reaction mixture, add again acid chloride (II) (33mg, 20mol%), potassium hydroxide (588 μ L, 3M, 2.5eq.) and three-tertiary butyl phosphine (44mg, 0.22mmol, 30mol%, 10%w/w hexane solution).Apply reaction conditions (135 ℃ of μ w 1 hour) LC-MS once more for again reaction mixture and show that reaction does not have remarkable break-throughs.With the reaction mixture water treatment.Volatile matter is evaporated.The gained mixture is extracted with EtOAc.With the extraction liquid dried over sodium sulfate that merges, filtration and vacuum concentration are to yellow oil.Oily matter is dissolved among the DMSO, by twice of anti-phase prep-HPLC purifying (post: Kromasil, 100-5C18,100 * 21.1mm), use 10%-90%H
2O (0.1%TFA, v/v)/MeCN (0.1%TFA, v/v) wash-out.The gained glassy mass is purifying on the prep-TLC plate, with 100% methylene dichloride wash-out, has obtained this title compound.LC-MS：588.21(M+1)
+。
1H NMR (CDCl
3, 500MHz) 1: 1 mixture of rotational isomer
δ7.83(s，1H)，7.67(s，1H)7.65(s，1H)，7.32-7.41(m，1H)，7.09-7.16(m，1H)，6.96-7.06(m，1H)，6.64-6.70(m，1H)，5.47(d，J＝8.0Hz，0.5H)，5.19(d，J＝7.8Hz，0.5H)，4.96(d，J＝14.9Hz，0.5H)，4.80(d，J＝15.1Hz，0.5H)，4.31(d，J＝15.1Hz，0.5H)，3.91(d，J＝15.1Hz，0.5H)，3.78(s，1.5H)，3.75(s，1.5H)，3.62-3.69(m，1H)，3.15-3.26(m，1H)，1.14-1.25(m，6H)，0.54(d，J＝6.6Hz，1.5H)，0.33(d，J＝6.4Hz，1.5H).
Embodiment 332
Steps A: methyl alcohol 2-bromo-5-nitrophenyl)
(10g 38.46mmol) is dissolved among the THF (100mL), is cooled to interior temperature=-15～-10 ℃ with 2-bromo-5-nitrobenzoic acid methyl esters.In this mixture, add lentamente diisobutyl aluminium hydride solution (solution of 1.0M in toluene, 57mL, 57mmol), temperature in keeping＜0 ℃.The gained mixture stirring at room 1 hour, is used NH then
4The Cl aqueous solution (150mL) is handled.Crude mixture with EtOAc (100mL) dilution, is filtered then.Volatile matter is removed in decompression, uses EtOA (200mL * 2) extraction then.With the extraction liquid dried over sodium sulfate that merges, filter and be evaporated to oily matter.Gained oily matter is passed through silicon-dioxide purifying (Biotage 65i, EtOAc/ hexane, gradient; 10%-15%).Obtain this title compound, be the yellow solid crystallization.
1H NMR(CDCl
3，500MHz)δ8.44(d，J＝2.74Hz 1H)，8.02(dd，J＝8.7，2.8Hz.1H)，7.72(d，J＝8.7，1H)，4.83(s，3H).
Step B:1-bromo-2-(brooethyl)-4-oil of mirbane
At 0 ℃ to 2-bromo-5-nitrophenyl) methyl alcohol (and 4.746g, 20.45mmol) add in the solution in anhydrous methylene chloride (150mL) triphenylphosphine (6.43g, 24.5mmol) and carbon tetrabromide (8.15g, 24.5mmol).This mixture was stirred 30 minutes at 0 ℃, stirred 1 hour at 20 ℃ then.TLC shows the raw material completely consumed.Volatile matter is removed in decompression.Gained oily matter by silicon-dioxide purifying (Biotage 4OM is with EtOAc/ hexane wash-out, gradient), is obtained this title compound, be colorless solid.
1H NMR(CDCl
3，500MHz)δ8.33(d，J＝2.74Hz 1H)，8.03(dd.J＝8.7，2.5Hz.1H)，7.78(d，J＝8.7，1H)，4.63(s，3H).
Step C:(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-(2-bromo-5-nitrobenzyl)-4-methyl isophthalic acid, 3- azoles alkane-2-ketone
At 0 ℃, to (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone (5.3g, 16.95mmol) disposable adding NaH (746mg in the solution in THF (100mL), the suspension of 60w/w% in mineral oil, 18.65mmol, 1.1eq.).The gained foam mixture is stirred in ice bath.THF (100mL) is added this reaction.This mixture was stirred 30 minutes at 0 ℃.Add 1-bromo-2-(brooethyl)-4-oil of mirbane (5.0g, 16.95mmol) solution in THF (25mL).The gained mixture is stirred cooling 30 minutes, be warmed to room temperature then.This is reflected at 1.5 hours fully.Should react and use saturated NH
4The Cl aqueous solution (100mL) is handled.Crude mixture is extracted with EtOAc, and use dried over sodium sulfate.Gained classifying gel shape thing by the silicon-dioxide purifying (Biotage 4OM tube, the EtOAc/ hexane, gradient, 25%-45%).Obtain this title compound, be solid crystal.
LC-MS：529.11(M+1)
+.
1HNMR(CDCl
3，500MHz)δ8.24(d，J＝2.5Hz，1H)，8.07(dd，J＝8.7，2.8Hz，1H)，7.91(s，1H)，7.79-7.83(m，3H)，5.82(d，J＝7.8Hz，1H)，4.82(d，J＝16.2Hz，1H)，4.44(d，J＝16.3，1H)，4.11-4.20(m，1H)，0.84(d，J＝6.6Hz，3H).
Step D:(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[(4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-nitrobiphenyl-2-yl) methyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
To (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-(2-bromo-5-nitrobenzyl)-4-methyl isophthalic acid, 3- azoles alkane-2-ketone (3.877g, 7.35mmol) at toluene (24mL): ethanol (12mL): add (4-fluoro-5-sec.-propyl-2-p-methoxy-phenyl) boric acid (2.337g in the solution in water (6mL) mixture, 11.03mmol), tetrakis triphenylphosphine palladium (0) (425mg, 5mol%) and yellow soda ash (1.56g, 14.72mmol).To feed nitrogen in the gained mixture, in 90 ℃ of oil baths, heated 10 hours then.Sample aliquot shows the raw material completely consumed.With this reaction brine treatment.The gained mixture is extracted and uses dried over sodium sulfate with EtOAc.The glassy mixture of gained is by silicon-dioxide purifying (Biotage 4OS tube, EtOAc/ hexane, gradient).Obtain this title compound, be solid crystal.LC-MS：615.26(M+1)
+。
1H NMR (CDCl
3, 500MHz) 1: 1 mixture of rotational isomer
δ8.31(s，1H)，8.20-8.26(m，1H)，7.86(s，1H)，7.70(s，2H)，7.39-7.43(m，1H)，6.96-7.01(m，1H)，6.67-6.72(m，1H)，5.64(d，J＝8.0Hz，0.5H)，5.48(d，J＝8.0Hz，0.5H)，4.90(d，J＝16.3Hz，0.5H)，4.86(d，J＝16.3Hz，0.5H)，4.10-4.16(m，0.5H)，3.84-3.94(m，1.5H)，3.77(s，1.5H)，3.75(s，1.5H)，3.15-3.26(m，1H)，1.15-1.29(m，6H)，0.57(d，J＝6.6Hz，1.5H)，0.40(d，J＝6.6Hz，1.5H).
Embodiment 333
(4S, 5R)-3-[(4-amino-4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl biphenyl-2-yl) methyl]-5-[3,5-two (trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
Will (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[(4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-nitrobiphenyl-2-yl) methyl]-the 4-methyl isophthalic acid, (1.94g, 3.16mmol) solution in methyl alcohol (20mL) applies H to 3- azoles alkane-2-ketone
2(40psi., Pa Er wobbler) in 20 ℃ 1.5 hours.LCMS shows and has micro material.Crude mixture is filtered (521) via bed of diatomaceous earth.With filtrate vacuum-evaporation, obtained glassy product.LC-MS：585.32(M+1)
+。
1H NMR (CDCl
3, 500MHz) 1: 1 mixture of rotational isomer
δ7.83(s，1H)，7.67(s，2H)，6.93-7.06(m，2H)，6.87(s，0.5H)，6.72-6.82(m，1.5H)，5.57(d，J＝8.0Hz，0.5H)，5.36(d，J＝8.0Hz，0.5H)，4.77(d，J＝5.5Hz，0.5H)，4.74(d，J＝6.5Hz，0.5H)，3.95(d，J＝15.5Hz，0.5H)，3.75-3.86(m，1.5H)，3.73(s，3H)，3.12-3.24(m，1H)，1.11-1.29(m，6H)，0.47(d，J＝6.5Hz，1.5H)，0.29(d，J＝6Hz，1.5H).
Embodiment 334
(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[(4-bromo-4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl biphenyl-2-yl) methyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
To (4S, 5R)-3-[(4-amino-4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl biphenyl-2-yl) methyl]-5-[3,5-two (trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone (526mg, 0.90mmol) add in the solution in bromofom (2.5mL) nitrite tert-butyl (186mg, 1.80mmol).The gained mixture was stirred 20 minutes at 80 ℃.Sample aliquot shows and reacts completely.By silica gel chromatography purification reaction crude product, obtained this title compound, be yellow glass shape thing.LC-MS：650.09(M+1)
+。
1H NMR (CDCl
3, 500MHz) 1: 1 mixture of rotational isomer
δ7.85(s，1H)，7.69(s，2H)，7.60(s，0.5H)，7.48-7.53(m，1.5H)，7.07-7.11(m，1H)，6.93-6.99(m，1H)，6.62-6.67(m，1H)，5.59(d，J＝8.0Hz，0.5H)，5.39(d，J＝7.0Hz，0.5H)，4.82(d，J＝6.5Hz，0.5H)，4.75(d，J＝6.5Hz，0.5H)，3.98(d，J＝16.0Hz，0.5H)，3.76-3.85(m，1.5H)，3.75(s，1.5H)，3.74(s，1.5H)，3.13-3.23(m，1H)，1.13-1.29(m，6H)，0.52(d，J＝6.5Hz，1.5H)，0.34(d，J＝7.0Hz，1.5H).
Embodiment 335
(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[(4-cyclopropyl-4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl biphenyl-2-yl) methyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
To (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[(4-bromo-4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl biphenyl-2-yl) methyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone (100mg, 0.15mmol) 1, add cyclopropylboronic acid (10mg in the solution in the 4-dioxane (0.5mL), 0.19mmol), [1,1 '-two (diphenylphosphino) ferrocene] palladium chloride (II) (82mg, 8mol%), two (tri-butyl phosphine) palladium (0) (10mg, 13mol%) and potassium hydroxide aqueous solution (78 μ L, 3M, 1.5eq.).With this reaction mixture nitrogen purging, be sealed in the microwave container then.Be reflected at 150 ℃ to this and applied microwave irradiation 30 minutes.Sample aliquot shows the raw material completely consumed.With this reacting coarse product water aftertreatment.The gained mixture is extracted with EtOAc, use dried over sodium sulfate.Use two preparation TLC plate purifying, use respectively 20%EtOAc in hexane mixture and the mixture of 5%EtOAc in methylene dichloride as eluent, obtained this title compound, be glassy mass.LC-MS：610.26(M+1)
+。
1H NMR (CDCl
3, 500MHz) 1: 1 mixture of rotational isomer
δ7.84(s，1H)，7.65-7.70(m，2H)，7.21(s，0.5H)，7.08-7.14(m，1.5H)，6.95-7.04(m，2H)，6.61-6.67(m，1H)，5.52(d，J＝8.5Hz，0.5H)，5.27(d，J＝8.0Hz，0.5H)，4.85(d，J＝15.5Hz，0.5H)，4.81(d，J＝15.5Hz，0.5H)，4.00(d，J＝15.5Hz，0.5H)，3.69-3.81(m，4.5H)，3.13-3.24(m，1H)，1.90-1.99(m，1H)，1.12-1.30(m，6H)，0.98-1.15(m，2H)，0.71-0.77(m，2H)，0.48(d，J＝6.5Hz，1.5H)，0.29(d，J＝6.5Hz，1.5H).
Embodiment 336
(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(methylthio group) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
To (4S, 5R)-3-[(4-amino-4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl biphenyl-2-yl) methyl]-5-[3,5-two (trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone (200mg, 0.34mmol) add in the solution in methyl disulfide (2mL) nitrite tert-butyl (70mg, 0.68mmol).The gained mixture was stirred 30 minutes at 80 ℃.Sample aliquot shows and reacts completely.Use two preparation TLC plate purifying, use respectively 20%EtOAc in hexane mixture and the mixture of 10%EtOAc in methylene dichloride as eluent, obtained this title compound, be glassy mass.LC-MS：616.21(M+1)
+。
1H NMR (CDCl
3, 500MHz) 1: 1 mixture of rotational isomer
δ7.84(s，1H)，7.67(s，2H)，7.35(s，0.5H)，7.22-7.28(m，1.5H)，7.12-7.19(m，1H)，6.94-7.02(m，1H)，6.61-6.68(m，1H)，5.55(d，J＝8.0Hz，0.5H)，5.31(d，J＝9.5Hz，0.5H)，4.85(d，J＝16.0Hz，0.5H)，4.83(d，J＝15.5Hz，0.5H)，3.99(d，J＝15.5Hz，0.5H)，3.69-3.81(m，4.5H)，3.12-3.24(m，1H)，2.54，(s，1.5H)，2.53(s，1.5H)，1.11-1.27(m，6H)，0.50(d，J＝6.5Hz，1.5H)，0.31(d，J＝7.0Hz，1.5H).
Embodiment 337
(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(methyl sulphonyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
To (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-{[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(methylthio group) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone (156mg, 0.25mmol) add in the solution in methylene dichloride (3mL) 3-chlorine peroxybenzoic acid (175mg, 1.01mmol).The gained mixture was stirred 1 hour at 20 ℃.Sample aliquot shows and reacts completely.This reacting coarse product is distributed between water and methylene dichloride.Isolate organic layer, and use dried over sodium sulfate.Use three preparation TLC plate purifying, use respectively the mixture of 50%EtOAc in hexane, 20%EtOAc in methylene dichloride mixture and methylene dichloride as eluent, obtained this title compound, be glassy mass.LC-MS：648.29(M+1)
+。
1H NMR (CDCl
3, 500MHz) 1: 1 mixture of rotational isomer
δ7.99(s，0.5H)，7.92-7.96(m，1.5H)，7.86(s，1H)，7.70(s，2H)，7.42-7.46(m，1H)，6.96-7.00(m，1H)，6.69(d，J＝12Hz，1H)，5.64(d，J＝8.0Hz，0.5H)，5.45(d，J＝8.0Hz，0.5H)，4.93(d，J＝6.0Hz，0.5H)，4.90 (d，J＝6.5Hz，0.5H)，4.09(d，J＝16Hz，0.5H)，3.88(d，J＝16Hz，0.5H)，3.80-3.88(m，1H)，3.78(s，1.5H)，3.75(s，1.5H)，3.16-3.25(m，1H)，3.14(s，1.5H)，3.13(s，1.5H)，1.22-1.28(m，6H)，0.57(d，J＝6.5Hz，1.5H)，0.38(d，J＝6.5Hz，1.5H).
Embodiment 338
2-((4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-4-methyl-2-oxo-1,3- azoles alkane-3-yl } methyl)-4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl biphenyl-4-formonitrile HCN
To (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[(4-bromo-4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl biphenyl-2-yl) methyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone (100mg, 0.15mmol) at N, add in the solution in the dinethylformamide (1.5mL) cupric cyanide (I) (17mg, 0.19mmol).With gained reaction mixture and nitrogen purging, be sealed in the microwave container.Applied microwave irradiation 30 minutes at 150 ℃ for this container.LC-MS shows and only has the bromide raw material.(10mg 6mol%), applied microwave irradiation 30 minutes at 150 ℃ once more to add tetrakis triphenylphosphine palladium (0) in this reaction mixture.Sample aliquot shows and has formed required product, and all raw material bromides all consume.This reacting coarse product is distributed between water and hexane.Water is stripped with ether.With the extraction liquid dried over sodium sulfate that merges.Use two preparation TLC plate purifying, use mixture and 4%EtOAc the mixture in methylene dichloride of 20%EtOAc in hexane to launch respectively, obtained this title compound, be glassy mass.LC-MS：595.03(MH+1)
+。
1H NMR (CDCl
3, 500MHz) 1: 1 mixture of rotational isomer
δ7.86(s，1H)，7.61(S，0.5H)，7.67-7.71(m，2.5H)，7.64-7.68(m，1H)，7.32-7.36(m，1H)，6.98(d，J＝8.5Hz，0.5H)，6.95(d，J＝8.5Hz，0.5H)，6.68(d，J＝12Hz，1H)，5.62(d，J＝8.0Hz，0.5H)，5.46(d，J＝8.0Hz，0.5H)，4.85(d，J＝16.0Hz，0.5H)，4.80(d，J＝16.0Hz，0.5H)，4.06(d，J＝16Hz，0.5H)，3.79-3.86(m，1H)，3.70-3.78(m，3.5H)，3.16-3.24(m，1H)，3.75(s，1.5H)，3.16-3.25(m，1H)，3.14(s，1.5H)，3.13(s，1.5H)，1.15-1.27(m，6H)，0.54(d，J＝7.0H2，1.5H)，0.37(d，J＝6.5Hz，1.5H)
Embodiment 339
(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[(4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-methyl diphenyl-2-yl) methyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
To (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[(4-bromo-4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl biphenyl-2-yl) methyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone (82.5mg, 0.13mmol) 1, add in the solution in the 4-dioxane (1mL) trimethylboroxin (39mg, 0.31mmol), Pd (PPh
3)
4(15mg, 10mol%) and salt of wormwood (35mg, 0.25mmol).With gained reaction mixture nitrogen purging, be sealed in the microwave container.Applied microwave irradiation 15 minutes at 130 ℃ for this container.This crude mixture is diluted with salt solution, extract with EtOAc.With the organic extract liquid dried over sodium sulfate that merges.Use two preparation TLC plate purifying, use mixture and the methylene dichloride of 20%EtOAc in hexane to launch respectively, obtained this title compound, be glassy mass.LC-MS：584.08(M+1)
+。
1H NMR (CDCl
3, 500MHz) 1: 1 mixture of rotational isomer
δ7.84(s，1H)，7.65-7.70(m，2H)，7.29(s，0.5)，7.18-7.22(m，1.5H)，7.10-7.15(m，1H)，7.01(d，J＝8.0Hz，0.5H)，6.98(d，J＝8.5Hz，0.5H)，6.66(d，J＝5.0Hz，0.5H)，6.64(d，J＝5.5Hz，0.5H)，5.54(d，J＝8.5Hz，0.5H)，5.31(d，J＝8.0Hz，0.5H)，4.82(d，J＝15.5Hz，1H)，4.02(d，J＝15Hz，0.5H)，3.71-3.82(m，5H)，3.15-3.24(m，1H)，2.42(s，1.5H)，2.41(s，1.5H)，1.13-1.27(m，6H)，0.48(d，J＝6.5Hz，1.5H)，0.31(d，J＝6.5Hz，1.5H).
Embodiment 340
(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[(4 '-fluorine 4-pseudoallyl-5 '-sec.-propyl-2 '-methoxyl biphenyl-2-yl) methyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
To (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[(4-bromo-4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl biphenyl-2-yl) methyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone (38mg, 0.059mmol) 1, add (2-chloro-5-isopropyl phenyl) boric acid (10mg in the solution in the 4-dioxane (0.5mL), 0.12mmol), [1,1 '-two (diphenylphosphino) ferrocene] palladium chloride (II) (2.4mg, 5mol%) and potassium hydroxide aqueous solution (40 μ L, 3M, 2eq.).With this reaction mixture nitrogen purging, be sealed in the microwave container then.Be reflected at 140 ℃ to this and applied microwave irradiation 20 minutes.With crude mixture water and EtOAc aftertreatment.The organic extract liquid that merges with dried over sodium sulfate and vacuum concentration, has been obtained crude product.It by preparation TLC plate purifying, with the mixture wash-out of 20%EtOAc in hexane, has been obtained this title compound.LC-MS：610.04(M+1)
+。
1H NMR (CDCl
3, 500MHz) 1: 1 mixture of rotational isomer
δ7.84(s，1H)，7.64-7.70(m，2H)，7.56(s，0.5)，7.45-7.50(m，1.5H)，7.18-7.23(m，1H)，7.02(d，J＝9.0Hz，0.5H)，6.99(d，J＝8.5Hz，0.5H)，6.67(d，J＝7.0Hz，0.5H)，6.64(d，J＝5.5Hz，0.5H)，5.52(d，J＝8.0Hz，0.5H)，5.43(d，J＝8.5Hz，1H)，5.26(d，J＝8.0Hz，0.5H)，5.13-5.17(m，1H)，4.91(d，J＝15.0Hz，0.5H)，4.86(d，J＝15.5Hz，0.5H)，4.04(d，J＝15.5Hz，0.5H)，3.83(d，J＝15.5，0.5H)，3.70-3.78(m，3H)，3.14-3.25(m，1H)，2.18-2.22(m，3H)，1.14-1.29(m，6H)，0.50(d，J＝6.5Hz，1.5H)，0.31(d.J＝6.5Hz，1.5H).
Embodiment 341
(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[(4 '-fluoro-4,5 '-di-isopropyl-2 '-methoxyl biphenyl-2-yl) methyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
Give (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[(4 '-fluoro-4-pseudoallyl-5 '-sec.-propyl-2 '-methoxyl biphenyl-2-yl) methyl]-the 4-methyl isophthalic acid, (15mg, 0.025mmol) solution in methyl alcohol (1mL) applies H to 3- azoles alkane-2-ketone
2(air bag atmosphere) spends the night in 20 ℃.Crude mixture is filtered via the injection filter.With filtrate vacuum-evaporation, by preparation TLC plate purifying, launch with the mixture of 20%EtOAc in hexane, obtained this title compound.LC-MS：612(M+1)
+。
1H NMR (CDCl
3, 500MHz) 1: 1 mixture of rotational isomer
δ7.84(s，1H)，7.64-7.68(m，2H)，7.30(s，0.5)，7.20-7.27(m，1.5H)，7.13-7.17(m，1H)，7.02(d，J＝8.5Hz，0.5H)，6.99(d，J＝8.0Hz，0.5H)，6.65(d，J＝6.0Hz，0.5H)，6.63(d，J＝6.0Hz，0.5H)，5.52(d，J＝8.0Hz，0.5H)，5.25(d，J＝8.0Hz，1H)，4.87(d，J＝15.5Hz，0.5H)，4.82(d，J＝15.5Hz，0.5H)，4.03(d，J＝15.0Hz，0.5H)，3.81(d，J＝15.0Hz，0.5H)，3.69-3.77(m，4II)，3.14-3.24(m，1H)，2.92-3.02(m，1H)，1.14-1.33(m，12H)，0.48(d，J＝6.5Hz，1.5H)，0.30(d，J＝7.0Hz，1.5H.
Intermediate 25
(4S, 5R)-3-(5-amino-2-bromobenzyl)-5-[3,5-two (trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
With (4S, 5R)-and 5-[3,5-two (trifluoromethyl) phenyl]-3-(2-bromo-5-nitrobenzyl)-4-methyl isophthalic acid, 3- azoles alkane-2-ketone (614mg, 1.17mmol), tin chloride (II) dehydrate (1.314g, 5.823mmol) and the mixture of ethanol (3mL) stirred 36 hours at 20 ℃.With this reacting coarse product water aftertreatment.The gained mixture is extracted with EtOAc, and use dried over sodium sulfate.SiO
2Behind the purifying (Biotage 40+M, gradient, the mixture of 0%-35%EtOAc in hexane), obtain this title compound, be glassy mass.
LC-MS：499.05(M+1)
+.
1H NMR(CDCl
3，500MHz)δ7.88(s，1H)，7.77(s，2H)，7.31(d，J＝8.5，1H)，6.77(d，J＝2.7，1H)，6.54(dd，J＝8.5，2.7Hz，1H)，5.69(d，J＝8.0Hz，1H)，4.77(d，J＝15.3，1H)，4.29(d，J＝15.3Hz，1H)，4.05-4.12(m，1H)，0.79(d，J＝6.4Hz，3H).
Intermediate 26
(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[2-bromo-5-(methylthio group) benzyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
To (4S, 5R)-3-(5-amino-2-bromobenzyl)-5-[3,5-two (trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone (457mg, 0.92mmol) add in the solution in methyl disulfide (4mL) nitrite tert-butyl (182 μ L, d=0.867,1.38mmol).The gained mixture was stirred 1 hour at 80 ℃.Sample aliquot shows and reacts completely.By preparation TLC plate purifying, with the mixture of 25%EtOAc in hexane, obtained this title compound, be glassy mass.LC-MS：529.71(M+1)
+。
Embodiment 342
(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-{[2 '-chloro-4 '-fluoro-5 '-sec.-propyl-4-(methylthio group) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
To (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[2-bromo-5-(methylthio group) benzyl]-the 4-methyl isophthalic acid, (60mg is 0.114mmol) 1 for 3- azoles alkane-2-ketone, add (2-chloro-4-fluoro-5-isopropyl phenyl) boric acid (10mg in the solution in the 4-dioxane (1mL), 0.12mmol), [1,1 '-two (diphenylphosphino) ferrocene] palladium chloride (II) (28mg, 30mol%) and potassium hydroxide aqueous solution (95 μ L, 3M, 2eq.).With this reaction mixture nitrogen purging, be sealed in the microwave container then.Be reflected at 150 ℃ to this and applied microwave irradiation 30 minutes.With crude mixture water and EtOAc aftertreatment.The organic extract liquid that merges with dried over sodium sulfate and vacuum concentration, has been obtained crude product.It by preparation TLC plate purifying, has been obtained this title compound.LC-MS：619.95(M+1)
+。
1H NMR (CDCl
3, 500MHz) 1: 1 mixture of rotational isomer
δ7.83-7.88(m，1H)，7.72(s，1H)7.68(s，1H)，7.30-7.35(m，1H)，7.24-7.29(m，1H)，7.11-7.19(m，2.5H)，7.04-7.07(m，0.5H)，5.62(d，J＝8.2Hz，0.5H)，5.24(d，J＝8.0Hz，0.5H)，4.87(d，J＝15.3Hz，0.5H)，4.70(d，J＝15.8Hz，0.5H)，3.79-3.98(m，2H)，3.18(m，1H)，2.55(s，1.5H)，2.54(s，1.5H)，1.20-1.29(m，6H)，0.53(d，J＝6.4Hz，1.5H)，0.47(d，J＝6.6Hz，1.5H).
Embodiment 343
(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[(2 '-chloro-5 '-sec.-propyl-4-nitrobiphenyl-2-yl) methyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
To (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-(2-bromo-5-nitrobenzyl)-4-methyl isophthalic acid, 3- azoles alkane-2-ketone (950mg, 1.80mmol) at toluene (5.2mL): ethanol (2.6mL): add (2-chloro-5-isopropyl phenyl) boric acid (325mg in the solution in water (1.3mL) mixture, 1.64mmol), tetrakis triphenylphosphine palladium (0) (188mg, 10mol%) and yellow soda ash (346mg, 3.26mmol).The gained mixture was heated 12 hours in 80 ℃ of oil baths.Be evaporated to this reacting coarse product dried.The mixture of gained resistates by water and EtOAc carried out aftertreatment.The organic extract liquid that merges with dried over sodium sulfate and vacuum concentration, has been obtained crude product, it has been passed through SiO
2Purifying (Biotage 40+S tube, EtOAc/ hexane, gradient) has obtained this title compound.LC-MS：601.19(M+1)
+。
1H NMR (CDCl
3, 500MHz) 1: 1 mixture of rotational isomer
δ8.31-8.30(m，1H)，8.24-8.28(m，1H)，7.85-7.89(m，1H)，7.68-7.76(m，2H)，7.42-7.48(m，2H)，7.26-7.30(m，1H)，7.04-7.11(m，1H)，5.74(d，J＝7.8Hz，0.5H)，5.58(d，J＝8.0Hz，0.5H)，4.92(d，J＝15.8Hz，0.5H)，4.76(d，J＝16.2Hz，0.5H)，3.97-4.04(m，1.5H)，3.82(dt，J＝8.0，6.6Hz，0.5H)，2.89-2.99(m，1H)1.22-1.29(m，6H)，0.60(d，J＝6.4Hz，1.5H)，0.52(d，J＝6.6Hz，1.5H).
Embodiment 344
(4S, 5R)-3-[(4-amino-2 '-chloro-5 '-isopropyl biphenyl-2-yl) methyl]-5-[3,5-two (trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
Will (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[(2 '-chloro-5 '-sec.-propyl-4-nitrobiphenyl-2-yl) methyl]-the 4-methyl isophthalic acid, (425mg, 0.71mmol) solution in methyl alcohol (10mL) applies H in 20 ℃ to 3- azoles alkane-2-ketone
2(40psi., Pa Er wobbler) 6 hours.Crude mixture is filtered (521) via bed of diatomaceous earth.With filtrate vacuum-evaporation, obtained glassy mass.By preparation TLC plate purifying, launch with the mixture of 20%EtOAc in hexane, obtained this title compound.LC-MS：571.22(M+1)
+。
1HNMR (CDCl
3, 500MHz) 6: 4 mixtures of rotational isomer
δ7.82-7.86(m，1H)，7.65-7.71(m，2H)，7.34-7.38(m，1H)，7.11-7.17(m，2H)，7.02-7.06(m，1H)，6.76-6.82(m，1H)，6.68-6.74(m，1H)，5.58(d，J＝8.0Hz，0.4H)，5.51(d，J＝8.2Hz，0.6H)，4.82(d，J＝15.3Hz，0.6H)，4.70(d，J＝15.6Hz，0.4H)，3.69-4.00(m，4H)，2.84-2.94(m，1H)，1.19-1.28(m，6H)，0.45(d，J＝6.6Hz，1.2H)，0.40(d，J＝6.6Hz，1.8H).
Embodiment 345
(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[(4-bromo-2 '-chloro-5 '-isopropyl biphenyl-2-yl) methyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
To (4S, 5R)-3-[(4-amino-2 '-chloro-5 '-isopropyl biphenyl-2-yl) methyl]-5-[3,5-two (trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone (100mg, 0.175mmol) add nitrite tert-butyl (23 μ L in the solution in bromofom (0.5mL) and methylene dichloride (1mL), d=0.867,90% is pure, 0.193mmol).The gained mixture was stirred 1 hour at 50 ℃.Sample aliquot shows and reacts completely.This reacting coarse product is deposited on 2 preparation TLC plates, uses the methylene dichloride wash-out, obtained this title compound.LC-MS：635.80(M+1)
+。
1HNMR (CDCl
3, 500MHz) 6: 4 mixtures of rotational isomer
δ7.84-7.88(m，1H)，7.67-7.74(m，2H)，7.60-7.63(m，1H)，7.51-7.57(m，1H)，7.38-7.42(m，1H)，7.19-7.23(m，1H)，7.11-7.16(m，1H)，7.09(d，J＝2.3Hz，0.6H)，7.03(d，J＝2.3Hz，0.4H)，5.66(d，J＝8.0Hz，0.4H)，5.55(d，J＝8.0Hz，0.6H)，4.86(d，J＝15.6Hz，0.6H)，4.70(d，J＝15.6Hz，0.4H)，3.77-4.00(m，2H)，2.87-2.95(m，1H)，1.20-1.28(m，6H)，0.53(d，J＝6.6Hz，1.2H)，0.45(d，J＝6.4Hz，1.8H)
Embodiment 346
(4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[(2 '-chloro-4-cyclopropyl-5 '-isopropyl biphenyl-2-yl) methyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
To (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-[(4-bromo-2 '-chloro-5 '-isopropyl biphenyl-2-yl) methyl]-the 4-methyl isophthalic acid, (27mg is 0.043mmol) 1 for 3- azoles alkane-2-ketone, add cyclopropylboronic acid (9mg in the solution in the 4-dioxane (1mL), 0.10mmol), [1,1 '-two (diphenylphosphino) ferrocene] palladium chloride (II) (10.4mg, 30mol%) and potassium hydroxide aqueous solution (42 μ L, 3M, 3eq.).With this reaction mixture nitrogen purging, be sealed in the microwave container then.Be reflected at 120 ℃ to this and applied microwave irradiation 20 minutes.With crude mixture water and EtOAc aftertreatment.The organic extract liquid that merges with dried over sodium sulfate and vacuum concentration, has been obtained crude product.It by preparation TLC plate purifying, with the mixture wash-out of 20%EtOAc in hexane, has been obtained this title compound.LC-MS：595.99(M+1)
+。
1H NMR (CDCl
3, 500MHz) 6: 4 mixtures of rotational isomer
δ7.82-7.86(m，1H)，7.66-7.72(m，2H)，7.36-7.40(m，1H)，7.21-7.23 (m，0.5H)，7.11-7.19(m，3H)，7.01-7.08(m，1.5H)，5.58(d，J＝8.0Hz，0.4H)，550(d，J＝8.0Hz，0.6H)，4.88(d，J＝15.1Hz，0.6H)，4.71(d，J＝15.6Hz，0.4H)，3.76-3.95(m，2H)，2.84-2.95(m，1H)，1.92-2.00(m，1H)，1.18-1.29(m，6H)，1.00-1.07(m，2h)，0.71-0.82(m，2H)，0.47(d，J＝6.6Hz，1.2H)，0.42(d，J＝6.6Hz，1.8H)
According to the method for describing among the embodiment 96, by (4R, 5R)-5-[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl)-biphenyl-2-yl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone has made the compound of describing in table 18.
Table 18
Embodiment 360
(4R, 5R)-3-[3,5-two (trifluoromethyl) benzyl]-5-[5 '-sec.-propyl-2 '-(trifluoromethoxy)-4-(trifluoromethyl) biphenyl-2-yl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
To 80mg (4R, 5R)-3-[3,5-two (trifluoromethyl) benzyl]-5-[2-iodo-5-(trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, add 100mg 5-sec.-propyl-2-(trifluoromethoxy) phenyl-boron dihydroxide, 0.15mL 2M aqueous sodium carbonate and 21mg Pd (PPh in the 3- azoles alkane-solution of 2-ketone in 2mL benzene, 1mL water and 0.5mL ethanol
3)
4The affix reflux exchanger is with this mixture heating up to 100 ℃.This mixture was stirred 24 hours at 100 ℃, then with 10mL EtOAc and the dilution of 10mL water.Separate each phase, and water is extracted with 10mL EtOAc.With the organic phase that merges 10mL salt water washing, use dried over sodium sulfate, and concentrate.At Biotage Horizon, by purified by flash chromatography,, use the mixture of 2-100%EtOAc in hexane to carry out linear gradient elution then on the 25M post resistates with 10CV with the mixture wash-out of 1CV 2%EtOAc in hexane.Use the same terms repurity product, obtained this title compound.Mass spectrum (ESI) 674.4 (M+1).
According to above-mentioned general method, made the compound of in table 19, listing.
Table 19
Intermediate 27
(4R, 5R)-4-ethyl-5-[2-iodo-5-(trifluoromethyl) phenyl]-1,3- azoles alkane-2-ketone
Steps A: (4S)-4-benzyl-3-butyryl radicals-1,3- azoles alkane-2-ketone
With adding n-BuLi in-78 ℃ of solution of about 1 minute clockwise S-benzyl- oxazolidone in 15mL THF, add butyryl chloride then.This mixture was stirred 30 minutes at-78 ℃, then with being warmed to room temperature in about 30 minutes.By adding the saturated NH of 3mL
4The Cl aqueous solution is handled excessive acyl chlorides, removes most of solvent by rotary evaporation then.With the resistates saturated NH of 17mL
4The Cl aqueous solution and 30mL CH
2Cl
2Dilution.Separate each mutually and with water 20mL CH
2Cl
2Extraction.With organic extract liquid 20mL 1N NaOH solution and the water washing of 20mL salt that merges, dry (Na
2SO
4) and concentrate.At Biotage Horizon, by purified by flash chromatography,, use the mixture of 2 → 100%EtOAc in hexane to carry out linear gradient elution then on the 40M post resistates with 10CV with the mixture wash-out of 1CV 2%EtOAc in hexane.Resistates stored in refrigeration chamber spends the night, during residue crystallized.The gained solid is developed with hexane, filtered, and dry under high vacuum.Mass spectrum (ESI) 178.2 (M-C
3H
7CO).
Step B:(4S)-and 4-benzyl-3-((2R)-2-{ (S)-hydroxyl [2-iodo-5-trifluoromethyl) phenyl] methyl } butyryl radicals)-1,3- azoles alkane-2-ketone
According to the method for describing in embodiment 95 steps A, by 5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-formaldehyde (embodiment 80, steps A) and (4S)-4-benzyl-3-butyryl radicals-1,3- azoles alkane-2-ketone has made this title compound.Mass spectrum (ESI) 530.1 (M-OH).
Step C:(4R, 5R)-4-ethyl-5-[2-iodo-5-(trifluoromethyl) phenyl]-1,3- azoles alkane-2-ketone
According to the method for describing among the embodiment 95 step B, by (4S)-4-benzyl-3-((2R)-2-{ (S)-hydroxyl [2-iodo-5-(trifluoromethyl) phenyl] methyl } butyryl radicals)-1,3- azoles alkane-2-ketone has made this title compound.Mass spectrum (ESI) 386.2 (M+1).
Intermediate 28
(4R, 5R)-4-benzyl-5-[2-iodo-5-(trifluoromethyl) phenyl]-1,3- azoles alkane-2-ketone
Steps A: (4S)-4-benzyl-3-(3-phenyl propionyl)-1,3- azoles alkane-2-ketone
According to the method for describing in intermediate 27 steps A, made this title compound by S-benzyl- oxazolidone and hydrocinnamoyl chloride.Mass spectrum (ESI) 178.2 (M-PhC2H4CO).
Step B:(4S)-and 4-benzyl-3-{ (2R, 3S)-2-benzyl-3-hydroxyl-3-[2-iodo-5-(trifluoromethyl) phenyl] propionyl }-1,3- azoles alkane-2-ketone
According to the method for describing in embodiment 95 steps A; by 5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-(embodiment 80 for 2-formaldehyde; steps A) and (4S)-and 4-benzyl-3-(3-phenyl propionyl)-1,3- azoles alkane-2-ketone has made this title compound.Mass spectrum (ESI) 592.3 (M-OH).
Step C:(4R, 5R)-4-benzyl-5-[2-iodo-5-(trifluoromethyl) phenyl]-1,3- azoles alkane-2-ketone
According to the method for describing among the embodiment 95 step B, by (4S)-4-benzyl-3-{ (2R, 3S)-2-benzyl-3-hydroxyl-3-[2-iodo-5-(trifluoromethyl) phenyl] propionyl-1,3- azoles alkane-2-ketone has made this title compound.Mass spectrum (ESI) 448.2 (M+1).
According to above-mentioned general method, made the compound of in table 20, listing.
Table 20
Embodiment 372
Preparation (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-3-([4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] methyl }-the 4-methyl isophthalic acid, the another kind of method of 3- azoles alkane-2-ketone (embodiment 73)
The compound of embodiment 73 can make by method as follows:
Step 1: the Suzuki linked reaction of boric acid 1 and aryl chloride 2
By with the 4.71kg solid K
2CO
3Be added to and make 3M K in the 10.3L water
2CO
3Solution.Apply cooling so that this solution is remained on 20-25 ℃.THF (12L), aryl chloride 2 (2.69kg) and the boric acid 1 (2.74kg) that makes in embodiment 78 are added to this K
2CO
3In, add 1L THF washings then.Use HPLC to analyze 1/2 the 1.00/1.00 ratio that confirms.By this solution being outgased with nitrogen purging 70 minutes.Add solid catalyst 1,1-two (two-tertiary butyl phosphino-) ferrocene palladium chloride (42g) adds the THF washings (1.5L) that outgases then.Organic layer becomes dark-brown immediately.With this biphase mixture under vigorous stirring in 36 ℃ of-40 ℃ of coolings.HPLC shows conversion (15-18 hour) fully, and this mixture is cooled to room temperature, removes water layer.In organic layer, add heptane (25.6L) and water (25.6L), separate each layer.Organic layer is washed with water (19L).With organic layer with 680g Darco KB-B room temperature treatment 60 minutes, filter via solka-floc, with the (～15L) washing of 10%THF/ heptane.With solvent about 45-50 ℃ change into heptane (～35L) until residue＜0.5v%THF.Add heptane again so that cumulative volume is about 45-50L.If do not form brilliant bed, in this solution, add the crystal seed of preparation manipulation before deriving from.These slurries are cooled to room temperature lentamente, are cooled to-15 ℃ then.After-15 ℃ of aging 1-2 hours, the LC of supernatant liquor shows in the supernatant liquor and has lost～the 2g/l product that this dope filtration, (～25L) washing has obtained compound 3 with cold heptane.
Step 2: 3 chlorinations are become 4:
In remaining on 10 ℃ the solution of biaryl thing 3 (3.4kg) in DMF (17L), add thionyl chloride (940ml), then this mixture is warmed to room temperature.With this mixture ageing until the conversion chlorine of measuring＞99.8% by HPLC.Add entry (3.4L) then.Add crystal seed (1wt%), with this mixture ageing 30 minutes, then with adding 5.1L water in 1 hour lentamente.With this solid filtering, at first use 20L1: 1DMF: water washing, use 3 * 20L water washing then.With solid product 4 20 ℃ of dryings until residue＜0.1wt% water.
Step 3: use compound 4 alkylations to generate the product of embodiment 73 product of embodiment 17:
The chiral intermediate that will in embodiment 17, prepare (4S, 5R)-5-[3,5-two (trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone is dissolved in DMF (2.8kg is dissolved among the 32.7L), is cooled to-15 ℃.(3.92L 1.05eq), is added in the dibenzyl chlorine 4 (2.8kg) among the DMF afterwards to add 2.0M NaHMDS with 1.5 hours then.This mixture is warmed to+12 ℃, aging until transforming fully.Add 5N HCl (3.4L) then, add 16L 10%IPAC/ heptane and 34L water afterwards, temperature is remained on 10 ℃-20 ℃.Separate each layer, and with organic layer with 14L 1: 1DMF: water washing twice, use the 14L water washing then 2 times.Analyze the productive rate of organic layer, then via the 2.4kg filtered through silica gel to remove excessive oxazolidone to＜0.5%.With 5%IPAC/ heptane wash silica gel.The organic solution that merges is distilled to remove IPAC to＜1%.Afterwards warm n-heptane solution is transferred in 20 ℃ of n-heptane solutions that contain the 10wt% crystal seed lentamente.Slurries are cooled to-20 ℃ and filtration.The cold heptane wash of filter cake, dry then, obtaining is the compound that makes in embodiment 73 at first.
Intermediate 29
(4R, 5R)-3-[3,5-two (trifluoromethyl) benzyl]-5-[2-iodo-3-nitro-5-(trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
To at 0 ℃ (4R, 5R)-3-[3,5-two (trifluoromethyl) benzyl]-5-[2-iodo-5-(trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone is added in the 2mL nitrosonitric acid in batches.This reaction mixture in stirred overnight at room temperature, was heated 4 hours at 75 ℃ then.With this reaction mixture cooling, be added drop-wise to then in the quick mixture that is stirring of 10mL water and 10mL EtOAc.Separate each mutually and with organic phase with the saturated NaHCO of 10mL respectively
3With the salt water washing, dry (Na
2SO
4) and concentrate.With resistates at Biotage Horizon, pass through purified by flash chromatography on the 25S post, use the mixture wash-out of 1CV 5%EtOAc in hexane, use the mixture of 5 → 100%EtOAc in hexane to carry out linear gradient elution then, obtained this title compound with 10CV.Mass spectrum (ESI) 643 (M+1).
Embodiment 373
(4R, 5R)-3-[3,5-two (trifluoromethyl) benzyl]-5-[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-6-nitro-4-(trifluoromethyl) biphenyl-2-yl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone
According to the method for describing among the embodiment 81, use 48mg (4R, 5R)-3-[3,5-two (trifluoromethyl) benzyl]-5-[2-iodo-3-nitro-5-(trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone and 48mg (4-fluoro-5-sec.-propyl-2-p-methoxy-phenyl) boric acid (embodiment 78), two kinds of atropisomers have been obtained, can be at Biotage Horizon, separate by flash chromatography on the 25S post, with the mixture wash-out of 1CV 5%EtOAc in hexane, use the mixture of 5 → 100%EtOAc in hexane to carry out linear gradient elution then, obtained steric hindrance isomer A[mass spectrum (ESI) 683.4 (M+1) with 10CV] and steric hindrance isomer B[mass spectrum (ESI) 683.3 (M+1)].
Embodiment 374
(4R, 5R)-3-[3,5-two (trifluoromethyl) benzyl]-5-[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-6-iodo-4-(trifluoromethyl) biphenyl-2-yl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone (steric hindrance isomer A)
To 17mg (4R, 5R)-3-[3,5-two (trifluoromethyl) benzyl]-5-[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-6-nitro-4-(trifluoromethyl) biphenyl-2-yl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone adds 5mg PtO in the solution of steric hindrance isomer A (embodiment 373) in 1mL EtOAc
2(Adam ' s catalyzer).With this reaction mixture hydrogen purge, under the hydrogen capsule, to stir 2 hours then, this moment, LC/MS analysis revealed major part was the nitroso-group product.This reaction mixture via diatomite filtration, with the EtOAc washing, is concentrated this filtrate, be to place under the reaction conditions and spend the night.This reaction mixture via diatomite filtration, is washed with EtOAc, and this filtrate is concentrated.Resistates is dissolved in 0.5mL CH
2I
2In, add 6 μ L nitrite tert-butyls.This reaction mixture was stirred 1.5 hours at 80 ℃.This reaction mixture is passed through preparation thin-layer chromatography purifying on 1000 μ M flat boards,, obtained this title compound with the mixture wash-out of 20%EtOAc in hexane.Mass spectrum (ESI) 764.3 (M+1).
Embodiment 375
(4R, 5R)-3-[3,5-two (trifluoromethyl) benzyl]-5-[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-6-iodo-4-(trifluoromethyl) biphenyl-2-yl]-the 4-methyl isophthalic acid, 3- azoles alkane-2-ketone (steric hindrance isomer B)
To 70mg (4R, 5R)-3-[3,5-two (trifluoromethyl) benzyl]-5-[2-iodo-3-nitro-4-(trifluoromethyl) phenyl]-the 4-methyl isophthalic acid, add 124mg SnCl in the 3- azoles alkane-solution of 2-ketone (intermediate 30) in 1mL EtOH
2With this reaction mixture in stirred overnight at room temperature; And then adding 60mg SnCl
2, with this mixture heating up to 80 ℃ and stir and spend the night.This reaction mixture is concentrated, with resistates at 10mL CH
2Cl
2And distribute between the 10mL 1N NaOH.With water with 2 * 10mL CH
2Cl
2Extraction is with the organic phase drying (Na that merges
2SO
4) and concentrate.According to the method for describing among the embodiment 81, use and derive from this reductive resistates and 70mg (4-fluoro-5-sec.-propyl-2-p-methoxy-phenyl) boric acid (embodiment 78), obtained corresponding biphenol compound, be the steric hindrance mixture of isomers.This mixture is dissolved in 0.5mL CH
2I
2In, add 14 μ L nitrite tert-butyls.This reaction mixture was stirred 1.5 hours at 80 ℃, and cooling directly is added on two 1000-μ M thin-layer chromatography flat boards then, with the mixture wash-out of 20%EtOAc in hexane, has obtained the steric hindrance isomer A and the B of this title compound of about equivalent.Mass spectrum (ESI) 764.2 (M+1).
Intermediate 31
4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-formaldehyde
According to the method for describing among the embodiment 81, use 200mg 2-iodo-5-(trifluoromethyl) phenyl aldehyde (embodiment 80, steps A) and 170mg (4-fluoro-5-sec.-propyl-2-p-methoxy-phenyl) boric acid (embodiment 78), obtained this title compound.Mass spectrum (ESI) 341.3 (M+1).
Intermediate 32
5-[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl]-1-(4-methoxy-benzyl) imidazolidin-2-one
Steps A: [4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] [(4-methoxy-benzyl) amino] acetonitrile
To 203mg 4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-formaldehyde (intermediate 31) is at 2mL CH
2Cl
2Add 100 μ L TMSCN in the interior solution, add 1mg ZnI then
2With this mixture stirring at room 30 minutes.Be added among the 2mL MeOH to methoxy-benzyl amine (157 μ L), this mixture heating up was refluxed 1.5 hours.With this reaction mixture cooling and concentrated.With resistates at Biotage Horizon, pass through purified by flash chromatography on the 25M post, with the mixture wash-out of 1CV 2%EtOAc in hexane, use the mixture of 2 → 100%EtOAc in hexane to carry out linear gradient elution then with 10CV, obtained this title compound.Mass spectrum (ESI) 487.2 (M+1).
Step B:5-[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl]-1-(4-methoxy-benzyl) imidazolidin-2-one
To 100mg[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] add 620 μ L 1MLiAlH in 0 ℃ of solution of [(4-methoxy-benzyl) amino] acetonitrile in 4mL THF
4At Et
2In the solution in the O.Remove cooling bath, with this mixture stirring at room 45 minutes.This mixture is cooled to 0 ℃ again, handles by dripping 24 μ L water, the 24 μ L 15%NaOH aqueous solution and 60 μ L water carefully.With solid filtering, use Et
2The O washing, and this filtrate is concentrated.Resistates is dissolved in 2mL CH
2Cl
2In, be cooled to 0 ℃.Add triethylamine (55 μ L), add triphosgene (32mg) then.This mixture was stirred 45 minutes at 0 ℃.This reaction mixture is distributed between 10mL EtOAc and 10mL water.Water is extracted with 10mL EtOAc, the organic layer that merges 10mL salt water washing, dry (Na
2SO
4) and concentrate.With resistates at Biotage Horizon, pass through purified by flash chromatography on the 25S post, with the mixture wash-out of 1CV 15%EtOAc in hexane, use the mixture of 15 → 100%EtOAc in hexane to carry out linear gradient elution then with 10CV, obtained this title compound.Mass spectrum (ESI) 517.3 (M+1).
Embodiment 376
1-[3,5-two (trifluoromethyl) benzyl]-4-[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] imidazolidin-2-one
Steps A: 1-[3,5-two (trifluoromethyl) benzyl]-4-[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl]-3-(4-methoxy-benzyl) imidazolidin-2-one
To 19mg 5-[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl]-add 3mg NaH (60% in oil dispersion liquid) in 0 ℃ of solution of 1-(4-methoxy-benzyl) imidazolidin-2-one (intermediate 32) in 1mL DMF.This solution was stirred 10 minutes at 0 ℃, add 8 μ L 3 then, 5-di-trifluoromethyl bromotoluene stirs this mixture 3 hours at 0 ℃.This reaction mixture is handled with a water, filter then, by reversed-phase HPLC purifying [Waters XTerra C8 19 * 50mm post, with 20mL/ minute flow velocity with 90% water (0.1%TFA)-100% acetonitrile (0.1%TFA) wash-out 5.15 minutes, kept 1.45 minutes, and then with 90% water elution 0.5 minute], obtained this title compound.Mass spectrum (ESI) 743.2 (M+1).
Step B:1-[3,5-two (trifluoromethyl) benzyl]-4-[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] imidazolidin-2-one
With 15mg 1-[3,5-two (trifluoromethyl) benzyl]-4-[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl]-solution of 3-(4-methoxy-benzyl) imidazolidin-2-one in 0.5mL TFA is in stirred overnight at room temperature.This reaction mixture is concentrated, then by reversed-phase HPLC purifying [Waters XTerra C8 19 * 50mm post, with 20mL/ minute flow velocity with 90% water (0.1%TFA)-100% acetonitrile (0.1%TFA) wash-out 5.15 minutes, kept 1.45 minutes, and then with 90% water elution 0.5 minute], obtained this title compound.Mass spectrum (ESI) 623.4 (M+1).
Embodiment 377
1-benzyl-4-[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] imidazolidin-2-one
Steps A: 1-benzyl-4-[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl]-3-(4-methoxy-benzyl) imidazolidin-2-one
According to the method for describing in embodiment 379 steps A, use 31mg 5-[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl]-1-(4-methoxy-benzyl) imidazolidin-2-one (intermediate 32) and 9 μ L bromotoluenes, obtained this title compound.Mass spectrum (ESI) 607.5 (M+1).
Step B:1-benzyl-4-[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl] imidazolidin-2-one
According to the method for describing among the embodiment 379 step B, use 5mg 1-benzyl-4-[4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-yl]-3-(4-methoxy-benzyl) imidazolidin-2-one, obtained this title compound.Mass spectrum (ESI) 487.4 (M+1).
Claims (21)
1. formula I compound or pharmaceutically acceptable salt thereof
Wherein:
Y is selected from-C (=O)-and-(CRR
1)-;
X is selected from-O-,-NH-,-N (C
1-C
5Alkyl)-and-(CRR
6)-;
Z is selected from-C (=O)-,-S (O)
2-and-C (=N-R
9)-, be R wherein
9Be selected from H ,-CN and-C
1-C
5Alkyl, described alkyl is optional to be replaced by 1-11 halogen;
Each R be independently selected from H ,-C
1-C
5Alkyl and halogen, wherein-C
1-C
5Alkyl is optional to be replaced by 1-11 halogen;
B is selected from A
1And A
2, A wherein
1Have following structure:
R
1And R
6Be independently selected from respectively H ,-C
1-C
5Alkyl, halogen and-(C (R)
2)
nA
2, wherein-C
1-C
5Alkyl is optional to be replaced by 1-11 halogen;
R
2Be selected from H ,-C
1-C
5Alkyl, halogen, A
1With-(C (R)
2)
nA
2, wherein-C
1-C
5Alkyl is optional to be replaced by 1-11 halogen;
Wherein B and R
2In the middle of have one to be A
1And B, R
1, R
2And R
6In the middle of have one to be A
2Or-(C (R)
2)
nA
2This pattern I compound comprises a group A
1With a group A
2
A
3Be selected from:
(a) be selected from the aromatic ring of phenyl and naphthyl;
(b) with the optional non-aromatics cycloalkyl ring condensed benzyl ring of 5-7 unit that comprises 1-2 two keys;
(c) 5-6 unit heterocycle, described heterocycle have 1-4 be independently selected from N, S, O and-N (O)-heteroatoms, and optional 1-3 two keys and carbonyl, the wherein A of comprising
3Be connected with A
3The tie point of benzyl ring be carbon atom; With
(d) comprise benzheterocycle with the heterocyclic fused benzyl ring of 5-6 unit, described heterocycle have 1-2 be independently selected from O, N and-S (O)
x-heteroatoms, and optional have 1-2 two key, wherein A
3Be connected with A
3The tie point of benzyl ring be carbon atom;
A
2Be selected from:
(a) be selected from the aromatic ring of phenyl and naphthyl;
(b) with the optional non-aromatics cycloalkyl ring condensed benzyl ring of 5-7 unit that comprises 1-2 two keys;
(c) 5-6 unit heterocycle, described heterocycle have 1-4 be independently selected from N, S, O and-N (O)-heteroatoms, and optional 1-3 two keys and the carbonyl of comprising;
(d) comprise benzheterocycle with the heterocyclic fused benzyl ring of 5-6 unit, described heterocycle has 1-2 heteroatoms that is independently selected from O, N and S, and optionally has 1-2 two keys; With
(e) optional have 1-3 two keys-C
3-C
8Cycloalkyl ring;
A wherein
3And A
2Optional respectively by the individual R that is independently selected from of 1-5
aSubstituting group replace;
Each R
aBe independently selected from-C
1-C
6Alkyl ,-C
2-C
6Alkenyl ,-C
2-C
8Alkynyl, optional have 1-3 two keys-C
3-C
8Cycloalkyl ,-OC
1-C
6Alkyl ,-OC
2-C
6Alkenyl ,-OC
2-C
6Alkynyl, optional have 1-3 two keys-OC
3-C
8Cycloalkyl ,-C (=O) C
1-C
6Alkyl ,-C (=O) C
3-C
8Cycloalkyl ,-C (=O) H ,-CO
2H ,-CO
2C
1-C
6Alkyl ,-C (=O) SC
1-C
6Alkyl ,-OH ,-NR
3R
4,-C (=O) NR
3R
4,-NR
3C (=O) OC
1-C
6Alkyl ,-NR
3C (=O) NR
3R
4,-S (O)
xC
1-C
6Alkyl ,-S (O)
yNR
3R
4,-NR
3S (O)
yNR
3R
4, halogen ,-CN ,-NO
2With 5-6 unit heterocycle, described heterocycle has 1-4 heteroatoms that is independently selected from N, S and O, and described heterocycle is also optional to be comprised carbonyl and optionally comprise 1-3 two keys, wherein said be connected with R
aThe tie point of ring be carbon atom, wherein said heterocycle optional by 1-5 be independently selected from halogen ,-C
1-C
3Alkyl and-OC
1-C
3The substituting group of alkyl replaces, wherein-and C
1-C
3Alkyl and-OC
1-C
3Alkyl is optional to be replaced by 1-7 halogen;
Wherein for R wherein
aBe selected from-C
1-C
6Alkyl ,-C
2-C
6Alkenyl ,-C
2-C
6Alkynyl, optional have 1-3 two keys-C
3-C
8Cycloalkyl ,-OC
1-C
6Alkyl ,-OC
2-C
6Alkenyl ,-OC
2-C
6Alkynyl, optional have 1-3 two keys-OC
3-C
8Cycloalkyl ,-C (=O) C
1-C
6Alkyl ,-C (=O) C
3-C
8Cycloalkyl ,-CO
2C
1-C
6Alkyl ,-C (=O) SC
1-C
6Alkyl ,-NR
3C (=O) OC
1-C
6Alkyl and-S (O)
xC
1-C
6The compound of alkyl, R
aOptional replaced, and optionally be independently selected from following substituting group replacement by 1-3 by 1-15 halogen: (a)-OH, (b)-CN, (c)-NR
3R
4, (d) optional have 1-3 two keys and optional by 1-15 halogen replacement-C
3-C
8Cycloalkyl (e) is optionally replaced by 1-9 halogen and optionally is independently selected from-OC by 1-2 is individual
1-C
2The substituting group of alkyl and phenyl replaces-OC
1-C
4Alkyl, (f) optional have 1-3 two keys and optional by 1-15 halogen replacement-OC
3-C
8Cycloalkyl, (g)-CO
2H, (h)-C (=O) CH
3, (i) optional by 1-9 halogen replacement-CO
2C
1-C
4Alkyl and (j) optional by 1-3 be independently selected from halogen ,-CH
3,-CF
3,-OCH
3With-OCF
3The phenyl that replaces of group;
Condition is: when B is A
1, X and Y are-CH
2-, Z is-C (=O)-, and R
2Be to have substituent R in the 4-position
aPhenyl, R wherein
aBe to choose substituted as mentioned above-OC wantonly
1-C
6During alkyl, then at R
2On do not have other R
aSubstituting group, wherein R
aBe selected from-OH ,-OC
1-C
6Alkyl ,-OC
2-C
6Alkenyl ,-OC
2-C
6Alkynyl and optional have 1-3 two keys-OC
3-C
8Cycloalkyl, all these groups are optional to be substituted as mentioned above,
N is 0 or 1;
P is the integer of 0-4;
X is 0,1 or 2;
Y is 1 or 2;
R
3And R
4Be independently selected from respectively H ,-C
1-C
5Alkyl ,-C (=O) C
1-C
5Alkyl and-S (O)
yC
1-C
5Alkyl, wherein in all cases ,-C
1-C
5Alkyl is optional to be replaced by 1-11 halogen; And R
5Be selected from H ,-OH ,-C
1-C
5Alkyl and halogen, wherein-C
1-C
5Alkyl is optional to be replaced by 1-11 halogen.
2. the compound of claim 1, wherein said compound is selected from the compound or pharmaceutically acceptable salt thereof with formula Ia, Ib and Id:
With
3. the compound or pharmaceutically acceptable salt thereof of claim 1, wherein:
Y is-(CRR
1)-;
R and R
6Be independently selected from respectively H and-C
1-C
5Alkyl, wherein-C
1-C
5Alkyl is optional to be replaced by 1-11 halogen;
R
1Be selected from H ,-C
1-C
5Alkyl and-(C (R)
2)
nA
2, wherein-C
1-C
5Alkyl is optional to be replaced by 1-11 halogen;
Wherein B and R
2In the middle of have one to be A
1And B, R
1And R
2In the middle of have one to be A
2Or-(C (R)
2)
nA
2This pattern I compound comprises a group A
1With a group A
2
A
3Be selected from:
(a) be selected from the aromatic ring of phenyl and naphthyl;
(b) 5-6 unit heterocycle, described heterocycle have 1-4 be independently selected from N, S, O and-N (O)-heteroatoms, and optional 1-3 two keys and carbonyl, the wherein A of comprising
3Be connected with A
3The tie point of benzyl ring be carbon atom; With
(c) comprise benzheterocycle with the heterocyclic fused benzyl ring of 5-6 unit, described heterocycle have 1-2 be independently selected from O, N and-S (O)
x-heteroatoms, and optional have 1-2 two key, wherein A
3Be connected with A
3The tie point of benzyl ring be carbon atom;
A
2Be selected from:
(a) be selected from the aromatic ring of phenyl and naphthyl;
(b) 5-6 unit heterocycle, described heterocycle have 1-4 be independently selected from N, S, O and-N (O)-heteroatoms, and optional 1-3 two keys and the carbonyl of comprising;
(c) comprise benzheterocycle with the heterocyclic fused benzyl ring of 5-6 unit, described heterocycle has 1-2 heteroatoms that is independently selected from O, N and S, and optionally has 1-2 two keys; With
(d) optional have 1-3 two keys-C
3-C
8Cycloalkyl ring;
A wherein
3And A
2Optional by the individual R that is independently selected from of 1-4
aSubstituting group replace;
Each R
aBe independently selected from :-C
1-C
6Alkyl ,-C
2-C
6Alkenyl, optional have 1-3 two keys-C
3-C
8Cycloalkyl ,-OC
1-C
6Alkyl ,-C (=O) C
1-C
6Alkyl ,-C (=O) H ,-CO
2H ,-CO
2C
1-C
6Alkyl ,-OH ,-NR
3R
4,-NR
3C (=O) OC
1-C
6Alkyl ,-S (O)
xC
1-C
6Alkyl, halogen ,-CN ,-NO
2With 5-6 unit heterocycle, described heterocycle has 1-4 heteroatoms that is independently selected from N, S and O, and described heterocycle is also optional to be comprised carbonyl and optionally comprise 1-3 two keys, wherein said heterocycle be connected with R
aThe tie point of ring be carbon atom, wherein said heterocycle optional by 1-5 be independently selected from halogen ,-C
1-C
3Alkyl and-OC
1-C
3The substituting group of alkyl replaces, wherein-and C
1-C
3Alkyl and-OC
1-C
3Alkyl is optional to be replaced by 1-7 halogen; Wherein for R wherein
aBe selected from-C
1-C
6Alkyl ,-C
2-C
6Alkenyl, optional have 1-3 two keys-C
3-C
8Cycloalkyl ,-OC
1-C
6Alkyl ,-C (=O) C
1-C
6Alkyl ,-CO
2C
1-C
6Alkyl ,-NR
3C (=O) OC
1-C
6Alkyl and-S (O)
xC
1-C
6The compound of alkyl, R
aOptional replaced, and optionally be selected from following substituting group replacement by 1 by 1-15 halogen: (a)-OH, (b)-NR
3R
4, (c) optionally replaced by 1-9 halogen and optionally be independently selected from-OC by 1-2 is individual
1-C
2The substituting group of alkyl and phenyl replaces-OC
1-C
4Alkyl and (d) phenyl, described phenyl optional by 1-3 be independently selected from halogen ,-CH
3,-CF
3,-OCH
3With-OCF
3Group replace; Condition is: when B is A
1, X and Y are-CH
2-, Z is-C (=O)-, and R
2Be to have substituent R in the 4-position
aPhenyl, R wherein
aBe to choose substituted as mentioned above-OC wantonly
1-C
6During alkyl, then at R
2On do not have other R
aSubstituting group, wherein R
aBe-OH or optional substituted as mentioned above-OC
1-C
6Alkyl;
P is the integer of 0-2;
R
3And R
4Be independently selected from respectively H and-C
1-C
5Alkyl, wherein in all cases ,-C
1-C
5Alkyl is optional to be replaced by 1-11 halogen; And
R
5Be selected from H ,-OH and-C
1-C
5Alkyl, wherein-C
1-C
5Alkyl is optional to be replaced by 1-11 halogen.
4. the compound or pharmaceutically acceptable salt thereof of claim 1, wherein:
Y is-(CRR
1)-;
Z is selected from-C (=O)-,-S (O)
2-and-C (=N-R
9)-, be R wherein
9Be selected from H ,-CN and CH
3Each R is independently selected from H and C
1-C
2Alkyl;
R
6Be selected from H and-C
1-C
3Alkyl, wherein C
1-C
3Alkyl is optional to be replaced by 1-5 halogen;
R
1Be selected from H ,-C
1-C
3Alkyl and-(C (R)
2)
nA
2, wherein-C
1-C
3Alkyl is optional to be replaced by 1-5 halogen;
R
2Be selected from H ,-C
1-C
3Alkyl, A
1With-(C (R)
2)
nA
2, wherein-C
1-C
3Alkyl is optional to be replaced by 1-5 halogen;
B and R
2In the middle of have one to be A
1And B, R
1And R
2In the middle of have one to be A
2Or-(C (R)
2)
nA
2This pattern I compound comprises a group A
1With a group A
2
A
3Be selected from:
(a) phenyl;
(b) 5-6 unit heterocycle, described heterocycle have 1-2 be independently selected from N, S, O and-N (O)-heteroatoms, A wherein
3Be connected with A
3The tie point of benzyl ring be carbon atom; With
(c) comprise benzheterocycle with 5 yuan of aromatic heterocycle condensed benzyl rings, described heterocycle have 1-2 be independently selected from O, N and-S (O)
x-heteroatoms, A wherein
3Be connected with A
3The tie point of benzyl ring be carbon atom;
A
2Be selected from:
(a) phenyl;
(b) 5-6 unit heterocycle, described heterocycle have 1-4 be independently selected from N, S, O and-N (O)-heteroatoms, and optionally comprise 1-3 two keys;
(c) comprise benzheterocycle with 5 yuan of heterocyclic fused benzyl rings, described heterocycle has 1-2 heteroatoms that is independently selected from O, N and S; With
(d)-C
5-C
6Cycloalkyl ring;
A wherein
3And A
2Optional respectively by the individual R that is independently selected from of 1-4
aSubstituting group replace;
Each R
aBe independently selected from-C
1-C
4Alkyl ,-C
2-C
4Alkenyl, cyclopropyl ,-OC
1-C
2Alkyl ,-C (=O) C
1-C
2Alkyl ,-C (=O) H ,-CO
2C
1-C
4Alkyl ,-OH ,-NR
3R
4,-NR
3C (=O) OC
1-C
4Alkyl ,-S (O)
xC
1-C
2Alkyl, halogen ,-CN ,-NO
2With 5-6 unit heterocycle, described heterocycle has 1-2 heteroatoms that is independently selected from N, S and O, wherein said heterocycle be connected with R
aThe tie point of ring be carbon atom, wherein said heterocycle is optional to be replaced by 1-5 substituting group that is independently selected from halogen;
Wherein for R wherein
aBe selected from-C
1-C
4Alkyl ,-C
2-C
4Alkenyl ,-OC
1-C
2Alkyl ,-C (=O) C
1-C
2Alkyl ,-CO
2C
1-C
4Alkyl ,-NR
3C (=O) OC
1-C
4Alkyl and-S (O)
xC
1-C
2The compound of alkyl, R
aAlkyl optional replaced by 1-5 halogen, and optionally be selected from following substituting group replacement by one: (a)-OH, (b)-NR
3R
4, (C) optionally replaced by 1-3 fluorine atom, and optional by a phenyl replacement-OCH
3And (d) phenyl, described phenyl optional by 1-3 be independently selected from halogen ,-CH
3,-CF
3,-OCH
3With-OCF
3Group replace; Condition is: when B is A
1, X and Y are-CH
2-, Z is-C (=O)-, and R
2Be to have substituent R in the 4-position
aPhenyl, R wherein
aBe to choose substituted as mentioned above-OC wantonly
1-C
2During alkyl, then at R
2On do not have other R
aSubstituting group, wherein R
aBe selected from-OH or optional substituted as mentioned above-OC
1-C
2Alkyl;
P is the integer of 0-2; And
R
3, R
4And R
5Be independently selected from H and-C
1-C
3Alkyl.
5. the compound or pharmaceutically acceptable salt thereof of claim 4, wherein
A
3Be selected from phenyl, thienyl, imidazolyl, pyrryl, pyrazolyl, pyridyl, N-oxidation-pyridyl, thiazolyl, pyridazinyl, pyrimidyl, pyrazinyl, benzothienyl, benzothienyl-S-oxide compound and benzothienyl-S-dioxide; And
A
2Be selected from phenyl, thienyl, imidazolyl, thiazolyl, pyrryl, pyrazolyl, 1,2,4-triazolyl, tetrazyl, benzodioxole base, pyridyl, N-oxidation-pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, cyclopentyl, cyclohexyl and THP trtrahydropyranyl.
6. the compound or pharmaceutically acceptable salt thereof of claim 5, wherein
X is selected from-O-,-NH-and-N (C
1-C
3Alkyl)-; And
Z is-C (=O)-.
7. the compound or pharmaceutically acceptable salt thereof of claim 4, wherein
A
2And A
3It all is phenyl; And
R
aBe selected from-C
1-C
4Alkyl, described alkyl is optional to be replaced by 1-5 fluorine atom, and optionally is selected from-OH and-OCH by one
3Group replace; Optional by 1-3 fluorine atom replacement-OC
1-C
2Alkyl;-C
2-C
4Alkenyl; By a group-NR
3R
4Replace-C
1-C
2Alkyl;-C
1-C
2Alkyl-O-C
1-C
2Alkyl-phenyl; Cyclopropyl;-C (=O) H;-OH;-NR
3R
4-S (O)
xC
1-C
2Alkyl; Halogen;-CN;-NO
2With comprise 1-2 Sauerstoffatom and optional quilt-C
1-C
2The 5-6 unit heterocycle that alkyl replaces;
Have the condition identical with claim 4.
8. the compound of claim 7, wherein said compound has formula Ii or its pharmacologically acceptable salt:
Wherein
R
7Be selected from Cl and-CF
3
Each R
bBe independently selected from-C
1-C
3Alkyl ,-OCH
3And F;
R
1Be selected from H and-C
1-C
2Alkyl;
R
cBe selected from halogen ,-CH
3,-CF
3With-CN;
Q is 2 or 3; And
T is the integer of 0-2.
9. the compound of claim 7, wherein said compound has formula Ij or its pharmacologically acceptable salt:
Wherein
R
7Be selected from Cl and-CF
3
Each R
bBe independently selected from-C
1-C
3Alkyl ,-OCH
3And F;
R
1Be selected from H and-C
1-C
2Alkyl;
R
cBe selected from halogen ,-CH
3,-CF
3With-CN;
Q is 2 or 3; And
T is the integer of 0-2.
10. the compound or pharmaceutically acceptable salt thereof of claim 1, wherein
A
3Be phenyl, described phenyl is optional by 1-4 substituent R
aReplace, wherein R
aBe independently selected from-C
1-C
5Alkyl ,-OC
1-C
3Alkyl ,-CO
2C
1-C
3Alkyl ,-CO
2H, halogen ,-NR
3R
4,-C (=O) C
1-C
3Alkyl ,-C (=O) H ,-C (=O) NR
3R
4,-SC
1-C
3Alkyl ,-C
2-C
3Alkenyl ,-CN ,-NO
2With 1,2,4- di azoly, wherein all that occur-C
1-C
3Alkyl and-C
1-C
5Alkyl is optional to be replaced by 1-6 substituting group that is independently selected from 1-5 halogen and one-OH group; And-C
2-C
3Alkenyl is optional to be replaced by 1-3 halogen;
A
2Be selected from phenyl, cyclohexyl and 5-6 unit heterocycle, described heterocycle have 1-2 be independently selected from O, N, S and-N (O)-heteroatoms, and optionally comprise 1-3 two key, wherein A
2Optional by individual following substituting group the replacement :-C that is independently selected from of 1-2
1-C
4Alkyl ,-OC
1-C
3Alkyl ,-NO
2,-CN ,-S (O)
xC
1-C
3Alkyl ,-NHS (O)
2C
1-C
3Alkyl ,-NR
3R
4,-NR
3C (=O) R
4,-C
2-C
3Alkenyl ,-C (=O) NR
3R
4, halogen and pyridyl, wherein in all cases, C
1-C
3Alkyl, C
1-C
4Alkyl and C
2-C
3Alkenyl is optional to be replaced by 1-3 halogen, and condition is, when B is A
1, X and Y are-CH
2-, Z is-C (=O)-, and R
2Be to have substituent R in the 4-position
aPhenyl, R wherein
aBe to choose substituted as mentioned above-OC wantonly
1-C
3During alkyl, then at R
2On do not have other R
aSubstituting group, wherein R
aBe substituted as mentioned above-OC
1-C
2Alkyl; R
3And R
4Be independently selected from respectively H and-C
1-C
3Alkyl; And
P is 0-2.
11. the compound or pharmaceutically acceptable salt thereof of claim 10, wherein
A
1Be
R wherein
7And R
8Be independently selected from respectively H, halogen ,-NR
3R
4,-C
1-C
3Alkyl ,-OC
1-C
3Alkyl ,-CN ,-NO
2And pyridyl, wherein in all cases, C
1-C
3Alkyl is optional to be replaced by 1-3 halogen; And
A
2Be selected from phenyl, pyridyl and cyclohexyl, wherein A
2Choose wantonly by 1-2 and be independently selected from-C
1-C
4Alkyl ,-OC
1-C
3Alkyl ,-NO
2The substituting group of ,-CN and halogen replaces, wherein the C in all use
1-C
4Alkyl and C
1-C
3Alkyl is optional to be replaced by 1-3 halogen, and condition is, when B is A
1, X and Y are-CH
2-, Z is-C (=O)-, and R
2Be to have substituent R in the 4-position
aPhenyl, R wherein
aBe to choose wantonly by 1-3 halogen to replace-OC
1-C
3During alkyl, then at R
2On do not have other R
aSubstituting group, wherein R
aBe to choose wantonly by 1-3 halogen to replace-OC
1-C
3Alkyl.
12. the compound or pharmaceutically acceptable salt thereof of claim 11, wherein
A
1Be
R
7Be selected from H, halogen ,-NR
3R
4,-C
1-C
3Alkyl ,-OC
1-C
3Alkyl ,-CN ,-NO
2And pyridyl, wherein in all cases, C
1-C
3Alkyl is optional to be replaced by 1-3 halogen; And R
8Be selected from H, halogen ,-CH
3,-CF
3,-OCH
3With-OCF
3
13. comprise the compound or pharmaceutically acceptable salt thereof of claim 1 and the pharmaceutical composition of pharmaceutically acceptable carrier.
14. the compound of claim 4, wherein said compound are selected from following compounds or its pharmacologically acceptable salt:
With
15. the compound of claim 4, wherein said compound are selected from the have formula compound or pharmaceutically acceptable salt thereof of (a)-(c):
(a)
Wherein R is selected from
(b)
Wherein R is selected from
(c)
Wherein R is selected from
16. the compound of claim 4, wherein said compound are selected from following compounds or its pharmacologically acceptable salt:
17. the compound of claim 4, wherein said compound are selected from the have formula compound or pharmaceutically acceptable salt thereof of (a)-(k):
(a)
Wherein for compound (1)-(6), A
3, A
2Be selected from Z:
(b)
A wherein
3Be selected from:
(c)
Wherein for compound (1)-(6), A
3And A
2Be selected from:
(d)
Wherein R is selected from:
(e)
Wherein R is Et or n-Pr;
(f)
Wherein for compound (1)-(4), R and A
3Be selected from:
(g)
Wherein R is selected from:
(h)
A wherein
2Be selected from:
With
(i)
Wherein R is selected from:
With
(j)
A wherein
3Be selected from:
(k)
Wherein for compound (1)-(3), A
3, R
2And R
3Be selected from:
18. an atherosclerotic method for the treatment of among the patient who needs treatment, described method comprises the compound or pharmaceutically acceptable salt thereof to the claim 1 of described patient's drug treatment significant quantity.
19. one kind raises and needs the method for the HDL-C among the patient of treatment, comprises the compound or pharmaceutically acceptable salt thereof to the claim 1 of described patient's drug treatment significant quantity.
20. the compound or pharmaceutically acceptable salt thereof of claim 1 is used for the treatment of application in the atherosclerotic medicine in production.
21. a pharmaceutical composition, described composition comprise the compound or pharmaceutically acceptable salt thereof, pharmaceutically acceptable carrier of claim 1 and one or more are selected from following activeconstituents:
(i) HMG-CoA reductase inhibitor;
(ii) bile acid chelating agent;
(iii) nicotinic acid and related compound;
(iv) PPAR alfa agonists;
(v) cholesterol absorption inhibitor;
(vi) acyl-CoA: cholesterol acyltransferase (ACAT) inhibitor;
(vii) phenol antioxidant;
(viii) microsomal triglyceride transfer protein (MTP)/ApoB secretion inhibitor;
(ix) antioxidant vitamin;
(x) intend the Tiroidina medicine;
(xi) LDL (low-density lipoprotein) receptor inducer;
(xii) anticoagulant;
(xiii) vitamin B12 (also being called Vitral);
(xiv) folic acid or its pharmacologically acceptable salt or ester;
(xv) FXR and LXR part;
(xvi) promoting agent of raising ABCA1 genetic expression; With
(xvii) ileal bile acid carrier.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US58527404P | 2004-07-02 | 2004-07-02 | |
| US60/585,274 | 2004-07-02 | ||
| US60/646,103 | 2005-01-21 |
Related Child Applications (4)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201110245074.8A Division CN102311401B (en) | 2004-07-02 | 2005-07-01 | CETP inhibitors |
| CN201410720701.2A Division CN104557757A (en) | 2004-07-02 | 2005-07-01 | CETP inhibitors |
| CN201410720703.1A Division CN104447603A (en) | 2004-07-02 | 2005-07-01 | CETP inhibitors |
| CN201110245073.3A Division CN102304096B (en) | 2004-07-02 | 2005-07-01 | CETP inhibitors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1980904A true CN1980904A (en) | 2007-06-13 |
Family
ID=38131543
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2005800226187A Pending CN1980904A (en) | 2004-07-02 | 2005-07-01 | CETP inhibitors |
Country Status (5)
| Country | Link |
|---|---|
| CN (1) | CN1980904A (en) |
| HN (1) | HN2005000340A (en) |
| TN (1) | TNSN06456A1 (en) |
| UA (1) | UA86077C2 (en) |
| ZA (1) | ZA200610565B (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009062371A1 (en) * | 2007-10-15 | 2009-05-22 | Shanghai Hengrui Pharmaceutical Co., Ltd. | Carbamate derivatives, and the use as medicament |
| CN101212966B (en) * | 2005-07-01 | 2012-03-14 | 默沙东公司 | Process for synthesizing a CETP inhibitor |
| CN102516237A (en) * | 2011-12-05 | 2012-06-27 | 成都苑东药业有限公司 | Oxazolidinone derivative |
| CN102603499A (en) * | 2012-03-01 | 2012-07-25 | 南京药石药物研发有限公司 | Synthetic method of 1-bromo-4-fluorin-5-isopropyl-2-metoxybenzene |
| CN103269592A (en) * | 2010-10-29 | 2013-08-28 | 默沙东公司 | Cyclic amine substituted oxazolidinone cetp inhibitor |
| CN104053441A (en) * | 2011-11-30 | 2014-09-17 | 株式会社大熊制药 | Pharmaceutical composition for preventing or treating hyperlipidemia |
| CN116078377A (en) * | 2023-03-06 | 2023-05-09 | 泽升科技(广州)有限公司 | Production process for preparing deuterated benzene by using supported catalyst |
-
2005
- 2005-06-29 HN HN2005000340A patent/HN2005000340A/en unknown
- 2005-07-01 UA UAA200701058A patent/UA86077C2/en unknown
- 2005-07-01 CN CNA2005800226187A patent/CN1980904A/en active Pending
-
2006
- 2006-12-15 ZA ZA200610565A patent/ZA200610565B/en unknown
- 2006-12-29 TN TNP2006000456A patent/TNSN06456A1/en unknown
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101212966B (en) * | 2005-07-01 | 2012-03-14 | 默沙东公司 | Process for synthesizing a CETP inhibitor |
| WO2009062371A1 (en) * | 2007-10-15 | 2009-05-22 | Shanghai Hengrui Pharmaceutical Co., Ltd. | Carbamate derivatives, and the use as medicament |
| CN103269592A (en) * | 2010-10-29 | 2013-08-28 | 默沙东公司 | Cyclic amine substituted oxazolidinone cetp inhibitor |
| CN103269592B (en) * | 2010-10-29 | 2016-05-11 | 默沙东公司 | Cyclammonium replaces oxazolidone CETP inhibitor |
| CN104053441A (en) * | 2011-11-30 | 2014-09-17 | 株式会社大熊制药 | Pharmaceutical composition for preventing or treating hyperlipidemia |
| CN104053441B (en) * | 2011-11-30 | 2016-04-20 | 株式会社大熊制药 | For preventing or treat the pharmaceutical composition of hyperlipemia |
| CN102516237A (en) * | 2011-12-05 | 2012-06-27 | 成都苑东药业有限公司 | Oxazolidinone derivative |
| CN102516237B (en) * | 2011-12-05 | 2014-02-26 | 成都苑东药业有限公司 | Oxazolidinone derivative |
| CN102603499A (en) * | 2012-03-01 | 2012-07-25 | 南京药石药物研发有限公司 | Synthetic method of 1-bromo-4-fluorin-5-isopropyl-2-metoxybenzene |
| CN116078377A (en) * | 2023-03-06 | 2023-05-09 | 泽升科技(广州)有限公司 | Production process for preparing deuterated benzene by using supported catalyst |
| CN116078377B (en) * | 2023-03-06 | 2023-06-27 | 泽升科技(广州)有限公司 | Production process for preparing deuterated benzene by using supported catalyst |
Also Published As
| Publication number | Publication date |
|---|---|
| TNSN06456A1 (en) | 2008-02-22 |
| UA86077C2 (en) | 2009-03-25 |
| HN2005000340A (en) | 2009-11-06 |
| ZA200610565B (en) | 2008-07-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102311401B (en) | CETP inhibitors | |
| CN103958524B (en) | The Er Huan oxazolidone CETP inhibitor condensed | |
| JP5040036B2 (en) | 1,3-Oxazolidin-2-one derivatives useful as CETP inhibitors | |
| EP1971595B1 (en) | Cetp inhibitors | |
| JP5852662B2 (en) | Cyclic amine substituted oxazolidinone CETP inhibitors | |
| EP1973889B1 (en) | Cetp inhibitors | |
| CN1980904A (en) | CETP inhibitors |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1107342 Country of ref document: HK |
|
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Open date: 20070613 |
|
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: WD Ref document number: 1107342 Country of ref document: HK |