CN100415735C - Amino alcohol derivatives - Google Patents
Amino alcohol derivatives Download PDFInfo
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- CN100415735C CN100415735C CNB2006100025042A CN200610002504A CN100415735C CN 100415735 C CN100415735 C CN 100415735C CN B2006100025042 A CNB2006100025042 A CN B2006100025042A CN 200610002504 A CN200610002504 A CN 200610002504A CN 100415735 C CN100415735 C CN 100415735C
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Abstract
Compounds of formula (I) which exhibit excellent immune suppression activity, pharmacologically acceptable salts thereof, esters thereof or other derivatives: wherein R<1 >and R<2 >are a hydrogen atom, an amino protecting group; R<3 >is a hydrogen atom, a hydroxy protecting group; R<4 >is a lower alkyl group; n is an integer from 1 to 6; X is an ethylene group; Y is a C1-C10 alkylene group, a C1-C10 alkylene group substituted with 1 to 3 substituents selected from substituent group a and b; R<5 >is an aryl group; R<6 >and R<7 >are a hydrogen atom, a group selected from substituent group a; with the proviso when R<5 >is a hydrogen atom, Y is not a single bond or a straight chain C1-C10 alkylene group.
Description
The application is for dividing an application, and the application number of original application is 01815340.2, and the applying date is July 10 calendar year 2001, and denomination of invention is " aminoalcohol derivative ".
Technical field
The present invention relates to have aminoalcohol derivative, its pharmacy acceptable salt, its ester or other derivative of good immunosuppressive action; Contain the pharmaceutical composition of described compound as effective constituent; Described compound is used for the application of pharmaceutical compositions; Perhaps the described compound of significant quantity on the pharmacology is given the prevention or the methods of treatment of the autoimmune disorders etc. of warm-blooded animal.
The invention still further relates to the novel opticity amino alcohol compound of the synthetic intermediate that can be used as medicines such as above-mentioned aminoalcohol derivative, particularly opticity 4,4-Er substituted oxazole alkane-2-ketone compound.
The invention further relates to opticity 2-replacement-2-amino-1, the new preparation process with fine selectivity of ammediol monoester derivates, described derivative are the important synthetic intermediates of above-mentioned opticity amino alcohol compound.
Technical background
In the treatment of immune correlated diseases such as rheumatosis or other autoimmune disorders, the Inflammatory response for being caused by the abnormal immune reaction all is to use anti-inflammatory agenies such as steroid all the time.But this is a symptomatic therapy, but not the essence methods of treatment.
It is reported diabetes, ephritis morbidity also with immune relevant unusually [KidneyInternational, 51,94 (1997); Journal of Immunology, 157,4691 (1996)], but still untappedly go out to improve its unusual medicine.
Exploitation suppresses the method for immunne response for preventing that the various autoimmune disorderss of immunological rejection, treatment and prevention in organ and the Transplanted cells from also being very important.But, known ciclosporin A (CsA), tacrolimus known immunosuppressor of past such as (TRL) have toxicity to kidney and liver, in order to alleviate these side effects, extensively adopt and unite treatments such as use, but present situation is not reach the degree that has no side effect, gives full play of immunosuppressive effect with steroid.
From above-mentioned background, carried out various trials, attempt to find out the compound that toxicity is low, have good immunosuppressive action.
Known immunosuppressor has for example shows compound down.
(1)WO?94/08943(EP627406)
Compound as the following general formula of having of immunosuppressor (a) is disclosed in this communique,
[in the above-claimed cpd (a),
R for can have substituent straight or branched carbochain can have in this chain two keys, triple bond, oxygen, sulphur ,-N (R
6R in the)-(formula
6Be hydrogen), can have substituent arylidene, can have substituent inferior heteroaryl, this end of the chain can have can have substituent aryl, can have substituent cycloalkyl, can have substituent heteroaryl., R
2, R
3, R
4, R
5Identical or different, respectively be hydrogen, alkyl.]。
The substituting group that the above-claimed cpd of described prior art (a) must have is 2 oxygen methyl (CH
2OR
4With-CH
2OR
5), the corresponding group that The compounds of this invention had is-CH
2OR
3Base and low alkyl group, this point is different with above-claimed cpd (a).
Do not have the compound of the similar of concrete open and The compounds of this invention (I) in the described communique, even select with the structure of The compounds of this invention (I) nearest like compound, show compound under also only disclosing.
Embodiment 29
Embodiment 293
(2)WO?96/06068
Compound as the following general formula of having of immunosuppressor (b) is disclosed in this communique,
[in the above-claimed cpd (b),
R
1, R
2And R
3Be hydrogen atom etc., W is hydrogen atom, alkyl etc., and Z is singly-bound or alkylidene group, and X is hydrogen atom or alkoxyl group, and Y represents hydrogen atom, alkyl, alkoxyl group, acyl group, acyloxy, amino, amido etc.]。
Phenyl is essential in the basic framework of above-claimed cpd (b), and the corresponding group of The compounds of this invention (I) is to be the heterocyclic thienyl, and this point is different with above-claimed cpd (b).
Do not have the compound of the similar of concrete open and The compounds of this invention (I) in the described communique, even select with the structure of The compounds of this invention (I) nearest like compound, show compound under also only disclosing.
Embodiment 26
Embodiment 57
Embodiment 87
(3)WO?98/45249
Compound as the following general formula of having of immunosuppressor (c) is disclosed in this communique,
[in the above-claimed cpd (c),
R
1, R
2, R
3, R
4Identical or different, respectively be hydrogen or acyl group.]。
The substituting group that above-claimed cpd (c) must have is 2 oxygen methyl (CH
2OR
3With-CH
2OR
4), the corresponding group that The compounds of this invention had is-CH
2OR
3Base and low alkyl group, this point is different with above-claimed cpd (c).In addition, in the basic framework of above-claimed cpd (c)-(CH
2)
2-Ji and-CO-(CH
2)
4Phenyl between the-Ji is essential group, and the corresponding group that The compounds of this invention (I) is had is to be the heterocyclic thienyl, and this point is different with above-claimed cpd (c).
Above-claimed cpd (c) has conduct-CO-(CH at the end of the chain
2)
4The necessary substituent phenyl of-Ji, and the corresponding group that The compounds of this invention (I) can have is cycloalkyl, heterocyclic radical, also is different in this.
Do not have the compound of the similar of concrete open and The compounds of this invention (I) in the described communique, even select with the structure of The compounds of this invention (I) nearest like compound, show compound under also only disclosing.
Embodiment 1
Embodiment 3
On the other hand, to have many are important compounds such as part constituent, synthetic intermediate of the material that itself has physiologically active, crude substance, medicine for opticity substituted amino acid and substituted-amino alcohol derivate (particularly alpha-substitution amino acid and alpha-substitution aminoalcohol derivative).
For example, Alpha-Methyl-α-vinyl amino acid is as the inhibitor of amino acid decarboxylase, α-ethynyl-Alpha-Methyl amino acid all is useful compound as the inhibitor of L-Glutamic decarboxylase, in addition, separate the ISP-1 (many spherical shells element) that obtains as meta-bolites from Xin Kelai Isaria (Isalia sinclairii) with immunosuppressive action, the known Conagenin that participates in the adjusting immunne response by the T cell etc. has the part constituent of the crude substance of physiologically active, and optically active alpha-substituted amino acid and aminoalcohol derivative also are compounds very noticeable on biological chemistry and the Synthetic Organic Chemistry.
Because these alpha-substitution amino acid and aminoalcohol derivative have unsymmetrical carbon, the method for effectively synthetic its a kind of enantiomorph of expectation.
The preparation method of opticity substituted amino acid and aminoalcohol derivative and the opticity 4 that can be used as the synthetic intermediate of medicines such as aforementioned opticity substituted amino acid and aminoalcohol derivative, the synthetic example of the opticity amino alcohol compound of 4-two substituted oxazoles alkane-2-ketone compound and so on is considerably less, the Tetrahedron:Asymmetry of known C.Cativiela etc. for example, 9,3517 (1998) introduction, generalized several different methods in " Synthesis of Optically Active alpha-amino group acid " (the Pergamon Press) of R.M.William work is broadly divided into two classes.
The first kind is to use the cis-selectivity alkylation of asymmetric auxiliary base, known representative method is that Seebach etc. is at Helv.Chim.Acta., 71, reported method or as long-tail in 224 (1988), assistant open countries etc. are at Tetrahedron Lett., 36,2097 (1995), Tetrahedron Lett., 36, in 4101 (1995) report like that, be Lewis acid synthesizes the alpha-substitution serine derivative by the height cis-selectivity aldolisation of applying flexibly method with the two lactam ethers carboxylicesterss of chirality and Mg (II) and Sn (II).
Second class is that long-tail, Yu Jing etc. are at Chemistry Lett.; 239 (1989), ChemistryLett.; the method of the enantioselectivity enzymatic hydrolysis of the employing alpha-substitution-α-protection amidomalonic acid diester of report reaction in 2381 (1994), representative is the method for reacting synthetic alpha-substitution serine derivative by the enantioselectivity enzymatic hydrolysis of prochirality σ symmetry diester.
All step is more to belong to the preparation method of the first kind, needs to use the asymmetric source of stoichiometry.And second class methods are owing to there is a reduction step, thereby just are restricted when having under reductive condition unsettled substituting group.
Though the example of this class report is a lot, method that can be practical is few.Generally speaking, with the racemic modification optical resolution, the method that obtains a kind of optically active isomer is the method that adopts usually, but the problem that its existence can't avoid total recovery to reduce.
Disclosure of an invention
Present inventors further investigate the derivative with immunosuppressive action, found that aminoalcohol derivative of the present invention (I) toxicity is low, has good immunosuppressive action, can be used for systemic lupus erythematosus, rheumatoid arthritis, polymyositis, dermatomyositis, scleroderma, the Behcet disease, the Chron disease, ulcerative colitis, lupoid hepatitis, aplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, multiple sclerosis, the autoimmune bleb generates, psoriasis, vasculitis syndrome, the Wegener granuloma, uveitis, idiopathic interstitial pneumonia, Goodpasture syndrome, sarcoidosis, the allergic granuloma vasculitis, bronchial asthma, myocarditis, myocardosis, aortitis syndrome, postmyocardial infarction syndrome, primary pulmonary hypertension, microvariations type nephrosis, membranous nephropathy, the film proliferative glomerulonephritis, focal glomerular sclerosis, crescent one-tenth nephritis, myasthenia gravis, the inflammatory neuropathy, atopic dermatitis, chronic actinic dermatitis, acute polyarthritis, the Sydenham tarantism, Sjogren's syndrome, the adult diabetes mellitus, insulin-dependent diabetes, juvenile diabetes, atherosclerosis, glomerulonephritis, the uriniferous tubules interstitial nephritis, primary biliary cirrhosis, primary sclerosing cholangitis, fulminant hepatitis, viral hepatitis, GVHD, the immune rejection that various organ transplantations cause, contact dermatitis, sick or other immune correlated disease of autoimmunity phlegm such as septicemia, thus the present invention finished.
Therefore, the object of the present invention is to provide that toxicity is low, acceptable salt, its ester or other derivative on the aminoalcohol derivative with good immunosuppressive action, its pharmacology.
Other purposes of the present invention are to provide and contain on above-mentioned aminoalcohol derivative, its pharmacology acceptable salt, its ester or other derivative as the medicinal compositions of effective constituent; The application of described compound in the above-mentioned medicinal compositions of preparation; Perhaps the described compound of significant quantity on the pharmacology is given the prevention or the methods of treatment of the above-mentioned diseases such as autoimmune disorders of warm-blooded animal.
In addition, present inventors are for solving existing the problems referred to above in opticity amino alcohol compound and intermediates preparation thereof, further investigate, found that with method in the past and compare, can prepare new opticity amino alcohol compound (La) and (Lb) by easy method, particularly opticity 4,4-Er substituted oxazole alkane-2-ketone derivatives, and this derivative can be used as the preparation intermediate of medicines such as opticity substituted amino acid and substituted-amino alcohol derivate.
Present inventors also further investigate above-mentioned opticity amino alcohol compound (La) and method for selective production (Lb); found that as its synthetic intermediate; preferred opticity 2-replacement-2-amino-1; ammediol monoester derivates (XLIVa) or (XLIVb); described compound (XLIVa) and (XLIVb) available 2-replacement-2-amino-1; ammediol derivative (XLII) is as raw material; in the presence of lipase, pass through only with a hydroxyl selectively acylating with generating vinyl carboxylate ester derivative (XLIII); prepare with good yield easily and easily, thereby finished the present invention.
That is,
(1) aminoalcohol derivative of the present invention has following general formula (I).Have acceptable salt, its ester or other derivative on the compound, its pharmacology of following formula (I):
[in the formula
R
1And R
2Identical or different, expression hydrogen atom or amino protecting group;
R
3The protecting group of expression hydrogen atom or hydroxyl;
R
4The expression low alkyl group;
N represents the integer of 1-6;
X represents ethylidene, vinylidene, ethynylene, has formula-D-CH
2-group (in the formula D represent carbonyl, have formula-CH (OH)-group, Sauerstoffatom, sulphur atom or nitrogen-atoms), aryl or be selected from the aryl that the group of substituting group group a replaces by 1-3;
Y represents singly-bound, C
1-C
10Alkylidene group, be selected from the C that the group of substituting group group a and b replaces by 1-3
1-C
10Alkylidene group, in carbochain or the end of the chain have the C of Sauerstoffatom or sulphur atom
1-C
10Alkylidene group or by 1-3 be selected from that the group of substituting group group a and b replaces, in carbochain or the end of the chain have the C of Sauerstoffatom or sulphur atom
1-C
10Alkylidene group;
R
5Expression hydrogen atom, cycloalkyl, aryl, heterocyclic radical, the cycloalkyl that is replaced by 1-3 group that is selected from substituting group group a and b, the aryl that is replaced by 1-3 group that is selected from substituting group group a and b or the heterocyclic radical that is replaced by 1-3 group that is selected from substituting group group a and b;
R
6And R
7Identical or different, expression hydrogen atom or be selected from the group of substituting group group a,
Condition is to work as R
5During for hydrogen atom, Y does not represent singly-bound and straight chain C
1-C
10Alkylidene group].
＜substituting group group a 〉
Halogen atom, low alkyl group, junior alkyl halides, lower alkoxy, lower alkylthio, carboxyl, lower alkoxycarbonyl, hydroxyl, rudimentary aliphatic acidyl, amino, single low-grade alkyl amino, two elementary alkyl amido, lower aliphatic amido, cyano group and nitro
＜substituting group group b 〉
Cycloalkyl, aryl, heterocyclic radical, the cycloalkyl that is replaced by 1-3 group that is selected from substituting group group a, the aryl that is replaced by 1-3 group that is selected from substituting group group a and the heterocyclic radical that is replaced by 1-3 group that is selected from substituting group group a.
In the above-claimed cpd (1), preferred compound can exemplify as follows.
(2) have acceptable salt, its ester or other derivative on the compound, its pharmacology of formula (Ia) in (1)
(3) have acceptable salt, its ester or other derivative on the compound, its pharmacology of formula (Ib) in (1)
(4) acceptable salt, wherein R on each compound or its pharmacology in (1)-(3)
1And R
2Identical or different, respectively be hydrogen atom, lower alkoxycarbonyl, aralkyl oxy carbonyl or the aralkyl oxy carbonyl that replaced by 1-3 group that is selected from substituting group group a;
(5) acceptable salt, wherein R on each compound or its pharmacology in (1)-(3)
1And R
2Be hydrogen atom;
(6) acceptable salt, wherein R on each compound or its pharmacology in (1)-(5)
3Be hydrogen atom, low alkyl group, rudimentary aliphatic acidyl, aromatic acyl group or the aromatic acyl group that replaced by 1-3 group that is selected from substituting group group a;
(7) acceptable salt, wherein R on each compound or its pharmacology in (1)-(5)
3Be hydrogen atom;
(8) acceptable salt, wherein R on each compound or its pharmacology in (1)-(7)
4Be C
1-C
4Alkyl;
(9) acceptable salt, wherein R on each compound or its pharmacology in (1)-(7)
4Be C
1-C
2Alkyl;
(10) acceptable salt, wherein R on each compound or its pharmacology in (1)-(7)
4Be methyl;
(11) acceptable salt on each compound or its pharmacology in (1)-(10), wherein n is 2 or 3;
(12) acceptable salt on each compound or its pharmacology in (1)-(10), wherein n is 2;
(13) acceptable salt on each compound or its pharmacology in (1)-(12), wherein X is ethylidene, ethynylene, aryl or the aryl that replaced by 1-3 group that is selected from substituting group group a;
(14) acceptable salt on each compound or its pharmacology in (1)-(12), wherein X is an ethylidene;
(15) acceptable salt on each compound or its pharmacology in (1)-(12), wherein X is an ethynylene;
(16) acceptable salt on each compound or its pharmacology in (1)-(12), wherein X is for having formula-D-CH
2-group;
(17) acceptable salt on each compound or its pharmacology in (1)-(12), wherein X is for having formula-D-CH
2-group (in the formula D represent carbonyl or have formula-CH (OH)-group);
(18) acceptable salt on each compound or its pharmacology in (1)-(17), wherein Y is C
1-C
10Alkylidene group or the C that is replaced by the individual group that is selected from substituting group group a and b of 1-3
1-C
10Alkylidene group;
(19) acceptable salt on each compound or its pharmacology in (1)-(17), wherein Y is C
1-C
6Alkylidene group or the C that is replaced by the individual group that is selected from substituting group group a and b of 1-3
1-C
6Alkylidene group;
(20) acceptable salt on each compound or its pharmacology in (1)-(17), wherein Y is ethylidene, trimethylene, tetramethylene or the ethylidene, trimethylene or the tetramethylene that are replaced by 1-3 group that is selected from substituting group group a and b;
(21) acceptable salt on each compound or its pharmacology in (1)-(17), wherein Y is ethylidene, trimethylene or tetramethylene;
(22) acceptable salt on each compound or its pharmacology in (1)-(17), wherein Y is ethylidene or trimethylene;
(23) acceptable salt on each compound or its pharmacology in (1)-(17), wherein Y in carbochain or the end of the chain have the C of Sauerstoffatom or sulphur atom
1-C
10Alkylidene group or by 1-3 be selected from that the group of substituting group group a and b replaces, in carbochain or the end of the chain have the C of Sauerstoffatom or sulphur atom
1-C
10Alkylidene group;
(24) acceptable salt on each compound or its pharmacology in (1)-(17), wherein Y in carbochain or the end of the chain have the C of Sauerstoffatom or sulphur atom
1-C
10Alkylidene group;
(25) acceptable salt on each compound or its pharmacology in (1)-(17), wherein Y in carbochain or the end of the chain have the C of Sauerstoffatom
1-C
10Alkylidene group;
(26) acceptable salt on each compound or its pharmacology in (1)-(17), wherein Y in carbochain or the end of the chain have the C of Sauerstoffatom
1-C
6Alkylidene group;
(27) acceptable salt on each compound or its pharmacology in (1)-(17), wherein Y is for having-O-CH
2-,-O-(CH
2)
2-,-O-(CH
2)
3-,-CH
2-O-,-(CH
2)
2-O-or-(CH
2)
3The group of-O-;
(28) acceptable salt on each compound or its pharmacology in (1)-(17), wherein Y is for having-CH
2The group of-O-;
(29) acceptable salt on each compound or its pharmacology in (1)-(17), wherein Y is for having-O-(CH
2)
2-or-(CH
2)
2The group of-O-;
(30) acceptable salt, wherein R on each compound or its pharmacology in (1)-(29)
5Be hydrogen atom;
(31) acceptable salt, wherein R on each compound or its pharmacology in (1)-(29)
5Cycloalkyl that replaces for cycloalkyl, heterocyclic radical, by 1-3 group that is selected from substituting group group a and b or the heterocyclic radical that is replaced by 1-3 group that is selected from substituting group group a and b;
(32) acceptable salt, wherein R on each compound or its pharmacology in (1)-(29)
5For cycloalkyl or by 1-3 cycloalkyl that is selected from the group replacement of substituting group group a and b;
(33) acceptable salt, wherein R on each compound or its pharmacology in (1)-(29)
5Be cycloalkyl;
(34) acceptable salt, wherein R on each compound or its pharmacology in (1)-(29)
5Be cyclohexyl;
(35) acceptable salt, wherein R on each compound or its pharmacology in (1)-(29)
5For aryl or by 1-3 aryl that is selected from the group replacement of substituting group group a and b;
(36) acceptable salt, wherein R on each compound or its pharmacology in (1)-(29)
5For aryl or by the aryl (described substituting group is selected from halogen atom, low alkyl group, junior alkyl halides, lower alkoxy, lower alkylthio and rudimentary aliphatic acidyl) of 1-3 substituting group replacement;
(37) acceptable salt, wherein R on each compound or its pharmacology in (1)-(29)
5For aryl or by the aryl (described substituting group is selected from halogen atom, low alkyl group, junior alkyl halides, lower alkoxy and rudimentary aliphatic acidyl) of 1-3 substituting group replacement;
(38) acceptable salt, wherein R on each compound or its pharmacology in (1)-(29)
5For phenyl or by the phenyl (described substituting group is selected from halogen atom, low alkyl group, junior alkyl halides, lower alkoxy and rudimentary aliphatic acidyl) of 1-3 substituting group replacement;
(39) acceptable salt, wherein R on each compound or its pharmacology in (1)-(29)
5For phenyl or by the phenyl (described substituting group is selected from fluorine atom, chlorine atom, methyl, trifluoromethyl, methoxyl group and ethanoyl) of 1-3 substituting group replacement;
(40) acceptable salt, wherein R on each compound or its pharmacology in (1)-(29)
5Be phenyl, the 3-fluorophenyl, the 4-fluorophenyl, 3, the 4-difluorophenyl, 3, the 5-difluorophenyl, the 3-chloro-phenyl-, the 4-chloro-phenyl-, 3, the 4-dichlorophenyl, 3, the 5-dichlorophenyl, the 3-aminomethyl phenyl, the 4-aminomethyl phenyl, 3, the 4-3,5-dimethylphenyl, 3, the 5-3,5-dimethylphenyl, the 3-trifluoromethyl, the 4-trifluoromethyl, 3,4-two (trifluoromethyl) phenyl, 3,5-two (trifluoromethyl) phenyl, the 3-p-methoxy-phenyl, the 4-p-methoxy-phenyl, 3, the 4-Dimethoxyphenyl, 3, the 5-Dimethoxyphenyl, 3,4, the 5-trimethoxyphenyl, 3-acetylphenyl or 4-acetylphenyl;
(41) acceptable salt, wherein R on each compound or its pharmacology in (1)-(40)
6And R
7Identical or different, respectively be hydrogen atom, halogen atom, low alkyl group, junior alkyl halides, lower alkoxy or lower alkylthio;
(42) acceptable salt, wherein R on each compound or its pharmacology in (1)-(40)
6And R
7Be hydrogen atom;
(43) be selected from acceptable salt, its ester or other derivative on any following compound, its pharmacology in (1):
2-amino-2-methyl-4-[5-(6-cyclohexyl hexyl) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-[5-(5-cyclohexyl amyl group) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-[5-(4-cyclohexyl butyl) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-[5-(6-cyclohexyl oneself-1-alkynyl) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-[5-(5-cyclohexyl penta-1-alkynyl) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-[5-(4-cyclohexyl fourth-1-alkynyl) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-[5-(6-cyclohexyl caproyl) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-[5-(5-cyclohexyl pentanoyl) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-[5-(4-cyclohexyl butyryl radicals) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-ethyl-4-[5-(6-cyclohexyl hexyl) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-ethyl-4-[5-(5-cyclohexyl amyl group) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-ethyl-4-[5-(4-cyclohexyl butyl) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-ethyl-4-[5-(6-cyclohexyl oneself-1-alkynyl) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-ethyl-4-[5-(5-cyclohexyl penta-1-alkynyl) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-ethyl-4-[5-(4-cyclohexyl fourth-1-alkynyl) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-ethyl-4-[5-(6-cyclohexyl caproyl) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-ethyl-4-[5-(5-cyclohexyl pentanoyl) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-ethyl-4-[5-(4-cyclohexyl butyryl radicals) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-[5-(6-phenyl hexyl) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-[5-(5-phenylpentyl) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-[5-(4-phenyl butyl) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-[5-(6-phenyl oneself-1-alkynyl) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-[5-(5-phenyl penta-1-alkynyl) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-[5-(4-phenyl fourth-1-alkynyl) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-[5-(6-phenyl caproyl) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-[5-(5-phenyl pentanoyl) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-[5-(4-phenyl butyryl radicals) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-[5-(5-cyclohexyloxy penta-1-alkynyl) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-[5-(4-cyclohexyloxy fourth-1-alkynyl) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-[5-(3-cyclohexyloxy proyl) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-[5-(5-cyclohexyloxy amyl group) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-[5-(4-cyclohexyloxy butyl) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-[5-(3-cyclohexyloxy propyl group) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-[5-(5-cyclohexyloxy pentanoyl) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-[5-(4-cyclohexyloxy butyryl radicals) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-[5-(3-cyclohexyloxy propionyl) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-[5-(5-phenoxy group penta-1-alkynyl) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-[5-(4-phenoxy group fourth-1-alkynyl) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-[5-(3-phenoxy group proyl) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-[5-(5-phenoxy group amyl group) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-[5-(4-phenoxy group butyl) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-[5-(3-phenoxy propyl) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-[5-(5-phenoxy group pentanoyl) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-[5-(4-phenoxy group butyryl radicals) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-[5-(3-phenoxy group propionyl) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-[5-(4-benzyloxy phenyl) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-[5-(4-cyclohexyl p-methoxy-phenyl) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-[5-(4-cyclohexyl ethoxyl phenenyl) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-[5-(3-cyclohexyl methoxy propyl alkynyl) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-[5-(3-cyclohexyl methoxy-propyl) thiophene-2-yl] fourth-1-is pure and mild
2-amino-2-methyl-4-[5-(3-cyclohexyl methoxy propyl acyl group) thiophene-2-yl] fourth-1-alcohol;
(44) be selected from acceptable salt, its ester or other derivative on any following compound, its pharmacology in (1):
2-amino-2-methyl-4-[5-(4-cyclohexyl butyl) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-[5-(5-cyclohexyl amyl group) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-[5-(5-phenylpentyl) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-[5-(4-cyclohexyloxy butyl) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-{5-[4-(4-fluorophenoxy) butyl] thiophene-2-yl } fourth-1-alcohol,
2-amino-2-methyl-4-{5-[4-(4-methoxyl group phenoxy group) butyl] thiophene-2-yl } fourth-1-alcohol,
2-amino-2-methyl-4-[5-(4-benzyloxy butyl) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-[5-(4-cyclohexyl fourth-1-alkynyl) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-[5-(4-phenyl fourth-1-alkynyl) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-[5-(5-cyclohexyl penta-1-alkynyl) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-[5-(5-phenyl penta-1-alkynyl) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-{5-[5-(4-fluorophenyl) penta-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
2-amino-2-methyl-4-{5-[5-(4-p-methoxy-phenyl) penta-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
2-amino-2-methyl-4-{5-[3-(4-methyl cyclohexane oxygen base) proyl] thiophene-2-yl } fourth-1-alcohol,
2-amino-2-methyl-4-{5-[3-(4-methylphenoxy) proyl] thiophene-2-yl } fourth-1-alcohol,
2-amino-2-methyl-4-{5-[3-(4-ethyl phenoxy group) proyl] thiophene-2-yl } fourth-1-alcohol,
2-amino-2-methyl-4-{5-[3-(4-methylthio group phenoxy group) proyl] thiophene-2-yl } fourth-1-alcohol,
2-amino-2-methyl-4-[5-(4-cyclohexyloxy fourth-1-alkynyl) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-{5-[4-(4-fluorophenoxy) fourth-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
2-amino-2-methyl-4-{5-[4-(4-methylphenoxy) fourth-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
2-amino-2-methyl-4-[5-(3-cyclohexyl methoxy propyl alkynyl) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-[5-(4-phenyl methoxyl group fourth-1-alkynyl) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-[5-(4-cyclohexyl butyryl radicals) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-[5-(4-phenyl butyryl radicals) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-[5-(5-cyclohexyl pentanoyl) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-[5-(5-phenyl pentanoyl) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-{5-[5-(4-fluorophenyl) pentanoyl] thiophene-2-yl } fourth-1-alcohol,
2-amino-2-ethyl-4-[5-(5-cyclohexyl amyl group) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-ethyl-4-[5-(5-cyclohexyl penta-1-alkynyl) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-ethyl-4-[5-(5-cyclohexyl pentanoyl) thiophene-2-yl] fourth-1-alcohol,
2-amino-2-methyl-4-{5-[3-(4-chlorophenoxy) proyl] thiophene-2-yl } fourth-1-alcohol,
2-amino-2-methyl-4-{5-[3-(3-methylphenoxy) proyl] thiophene-2-yl } fourth-1-alcohol,
2-amino-2-methyl-4-{5-[3-(3, the 4-dimethyl phenoxy) proyl] thiophene-2-yl } fourth-1-alcohol,
2-amino-2-methyl-4-{5-[3-(3-methoxyl group phenoxy group) proyl] thiophene-2-yl } fourth-1-alcohol,
2-amino-2-methyl-4-{5-[3-(3,4-dimethoxy phenoxy group) proyl] thiophene-2-yl } fourth-1-alcohol,
2-amino-2-methyl-4-{5-[3-(3,5-dimethoxy phenoxy group) proyl] thiophene-2-yl } fourth-1-alcohol,
2-amino-2-methyl-4-{5-[3-(3-ethanoyl phenoxy group) proyl] thiophene-2-yl } fourth-1-is pure and mild
2-amino-2-methyl-4-{5-[3-(4-ethanoyl phenoxy group) proyl] thiophene-2-yl } fourth-1-alcohol.
In the above-claimed cpd (I), also preferably will be selected from the compound that each arbitrary combination of (2) or (3), (4) or (5), (6) or (7), (8)-(10), (11) or (12), (13)-(17), (18)-(29), (30)-(40) and (41) or (42) forms.
(45) opticity amino alcohol compound of the present invention has following general formula (La) or (Lb).The compound that is expressed from the next:
[in the formula
R
1And R
2Identical or different, expression hydrogen atom or amino protecting group;
R
3aThe protecting group of expression hydrogen atom or hydroxyl; Perhaps
R
1Be hydrogen atom, and R
2And R
3aExpression ((C=O)-) group together;
R
4aExpression C
1-C
20Alkyl, wherein heteroatomic C arranged
2-C
20Alkyl, the C that is replaced by aryl or aromatic heterocyclic radical
1-C
20Alkyl, C
2-C
20Alkynyl, wherein heteroatomic C arranged
3-C
20Alkynyl, the C that is replaced by aryl or aromatic heterocyclic radical
2-C
20Alkynyl, C
2-C
20Alkenyl, wherein heteroatomic C arranged
3-C
20Alkenyl, the C that is replaced by aryl or aromatic heterocyclic radical
2-C
20Alkenyl, heteroatomic C wherein arranged by what aryl or aromatic heterocyclic radical replaced
2-C
20Alkyl or cycloalkyl;
M represents the integer of 0-4;
The aryl that Ar represents aryl, aromatic heterocyclic radical, replaced by 1-5 group that is selected from substituting group group a, the aromatic heterocyclic radical that is replaced by 1-5 group that is selected from substituting group group a.Condition is when Ar is aryl, R
1Do not represent hydrogen atom and R
2And/or R
3aDo not represent hydrogen atom.]。
＜substituting group group a 〉
Halogen atom, low alkyl group, junior alkyl halides, lower alkoxy, lower alkylthio, carboxyl, lower alkoxycarbonyl, hydroxyl, rudimentary aliphatic acidyl, amino, single low-grade alkyl amino, two elementary alkyl amido, lower aliphatic amido, cyano group and nitro.
Above-claimed cpd (La) or (Lb) in, preferred compound can exemplify as follows.
(46) compound of (45), it has general formula (La);
(47) compound of (45) or (46), wherein R
1Be hydrogen atom;
(48) each compound, wherein R in (45)-(47)
2And R
3aBe formula ((C=O)-) group together;
(49) each compound, wherein R in (45)-(47)
3aBe hydrogen atom;
(50) each compound, wherein R4 in (45)-(49)
aBe C
1-C
10Alkyl, wherein heteroatomic C arranged
2-C
10Alkyl, the C that is replaced by aryl or aromatic heterocyclic radical
1-C
10Alkyl, C
2-C
10Alkynyl, wherein heteroatomic C arranged
3-C
10Alkynyl, the C that is replaced by aryl or aromatic heterocyclic radical
2-C
10Alkynyl, C
2-C
10Alkenyl, wherein heteroatomic C arranged
3-C
10Alkenyl, the C that is replaced by aryl or aromatic heterocyclic radical
2-C
10Alkenyl, heteroatomic C wherein arranged by what aryl or aromatic heterocyclic radical replaced
2-C
10Alkyl or C
5-C
10Cycloalkyl;
(51) each compound, wherein R in (45)-(49)
4aBe C
1-C
10Alkyl, wherein heteroatomic C arranged
2-C
10Alkyl, the C that is replaced by aryl or aromatic heterocyclic radical
1-C
10Alkyl, C
2-C
10Alkynyl, C
2-C
10Alkenyl or C
5-C
10Cycloalkyl;
(52) each compound, wherein R in (45)-(49)
4aBe C
1-C
10Alkyl;
(53) each compound, wherein R in (45)-(49)
4aBe C
1-C
6Alkyl;
(54) each compound, wherein R in (45)-(49)
4aBe methyl or ethyl;
(55) each compound in (45)-(54), wherein Ar is phenyl, furyl, thienyl, benzothienyl or the phenyl, furyl, thienyl or the benzothienyl that are replaced by 1-4 group that is selected from above-mentioned substituting group group a;
(56) each compound in (45)-(54), wherein Ar is thienyl or is selected from the thienyl that the group of above-mentioned substituting group group a replaces by 1-4;
(57) each compound in (45)-(54), wherein Ar is benzothienyl or is selected from the benzothienyl that the group of above-mentioned substituting group group a replaces by 1-4;
(58) each compound in (45)-(57), wherein m is 0;
(59) each compound in (45)-(57), wherein substituting group group a is halogen atom, hydroxyl, low alkyl group, junior alkyl halides, lower alkoxy, carboxyl, rudimentary aliphatic acidyl, lower aliphatic amido, amino, cyano group and nitro.
(60) in addition, the present invention relates to have the preparation method of following general formula (XLIVa) or compound (XLIVb), promptly general formula (XLIVa) or (XLIVb) shown in 2-replacement-2-amino-1, the ammediol monoester derivates
[in the formula
R
1And R
2Identical or different, expression hydrogen atom or amino protecting group;
R
4aExpression C
1-C
20Alkyl, wherein heteroatomic C arranged
2-C
20Alkyl, the C that is replaced by aryl or aromatic heterocyclic radical
1-C
20Alkyl, C
2-C
20Alkynyl, wherein heteroatomic C arranged
3-C
20Alkynyl, the C that is replaced by aryl or aromatic heterocyclic radical
2-C
20Alkynyl, C
2-C
20Alkenyl, wherein heteroatomic C arranged
3-C
20Alkenyl, the C that is replaced by aryl or aromatic heterocyclic radical
2-C
20Alkenyl, heteroatomic C wherein arranged by what aryl or aromatic heterocyclic radical replaced
2-C
20Alkyl or cycloalkyl;
R
11Expression and R
4aDefinition in identical group.]
The preparation method, it is characterized in that: in the presence of lipase, with having formula (XLIII)
R
11COOCH＝CH
2 (XLIII)
Generating vinyl carboxylate ester derivative (R in the formula
11Expression meaning as hereinbefore) mutual-through type (XLII)
[R in the formula
1, R
2And R
4aExpression meaning as hereinbefore.]
Shown in 2-replacement-2-amino-1, a hydroxyl of ammediol derivative carries out selectively acylating.
In above-mentioned, preferred
(61) preparation method of (60), wherein R
1And R
2One of be hydrogen atom, another is amino protecting group;
(62) preparation method of (60) or (61), wherein R
4aBe C
1-C
10Alkyl, wherein heteroatomic C arranged
2-C
10Alkyl, the C that is replaced by aryl or aromatic heterocyclic radical
1-C
10Alkyl, C
2-C
10Alkynyl, wherein heteroatomic C arranged
3-C
10Alkynyl, the C that is replaced by aryl or aromatic heterocyclic radical
2-C
10Alkynyl, C
2-C
10Alkenyl, wherein heteroatomic C arranged
3-C
10Alkenyl, the C that is replaced by aryl or aromatic heterocyclic radical
2-C
10Alkenyl, heteroatomic C wherein arranged by what aryl or aromatic heterocyclic radical replaced
2-C
10Alkyl or C
5-C
10Cycloalkyl;
(63) preparation method of (60) or (61), wherein R
4aBe C
1-C
10Alkyl, wherein heteroatomic C arranged
2-C
10Alkyl, the C that is replaced by aryl or aromatic heterocyclic radical
1-C
10Alkyl, C
2-C
10Alkynyl, C
2-C
10Alkenyl or C
5-C
10Cycloalkyl;
(64) preparation method of (60) or (63), wherein R
11Be C
1-C
20Alkyl or the C that is replaced by aryl or heteroaryl
1-C
20Alkyl.
In the following formula, X, R
5, Ar and substituting group group b definition in, the example of " aryl ", " by the individual aryl that is selected from the group replacement of substituting group group a of 1-3 ", " by 1-3 aryl that is selected from the group replacement of substituting group group a and b " and " by 1-5 aryl that is selected from the group replacement of substituting group group a " middle aryl moiety has the aromatic hydrocarbyl of phenyl, indenyl, naphthyl and so on carbonatoms 6-10, preferred phenyl or naphthyl, most preferably phenyl.
In the following formula, " C in the definition of Y
1-C
10Alkylidene group " and " by 1-3 C that is selected from the group replacement of substituting group group a and b
1-C
10Alkylidene group " C
1-C
10Alkylene moiety is a methylene radical, the methyl methylene radical, ethylidene, 1, the 2-propylidene, 1, the 3-propylidene, 1-methyl ethylidene, 1, the 4-butylidene, the 1-methyl isophthalic acid, the 3-propylidene, the 2-methyl isophthalic acid, the 3-propylidene, the 3-methyl isophthalic acid, the 3-propylidene, the 1-methyl isophthalic acid, the 2-propylidene, 1,1-dimethyl ethylidene, pentamethylene, the 1-methyl isophthalic acid, the 4-butylidene, the 2-methyl isophthalic acid, the 4-butylidene, the 3-methyl isophthalic acid, the 4-butylidene, the 4-methyl isophthalic acid, the 4-butylidene, 1,1-dimethyl-1, the 3-propylidene, 2,2-dimethyl-trimethylene, 3,3-dimethyl-1, the 3-propylidene, 1, the 6-hexylidene, the 1-methyl isophthalic acid, the 5-pentylidene, the 2-methyl isophthalic acid, the 5-pentylidene, the 3-methyl isophthalic acid, the 5-pentylidene, the 4-methyl isophthalic acid, the 5-pentylidene, the 5-methyl isophthalic acid, the 5-pentylidene, 1,1-dimethyl-1, the 4-butylidene, 2,2-dimethyl-tetramethylene, 3,3-dimethyl-1, the 4-butylidene, 4,4-dimethyl-tetramethylene, 1, the inferior heptyl of 7-, the 1-methyl isophthalic acid, the 6-hexylidene, the 2-methyl isophthalic acid, the 6-hexylidene, the 5-methyl isophthalic acid, the 6-hexylidene, 3-ethyl-pentamethylene, 1,8-is octylene, the 2-methyl isophthalic acid, the inferior heptyl of 7-, the 5-methyl isophthalic acid, the inferior heptyl of 7-, 2-ethyl-hexamethylene, 2-ethyl-3-methyl isophthalic acid, the 5-pentylidene, 3-ethyl-2-methyl isophthalic acid, the 5-pentylidene, nonamethylene, the 2-methyl isophthalic acid, 8-is octylene, the 7-methyl isophthalic acid, 8-is octylene, 4-ethyl-1, the inferior heptyl of 7-, 3-ethyl-2-methyl isophthalic acid, the 6-hexylidene, 2-ethyl-1-methyl isophthalic acid, the 6-hexylidene, 1, the straight or branched alkylidene group of the inferior decyl of 10-and so on carbonatoms 1-10, preferred C
1-C
6Alkylidene group, more preferably C
1-C
5Alkylidene group is more preferably ethylidene, trimethylene or tetramethylene, most preferably ethylidene or trimethylene.
In the following formula, in the definition of Y " in carbochain or the end of the chain have the C of Sauerstoffatom or sulphur atom
1-C
10Alkylidene group " and " by 1-3 be selected from that the group of substituting group group a and b replaces, in carbochain or the end of the chain have the C of Sauerstoffatom or sulphur atom
1-C
10Alkylidene group " " in carbochain or the end of the chain have the C of Sauerstoffatom or sulphur atom
1-C
10Alkylidene group " be partly at above-mentioned " C
1-C
10Alkylidene group " the end of the chain or chain in have the group of Sauerstoffatom or sulphur atom, for example have-O-CH
2-,-O-(CH
2)
2-,-O-(CH
2)
3-,-O-(CH
2)
4-,-O-(CH
2)
5-,-O-(CH
2)
6-,-O-(CH
2)
7-,-O-(CH
2)
8-,-O-(CH
2)
9-,-O-(CH
2)
10-,-CH
2-O-CH
2-,-CH
2-O-(CH
2)
2-,-CH
2-O-(CH
2)
3-,-CH
2-O-(CH
2)
4-,-(CH
2)
2-O-CH
2-,-(CH
2)
2-O-(CH
2)
2-,-(CH
2)
2-O-(CH
2)
3-,-(CH
2)
2-O-(CH
2)
4-,-(CH
2)
3-O-CH
2-,-(CH
2)
3-O-(CH
2)
2-,-(CH
2)
3-O-(CH
3)
3-,-(CH
2)
4-O-CH
2-,-(CH
2)
4-O-(CH
2)
2-,-(CH
2)
5-O-CH
2-,-CH
2-O-,-(CH
2)
2-O-,-(CH
2)
3-O-,-(CH
2)
4-O-,-(CH
3)
5-O-,-(CH
2)
6-O-,-(CH
2)
7-O-,-(CH
2)
8-O-,-(CH
2)
9-O-,-(CH
2)
10-O-,-S-CH
2-,-S-(CH
2)
2-,-S-(CH
2)
3-,-S-(CH
2)
4-,-S-(CH
2)
5-,-S-(CH
2)
6-,-S-(CH
2)
7-,-S-(CH
2)
8-,-S-(CH
2)
9-,-S-(CH
2)
10-,-CH
2-S-CH
2-,-CH
2-S-(CH
2)
2-,-CH
2-S-(CH
2)
3-,-CH
2-S-(CH
2)
4-,-(CH
2)
2-S-CH
2-,-(CH
2)
2-S-(CH
2)
2-,-(CH
2)
2-S-(CH
2)
3-,-(CH
2)
2-S-(CH
2)
4-,-(CH
2)
3-S-CH
2-,-(CH
2)
3-S-(CH
2)
2-,-(CH
2)
3-S-(CH
2)
3-,-(CH
2)
4-S-CH
2-,-(CH
2)
4-S-(CH
2)
2-,-(CH
2)
5-S-CH
2-,-CH
2-S-,-(CH
2)
2-S-,-(CH
2)
3-S-,-(CH
2)
4-S-,-(CH
2)
5-S-,-(CH
2)
6-S-,-(CH
2)
7-S-,-(CH
2)
8-S-,-(CH
3)
9-S-,-(CH
2)
10-S-
Group, in the preferred carbochain or the end of the chain have the C of Sauerstoffatom
1-C
6Alkylidene group more preferably has-O-CH
2-,-O-(CH
2)
2-,-O-(CH
2)
3-,-CH
2-O-,-(CH
2)
2-O-or-(CH
2)
3The group of-O-most preferably has-CH
2-O-,-O-(CH
2)
2-or-(CH
2)
2The group of-O-.
In the following formula, R
4a, R
5, R
11In the definition of substituting group group b, the example of the cycloalkyl moiety of " cycloalkyl ", " by 1-3 cycloalkyl that is selected from the group replacement of substituting group group a " and " by 1-3 cycloalkyl that is selected from the group replacement of substituting group group a and b " has the saturated carbon cyclic group of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, norcamphyl (norbornyl), adamantyl (adamantyl), indanyl and so on carbonatoms 3-10, also can condense with other cyclic group of phenyl ring and so on.R
5With the preferred C of cycloalkyl in the definition of substituting group group b
5-C
6Cycloalkyl, most preferably cyclohexyl; And R
4aAnd R
11Definition in the preferred C of cycloalkyl
5-C
10Cycloalkyl.
In the following formula, " aromatic heterocyclic radical " and " by 1-5 aromatic heterocyclic radical that is selected from the group replacement of substituting group group a " expression contains 5-7 unit heterocyclic radical, for example furyl, thienyl, pyrryl, the azepine of 1-3 sulphur atom, Sauerstoffatom and/or nitrogen-atoms in the definition of Ar
Base, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2, the aromatic heterocyclic radical of 3-oxadiazole base, triazolyl, tetrazyl, thiadiazolyl group, pyranyl, pyridyl, pyridazinyl, pyrimidyl and pyrazinyl and so on.
In addition, above-mentioned " aromatic heterocyclic radical " can condense with other cyclic group, and its example has the group of benzothienyl, isobenzofuran-base, benzopyranyl, xanthenyl, phenothioxin base, indolizine base, pseudoindoyl, indyl, indazolyl, purine radicals, quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolyl, carbazyl, carbolinyl, acridyl, iso-dihydro-indole-group and so on.Preferred this class " aromatic heterocyclic radical " is furyl, thienyl, benzothienyl, most preferably thienyl or benzothienyl.
In the following formula, R
5In the definition of substituting group group b, " heterocyclic radical ", the heterocyclic radical of " by 1-3 heterocyclic radical that is selected from the group replacement of substituting group group a " and " by 1-3 heterocyclic radical that is selected from the group replacement of substituting group group a and b " partly represents to contain 1-3 sulphur atom, the 5-7 of Sauerstoffatom and/or nitrogen-atoms unit heterocycle, its example have above-mentioned " aromatic heterocyclic radical " and and THP trtrahydropyranyl, morpholinyl, thio-morpholinyl, pyrrolidyl, pyrryl, imidazolidyl, pyrazolidyl, piperidyl, piperazinyl oxazolidinyl isoxazole alkyl, the corresponding partially or completely reduced form of thiazolidyl and pyrazolidyl saturated heterocyclyl.The preferred 5-6 of described heterocyclic radical unit aromatic heterocyclic radical, most preferably morpholinyl, thio-morpholinyl or piperidyl.
In the following formula, " halogen atom " is fluorine, chlorine, bromine, iodine atom in the definition of substituting group group a, preferred fluorine atom or chlorine atom, most preferably fluorine atom.
In the following formula, R
4Be for example methyl with " low alkyl group " in the definition of substituting group group a, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, the 2-methyl butyl, neo-pentyl, the 1-ethyl propyl, hexyl, isohexyl, the 4-methyl amyl, the 3-methyl amyl, the 2-methyl amyl, the 1-methyl amyl, 3, the 3-dimethylbutyl, 2, the 2-dimethylbutyl, 1, the 1-dimethylbutyl, 1, the 2-dimethylbutyl, 1, the 3-dimethylbutyl, 2, the 3-dimethylbutyl, the 1-ethyl-butyl, the straight or branched alkyl of 2-ethyl-butyl and so on carbonatoms 1-6, preferred C
1-C
4Alkyl, more preferably C
1-C
2Alkyl, most preferable.
In the following formula, aforementioned " low alkyl group " that " junior alkyl halides " expression is replaced by halogen atom in the definition of substituting group group a, for example trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, two brooethyls, fluoro methyl, 2,2,2-trifluoroethyl, 2,2,2-three chloroethyls, 2-bromotrifluoromethane, 2-chloroethyl, 2-fluoro ethyl, 2-iodine ethyl, 3-chloropropyl, 4-fluorine butyl, 6-iodine hexyl, 2,2-two bromotrifluoromethanes and so on halo C
1-C
6Alkyl, preferred halo C
1-C
4Alkyl, more preferably halo C
1-C
2Alkyl, most preferably trifluoromethyl.
In the following formula, " lower alkoxy " expression aforementioned " low alkyl group " combines with Sauerstoffatom and the group that forms in the definition of substituting group group a, methoxyl group for example, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert.-butoxy, pentyloxy, isopentyloxy, 2-methyl butoxy, 1-ethyl propoxy-, 2-ethyl propoxy-, neopentyl oxygen, hexyloxy, 4-methyl pentyloxy, 3-methyl pentyloxy, 2-methyl pentyloxy, 3,3-dimethyl butoxy, 2,2-dimethyl butoxy, 1,1-dimethyl butoxy, 1,2-dimethyl butoxy, 1,3-dimethyl butoxy, 2, the straight or branched alkoxyl group of 3-dimethyl butoxy and so on carbonatoms 1-6, preferred C
1-C
4Alkoxyl group, more preferably C
1-C
2Alkoxyl group, most preferably methoxyl group.
In the following formula, " lower alkylthio " expression aforementioned " low alkyl group " combines with sulphur atom and the group that forms in the definition of substituting group group a, methylthio group for example, ethylmercapto group, the rosickyite base, the iprotiazem base, butylthio, the isobutyl sulfenyl, secondary butylthio, uncle's butylthio, penta sulfenyl, the isoamyl sulfenyl, 2-methyl butylthio, new penta sulfenyl, own sulfenyl, 4-methylpent sulfenyl, 3-methylpent sulfenyl, 2-methylpent sulfenyl, 3,3-dimethyl butyrate sulfenyl, 2,2-dimethyl butyrate sulfenyl, 1,1-dimethyl butyrate sulfenyl, 1,2-dimethyl butyrate sulfenyl, 1,3-dimethyl butyrate sulfenyl, 2, the straight or branched alkylthio of 3-dimethyl butyrate sulfenyl and so on carbonatoms 1-6, preferred C
1-C
4Alkylthio, more preferably C
1-C
2Alkylthio, most preferably methylthio group.
In the following formula, " lower alkoxycarbonyl " expression aforementioned " lower alkoxy " combines with carbonyl and the group that forms in the definition of substituting group group a, methoxycarbonyl for example, ethoxycarbonyl, the third oxygen carbonyl, the different third oxygen carbonyl, butoxy carbonyl, isobutyl boc, secondary butoxy carbonyl, tertbutyloxycarbonyl, penta oxygen carbonyl, isoamyl oxygen carbonyl, 2-methyl butoxy carbonyl, new penta oxygen carbonyl, own oxygen carbonyl, 4-methylpent oxygen carbonyl, 3-methylpent oxygen carbonyl, 2-methylpent oxygen carbonyl, 3,3-dimethyl butoxy carbonyl, 2,2-dimethyl butoxy carbonyl, 1,1-dimethyl butoxy carbonyl, 1,2-dimethyl butoxy carbonyl, 1,3-dimethyl butoxy carbonyl, 2, the straight or branched carbalkoxy of 3-dimethyl butoxy carbonyl and so on carbonatoms 1-6, preferred C
1-C
4Carbalkoxy, more preferably C
1-C
2Carbalkoxy, most preferably methoxycarbonyl.
In the following formula; " rudimentary aliphatic acidyl " expression hydrogen atom or saturated or unsaturated chain alkyl combines with carbonyl and the group that forms in the definition of substituting group group a; the straight or branched rudimentary aliphatic acidyl of formyl radical, ethanoyl, propionyl, butyryl radicals, isobutyryl, pentanoyl, isovaleryl, valeryl, caproyl, acryl, methacryloyl, crotonoyl and so on carbonatoms 1-7 for example, preferred C
1-C
4Rudimentary aliphatic acidyl, more preferably ethanoyl or propionyl, most preferably ethanoyl.
In the following formula, " single low-grade alkyl amino " expression aforementioned " low alkyl group " and 1 amino group that forms that combines in the definition of substituting group group a, methylamino for example, ethylamino, propyl group amino, sec.-propyl amino, butyl amino, isobutylamino, sec-butyl amino, tertiary butyl amino, amyl group amino, isopentyl amino, 2-methyl butyl amino, neo-pentyl amino, 1-ethyl propyl amino, hexyl amino, isohexyl amino, 4-methyl amyl amino, 3-methyl amyl amino, 2-methyl amyl amino, 1-methyl amyl amino, 3,3-dimethylbutyl amino, 2,2-dimethylbutyl amino, 1,1-dimethylbutyl amino, 1,2-dimethylbutyl amino, 1,3-dimethylbutyl amino, 2,3-dimethylbutyl amino, 2-ethyl-butyl amino and so on list-C
1-C
6Alkylamino, preferred list-C
1-C
4Alkylamino, more preferably list-C
1-C
2Alkylamino, most preferable amino.
In the following formula, " two elementary alkyl amido " expression 2 aforementioned " low alkyl groups " combines the group that forms, for example dimethylamino, diethylamino, N-ethyl-N-methylamino, dipropyl amino, dibutylamino, diamyl amino, dihexyl amino and so on two-C with amino in the definition of substituting group group a
1-C
6Alkylamino, preferred two-C
1-C
4Alkylamino, more preferably two-C
1-C
2Alkylamino, most preferably dimethylamino.
In the following formula; " lower aliphatic amido " expression aforementioned " rudimentary aliphatic acidyl " and the amino group that forms that combines in the definition of substituting group group a; the straight or branched lower aliphatic amido of formamido group, kharophen, propionamido, butyrylamino, isobutyryl amino, valeryl amino, isovaleryl amino, pivalyl amino, hexanamido, acrylamido, methacrylamido, crotonoyl amino and so on carbonatoms 1-7 for example; preferred kharophen or propionamido, most preferably kharophen.
In the following formula, R
1And R
2Definition in " amino protecting group " be meant and for example comprise the protecting group of the normally used amino in Synthetic Organic Chemistry field
Aforementioned " low alkyl group ";
" the aliphatic acyl classes " such as rudimentary aliphatic acidyls that aforementioned " rudimentary aliphatic acidyl ", chloracetyl, dichloro-acetyl, tribromo-acetyl base, tetrafluoro ethanoyl and so on halo rudimentary aliphatic acidyl, methoxyl group ethanoyl and so on are replaced by lower alkoxy;
Aromatic acyl group, 4-chlorobenzene formacyl, 4-fluoro benzoyls, 2 such as benzoyl, 1-indane carbonyl, 2-indane carbonyl, 1-or 2-naphthoyl, 4,6-trimethylbenzoyl, 4-toluyl, 4-methoxybenzoyl base, 4-nitro benzoyl, 2-nitro benzoyl, 2-(methoxycarbonyl) benzoyl, 4-phenyl benzoyl and so on are by 1-3 " aromatic acyl group classes " such as aromatic acyl groups that group replaced that is selected from aforementioned substituting group group a;
Aforementioned " lower alkoxycarbonyl ", 2,2,2-trichloro-ethoxycarbonyl, 2-trimethyl silyl ethoxycarbonyl and so on are by " the carbalkoxy classes " such as lower alkoxycarbonyl of halogen or the replacement of three low alkyl group silyls;
Ethylene oxy carbonyl, allyloxy carbonyl and so on " alkenyloxy carbonyl class ";
The aralkyl oxy carbonyl of carbobenzoxy-(Cbz) and so on, 4-methoxyl group benzyloxy carbonyl, 3,4-dimethoxy-benzyloxycarbonyl, 2-nitro carbobenzoxy-(Cbz), 4-nitro carbobenzoxy-(Cbz) and so on are by 1-3 " aralkyl oxy carbonyl classes " such as aralkyl oxy carbonyls that group replaced that is selected from aforementioned substituting group group a;
Trimethyl silyl, triethylsilyl, the sec.-propyl dimetylsilyl, t-butyldimethylsilyl, methyl di-isopropyl silyl, methyl di-t-butyl silyl, triisopropyl silyl and so on three low alkyl group silyls, the diphenyl methyl silyl, phenylbenzene butyl silyl, phenylbenzene sec.-propyl silyl, phenyl di-isopropyl silyl and so on three is replaced silyls etc. " silicomethane base class " by aryl or aryl and low alkyl group replaced;
Phenmethyl, styroyl, the 3-phenyl propyl, the Alpha-Naphthyl methyl, the betanaphthyl methyl, diphenyl methyl, trityl group, the Alpha-Naphthyl diphenyl methyl, the low alkyl group that 9-anthryl methyl and so on is replaced by 1-3 aryl, the 4-methyl-benzyl, 2,4, the 6-trimethyl benzyl, 3,4, the 5-trimethyl benzyl, the 4-methoxy-benzyl, 4-p-methoxy-phenyl diphenyl methyl, the 2-nitrobenzyl, the 4-nitrobenzyl, 4-benzyl chloride base, the 4-bromobenzyl, 4-cyano group benzyl, 4-cyano group benzyl diphenyl methyl, two (2-nitrophenyl) methyl, piperonyl and so on by 1-3 by aromatic ring through low alkyl group, lower alkoxy, nitro, " aralkyl " of the low alkyl group that aryl replaced that halogen or cyano group replacement form etc.; And
N, N-dimethylamino methylene, benzylidene, 4-methoxyl group benzylidene, 4-nitro benzylidene, salicylidene, 5-chlorine salicylidene, phenylbenzene methylene radical, (5-chloro-2-hydroxy phenyl) phenylmethylene and so on " form the substituted methylene radical of Schiff's base ".Preferred lower alkoxycarbonyl, aralkyl oxy carbonyl or the aralkyl oxy carbonyl that is replaced by the individual group that is selected from substituting group group a of 1-3.
R
3And R
3aDefinition in " protecting group of hydroxyl " expression can be by chemical process rimose " the general protecting group in the reaction " such as hydrogenolysis, hydrolysis, electrolysis, photodissociation and " can pass through hydrolysis and so on biological method rimose protecting group in vivo ".
The example of described " the general protecting group in the reaction " has:
Aforementioned " low alkyl group ";
Aforementioned " aliphatic acyl class ";
Aforementioned " aromatic acyl group class ";
Tetrahydropyrans-2-base, 3-bromine tetrahydropyrans-2-base, 4-methoxyl group tetrahydropyran-4-base, tetrahydric thiapyran-2-base, 4-methoxyl group tetrahydric thiapyran-4-group and so on " THP trtrahydropyranyl or tetrahydric thiapyran base class ";
Tetrahydrofuran (THF)-2-base, tetramethylene sulfide-2-base and so on " tetrahydrofuran base or tetramethylene sulfide base class ";
Aforementioned " silicomethane base class ";
Methoxymethyl, 1, the lower alkoxy lower alkoxy methyl, 2 of 1-dimethyl-1-methoxymethyl, ethoxyl methyl, propoxy-methyl, isopropoxy methyl, butoxymethyl, tert.-butoxy methyl and so on lower alkoxy methyl, 2-methoxy ethoxy methyl and so on, 2, " alkoxy methyls " such as halogenated lower alkoxy methyl of 2-trichlorine ethoxyl methyl, two (2-chloroethoxy) methyl and so on;
1-ethoxyethyl group, 1-(isopropoxy) ethyl and so on lower alkoxy ethyl, 2,2, the halogenated ethyls of 2-three chloroethyls and so on etc. " replace the ethyl class ";
Aforementioned " aralkyl ";
Aforementioned " carbalkoxy class ";
Aforementioned " alkenyloxy carbonyl class ";
Aforementioned " aralkyl oxy carbonyl ".
On the other hand, the example of " can by hydrolysis and so on biological method rimose protecting group " in vivo has ethyl ketonic oxygen ylmethyl, oxy acid methyl neopentyl, dimethylamino acetoxyl group methyl, 1-acetoxyl group ethyl and so on acyloxy alkyls;
1-(methoxycarbonyl oxygen base) ethyl, 1-(ethoxycarbonyl-oxygen base) ethyl, ethoxycarbonyl-oxygen ylmethyl, 1-(the different third oxygen ketonic oxygen base) ethyl, 1-(tertbutyloxycarbonyl oxygen base) ethyl, 1-(ethoxycarbonyl-oxygen base) propyl group, 1-(hexamethylene oxygen ketonic oxygen base) ethyl and so on 1-(alkoxycarbonyloxy) alkyls;
Phthalidyl;
" the ketonic oxygen base alkylses " such as oxo dioxa cyclopentenyl methyl of 4-methyl-oxo dioxa cyclopentenyl (dioxolenyl) methyl, 4-phenyl-oxo-dioxa cyclopentenyl methyl, oxo dioxa cyclopentenyl methyl and so on;
Aforementioned " aliphatic acyl class ";
Aforementioned " aromatic acyl group class ";
" the half ester salt residue of succsinic acid ";
" phosphate ester salt residue ";
" the one-tenth ester residues of amino acid etc. ";
Formamyl;
The inferior aralkyl of benzylidene and so on; The alkoxyl group ethylidene of methoxyl group ethylidene, oxyethyl group ethylidene and so on; The oxo methylene radical; Thio-methylene and so on " protecting groups of 2 hydroxyls ";
And " the ketonic oxygen base carbalkoxy " of new pentane acyloxy methoxycarbonyl and so on.Whether be such derivative, can be through the laboratory animal administration of intravenous injection to rat or mouse and so on, the body fluid of analyzing animal is afterwards determined according to detecting on original compound or its pharmacology acceptable salt.The preferred low alkyl group of the protecting group of such hydroxyl, rudimentary aliphatic acidyl, aromatic acyl group or the aromatic acyl group that is replaced by the individual group that is selected from substituting group group a of 1-3.
In above-mentioned, R
5Definition in the object lesson of " being selected from the cycloalkyl that the group of substituting group group a and b replaces " by 1-3 2-fluorine cyclopropyl is arranged; 2-chlorine cyclopropyl; 2-or 3-fluorine cyclopentyl; 2-or 3-chlorine cyclopentyl; 2-; 3-or 4-fluorine cyclohexyl; 2-; 3-or 4-chlorine cyclohexyl; 2-; 3-or 4-bromine cyclohexyl; 2-; 3-or 4-iodine cyclohexyl; 2-methyl cyclopropyl; 2-ethyl cyclopropyl; 2-or 3-methylcyclopentyl; 2-or 3-ethyl cyclopentyl; 2-; 3-or 4-methylcyclohexyl; 2-; 3-or 4-ethyl cyclohexyl; 2-trifluoromethyl cyclopropyl; 2-or 3-trifluoromethyl cyclobutyl; 2-or 3-trifluoromethyl cyclopentyl; 2-; 3-or 4-trifluoromethyl cyclohexyl; 2-methoxyl group cyclopropyl; 2-or 3-methoxyl group cyclobutyl; 2-or 3-methoxyl group cyclopentyl; 2-; 3-or 4-methoxyl group cyclohexyl; 2-; 3-or 4-oxyethyl group cyclohexyl; 2-; 3-or 4-propoxy-cyclohexyl; 2-; 3-or 4-isopropoxy cyclohexyl; 2-; 3-or 4-(1-ethyl propoxy-) cyclohexyl; 2-; 3-or 4-(2-ethyl propoxy-) cyclohexyl; 2-carboxyl cyclopropyl; 2-or 3-carboxyl cyclopentyl; 2-; 3-or 4-carboxyl cyclohexyl; 2-methoxycarbonyl cyclopropyl; 2-or 3-methoxycarbonyl cyclopentyl; 2-; 3-or 4-methoxycarbonyl cyclohexyl; 2-hydroxyl cyclopropyl; 2-or 3-hydroxycyclopent base; 2-; 3-or 4-hydroxy-cyclohexyl; 2-formyl radical cyclopropyl; 2-or 3-formyl radical cyclopentyl; 2-; 3-or 4-formyl radical cyclohexyl; 2-ethanoyl cyclopropyl; 2-or 3-ethanoyl cyclopentyl; 2-; 3-or 4-ethanoyl cyclohexyl; the amino cyclopropyl of 2-; 2-or 3-amino cyclopentyl; 2-; 3-or 4-aminocyclohexyl; 2-methylamino cyclopropyl; 2-or 3-methylamino cyclobutyl; 2-or 3-methylamino cyclopentyl; 2-; 3-or 4-methylamino cyclohexyl; 2-dimethylamino cyclopropyl; 2-or 3-dimethylamino cyclobutyl; 2-or 3-dimethylamino cyclopentyl; 2-; 3-or 4-dimethylamino cyclohexyl; 2-cyano group cyclopropyl; 2-or 3-cyano group cyclopentyl; 2-; 3-or 4-cyanocyclohexanoic base; 2-or 3-cyclohexyl ring amyl group; 2-; 3-or 4-cyclohexyl ring hexyl; the 2-phenycyclopropyl; 2-or 3-benzyl ring amyl group; 2-; 3-or 4-benzyl ring hexyl; 3; 4-difluoro cyclohexyl; 3; 4-dichloro cyclohexyl; 2; 3-dimethoxy cyclohexyl; 3; 4-dimethoxy cyclohexyl; 3; 5-dimethoxy cyclohexyl; 3; 4; 5-trimethoxy cyclohexyl; preferably (described substituting group is selected from halogen atom to the cycloalkyl that is replaced by 1-3 substituting group; low alkyl group; junior alkyl halides; lower alkoxy; lower alkylthio and rudimentary aliphatic acidyl); more preferably (described substituting group is selected from halogen atom to the cycloalkyl that is replaced by 1-3 substituting group; low alkyl group; junior alkyl halides; lower alkoxy and rudimentary aliphatic acidyl); (described substituting group is selected from halogen atom to be more preferably the cyclohexyl that is replaced by 1-3 substituting group; low alkyl group; junior alkyl halides; lower alkoxy and rudimentary aliphatic acidyl), most preferably (described substituting group is selected from fluorine atom to the cyclohexyl that is replaced by 1-3 substituting group; the chlorine atom; methyl; trifluoromethyl; methoxyl group and ethanoyl).
In above-mentioned, R
5Definition in the object lesson of " being selected from the aryl that the group of substituting group group a and b replaces " by 1-3 2-is arranged; 3-or 4-fluorophenyl; 2-; 3-or 4-chloro-phenyl-; 2-; 3-or 4-bromophenyl; 2-; 3-or 4-iodophenyl; 2-; 3-or 4-aminomethyl phenyl; 2-; 3-or 4-ethylphenyl; 2-; 3-or 4-propyl group phenyl; 2-; 3-or 4-butyl phenyl; 2-; 3-or 4-amyl group phenyl; 2-; 3-or 4-trifluoromethyl; 2-; 3-or 4-p-methoxy-phenyl; 2-; 3-or 4-ethoxyl phenenyl; 2-; 3-or 4-propoxy-phenyl; 2-; 3-or 4-isopropyl phenyl; 2-; 3-or 4-butoxy phenyl; 2-; 3-or 4-(1-ethyl propoxy-) phenyl; 2-; 3-or 4-(2-ethyl propoxy-) phenyl; 2-; 3-or 4-methylbenzene sulfenyl; 2-; 3-or 4-ethylbenzene sulfenyl; 2-; 3-or 4-carboxyl phenyl; 2-; 3-or 4-methoxycarbonyl phenyl; 2-; 3-or 4-carbethoxy phenyl; 2-; 3-or 4-hydroxy phenyl; 2-; 3-or 4-formyl radical phenyl; 2-; 3-or 4-acetylphenyl; 2-; 3-or 4-aminophenyl; 2-; 3-or 4-methylamino phenyl; 2-; 3-or 4-dimethylaminophenyl; 2-; 3-or 4-cyano-phenyl; 2-; 3-or 4-cyclopentyl phenyl; 2-; 3-or 4-cyclohexyl phenyl; 2-; 3-or 4-xenyl; 2; the 4-difluorophenyl; 3; the 4-difluorophenyl; 3; the 5-difluorophenyl; 2; the 4-dichlorophenyl; 3; the 4-dichlorophenyl; 3; the 5-dichlorophenyl; 3; the 4-dibromo phenyl; 2; the 3-3,5-dimethylphenyl; 3; the 4-3,5-dimethylphenyl; 3; the 5-3,5-dimethylphenyl; 2; the 3-Dimethoxyphenyl; 3; the 4-Dimethoxyphenyl; 3; the 5-Dimethoxyphenyl; 3; 4; the 5-trimethoxyphenyl; 3-fluoro-4-p-methoxy-phenyl; 4-methyl-2-p-methoxy-phenyl; 6-fluoro-4-methyl-2-p-methoxy-phenyl; 5-fluorine indenes-3-base; 5-fluorine indenes-3-base; 5-methyl indenes-3-base; 5-methoxyl group indenes-3-base; 5-fluorine indenes-2-base; 5-chlorine indenes-2-base; 5-methyl indenes-2-base; 5-methoxyl group indenes-2-base; 5-hydroxyl indenes-3-base; 5-nitro indenes-3-base; 5-cyclohexyl indenes-3-base; 5-phenylindan-3-base; 5-phenoxy group indenes-3-base; 5-benzyloxy indenes-3-base; 5-phenyl benzo-thiophene-3-base; 5-hydroxyl indenes-2-base; 5-nitro indenes-2-base; 5-cyclohexyl indenes-2-base; 5-phenylindan-2-base; 5-fluoronaphthalene-2-base; 5-methylnaphthalene-2-base; 5-methoxynaphthalene-2-base; 5-fluoronaphthalene-1-base; 5-methylnaphthalene-1-base; 5-methoxynaphthalene-1-base; 5-hydroxyl naphthalene-2-base; 5-nitro-naphthalene-2-base; 5-cyclohexyl naphthalene-2-base; 5-phenylnaphthalene-2-base; 5-phenoxy group naphthalene-2-base; 5-benzyloxy naphthalene-2-base; 5-phenyl sulphur naphthalene-2-base; 5-hydroxyl naphthalene-1-base; 5-nitro-naphthalene-1-base; 5-cyclohexyl naphthalene-1-base; 5-phenylnaphthalene-1-base; preferably (described substituting group is selected from halogen atom to the aryl that is replaced by 1-3 substituting group; low alkyl group; junior alkyl halides; lower alkoxy; lower alkylthio and rudimentary aliphatic acidyl); more preferably (described substituting group is selected from halogen atom to the aryl that is replaced by 1-3 substituting group; low alkyl group; junior alkyl halides; lower alkoxy and rudimentary aliphatic acidyl); (described substituting group is selected from halogen atom to be more preferably the phenyl that is replaced by 1-3 substituting group; low alkyl group; junior alkyl halides; lower alkoxy and rudimentary aliphatic acidyl); also (described substituting group is selected from fluorine atom to the phenyl that is more preferably replaced by 1-3 substituting group; the chlorine atom; methyl; trifluoromethyl; methoxyl group and ethanoyl); 3-fluorophenyl most preferably; the 4-fluorophenyl; 3; the 4-difluorophenyl; 3; the 5-difluorophenyl; the 3-chloro-phenyl-; the 4-chloro-phenyl-; 3; the 4-dichlorophenyl; 3; the 5-dichlorophenyl; the 3-aminomethyl phenyl; the 4-aminomethyl phenyl; 3; the 4-3,5-dimethylphenyl; 3; the 5-3,5-dimethylphenyl; the 3-trifluoromethyl; the 4-trifluoromethyl; 3; 4-two (trifluoromethyl) phenyl; 3; 5-two (trifluoromethyl) phenyl; the 3-p-methoxy-phenyl; the 4-p-methoxy-phenyl; 3; the 4-Dimethoxyphenyl; 3; the 5-Dimethoxyphenyl; 3; 4, the 5-trimethoxyphenyl; 3-acetylphenyl or 4-acetylphenyl.
In above-mentioned, R
5Definition in the object lesson of " being selected from the heterocyclic radical that the group of substituting group group a and b replaces " by 1-3 3-is arranged, 4-or 5-methyl furan-2-base, 2-, 4-or 5-methyl furan-3-base, 3-, 4-or 5-fluorine thiophene-2-base, 2-, 4-or 5-fluorine furans-3-base, 3-, 4-or 5-bromothiophene-2-base, 2-, 4-or 5-bromine furans-3-base, 3-, 4-or 5-thiotolene-2-base, 2-, 4-or 5-thiotolene-3-base, 3-, 4-or 5-ethylthiophene-2-base, 2-, 4-or 5-ethylthiophene-3-base, 3-, 4-or 5-methoxythiophene-2-base, 2-, 4-or 5-methoxythiophene-3-base, 3-or 4-methylthiazol-5-base, 3-, 4-or 5-fluorobenzene thiophthene-2-base, 3-, 4-or 5-bromobenzene thiophthene-2-base, 3-, 4-or 5-methylbenzene thiophthene-2-base, 3-, 4-or 5-anisole thiophthene-2-base, 2-, 4-or 5-fluorobenzene thiophthene-3-base, 2-, 4-or 5-bromobenzene thiophthene-3-base, 2-, 4-or 5-methylbenzene thiophthene-3-base, 2-, 4-or 5-anisole thiophthene-3-base, 4-, 5-, 6-or 7-methylbenzene thiophthene-2-base, 3-, 4-or 5-hydroxyl furans-2-base, 2-, 4-or 5-hydroxyl furans-3-base, 3-, 4-or 5-hydroxyl thiophene-2-base, 3-, 4-or 5-nitrothiophene-2-base, 3-, 4-or 5-phenyl thiophene-2-base, 2-, 4-or 5-hydroxyl thiene-3-yl-, 2-, 4-or 5-cyano thiophene-3-base, 1-, 2-or 3-pyridone-4-base, 1-, 2-or 3-cyanopyridine-4-base, 1-, 2-or 3-phenylpyridine-4-base, preferred 3-, 4-or 5-fluorine thiophene-2-base or 2-, 4-, or 5-fluorine furans-3-base.
In above-mentioned, R
4aAnd R
11Definition in " C
1-C
20Alkyl " example aforementioned " low alkyl group " arranged; heptyl; 1-methyl hexyl; 2-methyl hexyl; 3-methyl hexyl; 4-methyl hexyl, 5-methyl hexyl, 1-propyl group butyl, 4,4-dimethyl amyl group, octyl group, the 1-methylheptyl, the 2-methylheptyl, the 3-methylheptyl, the 4-methylheptyl, the 5-methylheptyl, the 6-methylheptyl, 1-propyl group amyl group, the 2-ethylhexyl, 5,5-dimethyl hexyl, nonyl, the 3-Methyl Octyl, the 4-Methyl Octyl, the 5-Methyl Octyl, the 6-Methyl Octyl, 1-propyl group hexyl, 2-ethyl heptyl, 6,6-dimethyl heptyl, decyl, 1-methyl nonyl, 3-methyl nonyl, 8-methyl nonyl, 3-ethyl octyl group, 3,7-dimethyl octyl group, 7,7-dimethyl octyl group, undecyl, 4,8-dimethyl nonyl, dodecyl, tridecyl, tetradecyl, pentadecyl, 3,7,11-trimethyldodecane base, hexadecyl, 4,8,12-trimethylammonium tridecyl, 1-methyl pentadecyl, 14-methyl pentadecyl, 13,13-dimethyl tetradecyl, heptadecyl, 15-methyl hexadecyl, octadecyl, 1-methyl heptadecyl, nonadecyl, eicosyl and 3,7,11, the alkyl of the carbonatoms 1-20 of 15-tetramethyl-hexadecyl and so on straight or branched, preferred C
1-C
10Alkyl, more preferably C
1-C
6Alkyl, most preferable or ethyl.
In above-mentioned, R
4aAnd R
11Definition in " heteroatomic C is arranged wherein
2-C
20Alkyl " be illustrated in aforementioned " C
1-C
20Alkyl " in 1 or 2 identical or different sulphur atom is arranged in " alkyl of carbonatoms 2-20 "; the group of Sauerstoffatom or nitrogen-atoms; its example has methylthiomethyl; 1-methylmercaptoethyl; 2-methylmercaptoethyl; ethylmercapto group methyl, 1-methylthio group propyl group, 2-methylthio group propyl group, 3-methylthio group propyl group, 2-ethylmercapto group ethyl, 2-methyl-2-methylmercaptoethyl, 1-methylthio group butyl, 2-methylthio group butyl, 3-methylthio group butyl, the 2-ethylsuleenyl propyl, 3-methyl-3-methylthio group propyl group, 4-methylthio group amyl group, 3-methylthio group amyl group, 2-methylthio group amyl group, 1-methylthio group amyl group, 3,3-diformazan sulfenyl butyl, 2,2-diformazan sulfenyl butyl, 1,1-diformazan sulfenyl butyl, 1-methyl-2-methylthio group butyl, 1,3-diformazan sulfenyl butyl, 2,3-diformazan sulfenyl butyl, 2-ethylmercapto group butyl, 1-methylthio group hexyl, 2-methylthio group hexyl, 3-methylthio group hexyl, 4-methylthio group hexyl, 5-methylthio group hexyl, 1-rosickyite Ji Dingji, 4-methyl-4-methylthio group amyl group, 1-methylthio group heptyl, 2-methylthio group heptyl, 3-methylthio group heptyl, 4-methylthio group heptyl, 5-methylthio group heptyl, 6-methylthio group heptyl, 1-rosickyite base amyl group, 2-ethylmercapto group hexyl, 5-methyl-5-methylthio group hexyl, 3-methylthio group octyl group, 4-methylthio group octyl group, 5-methylthio group octyl group, 6-methylthio group octyl group, 1-rosickyite base hexyl, 2-ethylmercapto group heptyl, 6-methyl-6-methylthio group heptyl, 1-methylthio group nonyl, 3-methylthio group nonyl, 8-methylthio group nonyl, 3-ethylmercapto group octyl group, 3-methyl-7-methylthio group octyl group, 7,7-diformazan sulfenyl octyl group, 4-methyl-8-methylthio group nonyl, 3,7-dimethyl-11-methylthio group dodecyl, 4,8-dimethyl-12-methylthio group tridecyl, 1-methylthio group pentadecyl, 14-methylthio group pentadecyl, 13-methyl isophthalic acid 3-methylthio group tetradecyl, 15-methylthio group hexadecyl, 1-methylthio group heptadecyl and 3,7,11-trimethylammonium-15-methylthio group hexadecyl and so on wherein has the alkyl of the carbonatoms 2-20 of 1 or 2 sulphur atom; Methyl oxygen ylmethyl, 1-methyl oxygen base ethyl, 2-methyl oxygen base ethyl, ethyl oxygen ylmethyl, 1-methyl oxygen base propyl group, 2-methyl oxygen base propyl group, 3-methyl oxygen base propyl group, 2-ethyl oxygen base ethyl, 2-methyl-2-methyl oxygen base ethyl, 1-methyl oxygen Ji Dingji, 2-methyl oxygen Ji Dingji, 3-methyl oxygen Ji Dingji, 2-ethyl oxygen base propyl group, 3-methyl-3-methyl oxygen base propyl group, 4-methyl oxygen base amyl group, 3-methyl oxygen base amyl group, 2-methyl oxygen base amyl group, 1-methyl oxygen base amyl group, 3,3-dimethyl oxygen Ji Dingji, 2,2-dimethyl oxygen Ji Dingji, 1,1-dimethyl oxygen Ji Dingji, 1-methyl-2-methyl oxygen Ji Dingji, 1,3-dimethyl oxygen Ji Dingji, 2,3-dimethyl oxygen Ji Dingji, 2-ethyl oxygen Ji Dingji, 1-methyl oxygen base hexyl, 2-methyl oxygen base hexyl, 3-methyl oxygen base hexyl, 4-methyl oxygen base hexyl, 5-methyl oxygen base hexyl, 1-propyl group oxygen Ji Dingji, 4-methyl-4-methyl oxygen base amyl group, 1-methyl oxygen base heptyl, 2-methyl oxygen base heptyl, 3-methyl oxygen base heptyl, 4-methyl oxygen base heptyl, 5-methyl oxygen base heptyl, 6-methyl oxygen base heptyl, 1-propyl group oxygen base amyl group, 2-ethyl oxygen base hexyl, 5-methyl-5-methyl oxygen base hexyl, 3-methyl oxygen Ji Xinji, 4-methyl oxygen Ji Xinji, 5-methyl oxygen Ji Xinji, 6-methyl oxygen Ji Xinji, 1-propyl group oxygen base hexyl, 2-ethyl oxygen base heptyl, 6-methyl-6-methyl oxygen base heptyl, 1-methyl oxygen base nonyl, 3-methyl oxygen base nonyl, 8-methyl oxygen base nonyl, 3-ethyl oxygen Ji Xinji, 3-methyl-7-methyl oxygen Ji Xinji, 7,7-dimethyl oxygen Ji Xinji, 4-methyl-8-methyl oxygen base nonyl, 3,7-dimethyl-11-methyl oxygen base dodecyl, 4,8-dimethyl-12-methyl oxygen base tridecyl, 1-methyl oxygen base pentadecyl, 14-methyl oxygen base pentadecyl, 13-methyl isophthalic acid 3-methyl oxygen base tetradecyl, 15-methyl oxygen base hexadecyl, 1-methyl oxygen base heptadecyl and 3,7,11-trimethylammonium-15-methyl oxygen base hexadecyl and so on wherein has the alkyl of the carbonatoms 2-20 of 1 or 2 Sauerstoffatom; N-methylamino methyl, 1-(N-methylamino) ethyl, 2-(N-methylamino) ethyl, N-ethylamino methyl, 1-(N-methylamino) propyl group, 2-(N-methylamino) propyl group, 3-(N-methylamino) propyl group, 2-(N-ethylamino) ethyl, 2-(N, the N-dimethylamino) ethyl, 1-(N-methylamino) butyl, 2-(N-methylamino) butyl, the 3-(N-methylamino) butyl, 2-(N-ethylamino) propyl group, 3-(N, the N-dimethylamino) propyl group, 4-(N-methylamino) amyl group, 3-(N-methylamino) amyl group, 2-(N-methylamino) amyl group, 1-(N-methylamino) amyl group, 3-(N, the N-dimethylamino) butyl, 2-(N, the N-dimethylamino) butyl, 1-(N, the N-dimethylamino) butyl, 1-methyl-2-(N-methylamino) butyl, 1,3-two (N-methylamino) butyl, 2,3-two (N-methylamino) butyl, 2-(N-ethylamino) butyl, 1-(N-methylamino) hexyl, 2-(N-methylamino) hexyl, 3-(N-methylamino) hexyl, 4-(N-methylamino) hexyl, 5-(N-methylamino) hexyl, 1-(N-propyl group amino) butyl, 4-methyl-4-(N-methylamino) amyl group, 1-(N-methylamino) heptyl, 2-(N-methylamino) heptyl, 3-(N-methylamino) heptyl, 4-(N-methylamino) heptyl, 5-(N-methylamino) heptyl, 6-(N-methylamino) heptyl, 1-(N-propyl group amino) amyl group, 2-(N-ethylamino) hexyl, 5-methyl-5-(N-methylamino) hexyl, 3-(N-methylamino) octyl group, 4-(N-methylamino) octyl group, 5-(N-methylamino) octyl group, 6-(N-methylamino) octyl group, 1-(N-propyl group amino) hexyl, 2-(N-ethylamino) heptyl, 6-methyl-6-(N-methylamino) heptyl, 1-(N-methylamino) nonyl, 3-(N-methylamino) nonyl, 8-(N-methylamino) nonyl, 3-(N-ethylamino) octyl group, 3-methyl-7-(N-methylamino) octyl group, 7,7-two (N-methylamino) octyl group, 4-methyl-8-(N-methylamino) nonyl, 3,7-dimethyl-11-(N-methylamino) dodecyl, 4,8-dimethyl-12-(N-methylamino) tridecyl, 1-(N-methylamino) pentadecyl, 14-(N-methylamino) pentadecyl, 13-methyl isophthalic acid 3-(N-methylamino) tetradecyl, 15-(N-methylamino) hexadecyl, 1-(N-methylamino) heptadecyl and 3,7,11-trimethylammonium-15-(N-methylamino) hexadecyl and so on wherein has the alkyl of the carbonatoms 2-20 of 1 or 2 nitrogen-atoms; Heteroatomic C is preferably wherein arranged
2-C
10Alkyl.
In above-mentioned, R
4aAnd R
11Definition in the " C that is replaced by aryl or aromatic heterocyclic radical
1-C
20Alkyl " aforementioned " C of expression
1-C
20Alkyl " by the group of 1 or 3 identical or different aforementioned " aryl " or aforementioned " aromatic heterocyclic radical " replacement.
In above-mentioned, R
4aAnd R
11Definition in " C
2-C
20Alkynyl " example ethynyl is arranged; 2-propynyl; 1-methyl-2-propynyl; 2-butyne base; 1-methyl-2-butyne base; 1-ethyl-2-butyne base, the 3-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-ethyl-3-butynyl, the valerylene base, 1-methyl-valerylene base, the 3-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, the 4-pentynyl, 1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 2-hexin base, 3-hexin base, 4-hexin base, 5-hexin base, the heptyne base, 1-methyl hexin base, 2-methyl hexin base, 3-methyl hexin base, 4-methyl hexin base, 5-methyl hexin base, 1-propyl group butynyl, 4,4-dimethyl-penten alkynyl, the octyne base, 1-methyl heptyne base, 2-methyl heptyne base, 3-methyl heptyne base, 4-methyl heptyne base, 5-methyl heptyne base, 6-methyl heptyne base, 1-propyl group pentynyl, 2-ethyl hexin base, 5,5-dimethyl hexin base, the n-heptylacetylene base, 3-methyl octyne base, 4-methyl octyne base, 5-methyl octyne base, 6-methyl octyne base, 1-propyl group hexin base, 2-ethyl heptyne base, 6,6-dimethyl-g alkynyl, decynyl, 1-methyl n-heptylacetylene base, 3-methyl n-heptylacetylene base, 8-methyl n-heptylacetylene base, 3-ethyl octyne base, 3,7-dimethyl-octa alkynyl, 7,7-dimethyl-octa alkynyl, the undecyne base, 4,8-dimethyl n-heptylacetylene base, the dodecyne base, the tridecyne base, 14 alkynyls, 15 alkynyls, 3,7,11-trimethylammonium dodecyne base, the hexadecyne base, 4,8,12-trimethylammonium tridecyne base, 1-methyl 15 alkynyls, 14-methyl 15 alkynyls, 13,13-dimethyl 14 alkynyls, 17 alkynyls, 15-methyl hexadecyne base, the octadecyne base, 1-methyl 17 alkynyls, 19 alkynyls, 20 alkynyls and 3,7,11, the straight or branched alkynyl of 15-tetramethyl-hexadecyne base and so on carbonatoms 2-20; Preferred C
2-C
10Alkynyl.
In above-mentioned, R
4aAnd R
11Definition in " heteroatomic C is arranged wherein
3-C
20Alkynyl " aforementioned " C of expression
2-C
20Alkynyl " in 1 or 2 identical or different sulphur atom is arranged in " alkynyl of carbonatoms 3-20 "; the group of Sauerstoffatom or nitrogen-atoms; its example has 1-methylmercaptan ethyl alkynyl; 2-methylmercaptan ethyl alkynyl; 1-methylthio group proyl; 2-methylthio group proyl, 3-methylthio group proyl, 2-ethylmercapto group ethynyl, 2-methyl-2-methylmercaptan ethyl alkynyl, 1-methylthio group butynyl, 2-methylthio group butynyl, 3-methylthio group butynyl, 2-ethylmercapto group proyl, 3-methyl-3-methylthio group proyl, 4-methylthio group pentynyl, 3-methylthio group pentynyl, 2-methylthio group pentynyl, 1-methylthio group pentynyl, 3,3-diformazan sulfenyl butynyl, 2,2-diformazan sulfenyl butynyl, 1,1-diformazan sulfenyl butynyl, 1-methyl-2-methylthio group butynyl, 1,3-diformazan sulfenyl butynyl, 2,3-diformazan sulfenyl butynyl, 2-ethylmercapto group butynyl, 1-methylthio group hexin base, 2-methylthio group hexin base, 3-methylthio group hexin base, 4-methylthio group hexin base, 5-methylthio group hexin base, 1-rosickyite base butynyl, 4-methyl-4-methylthio group pentynyl, 1-methylthio group heptyne base, 2-methylthio group heptyne base, 3-methylthio group heptyne base, 4-methylthio group heptyne base, 5-methylthio group heptyne base, 6-methylthio group heptyne base, 1-rosickyite base pentynyl, 2-ethylmercapto group hexin base, 5-methyl-5-methylthio group hexin base, 3-methylthio group octyne base, 4-methylthio group octyne base, 5-methylthio group octyne base, 6-methylthio group octyne base, 1-rosickyite base hexin base, 2-ethylmercapto group heptyne base, 6-methyl-6-methylthio group heptyne base, 1-methylthio group n-heptylacetylene base, 3-methylthio group n-heptylacetylene base, 8-methylthio group n-heptylacetylene base, 3-ethylmercapto group octyne base, 3-methyl-7-methylthio group octyne base, 7,7-diformazan sulfenyl octyne base, 4-methyl-8-methylthio group n-heptylacetylene base, 3,7-dimethyl-11-methylthio group dodecyne base, 4,8-dimethyl-12-methylthio group tridecyne base, 1-methylthio group 15 alkynyls, 14-methylthio group 15 alkynyls, 13-methyl isophthalic acid 3-methylthio group 14 alkynyls, 15-methylthio group hexadecyne base, 1-methylthio group 17 alkynyls and 3,7,11-trimethylammonium-15-methylthio group hexadecyne base and so on wherein has the alkynyl of the carbonatoms 3-20 of 1 or 2 sulphur atom; 1-methyl oxygen ethyl-acetylene base, 2-methyl oxygen ethyl-acetylene base, 1-methyl oxygen base proyl, 2-methyl oxygen base proyl, 3-methyl oxygen base proyl, 2-ethyl oxygen ethyl-acetylene base, 2-methyl-2-methyl oxygen ethyl-acetylene base, 1-methyl oxygen base butynyl, 2-methyl oxygen base butynyl, 3-methyl oxygen base butynyl, 2-ethyl oxygen base proyl, 3-methyl-3-methyl oxygen base proyl, 4-methyl oxygen base pentynyl, 3-methyl oxygen base pentynyl, 2-methyl oxygen base pentynyl, 1-methyl oxygen base pentynyl, 3,3-dimethyl oxygen base butynyl, 2,2-dimethyl oxygen base butynyl, 1,1-dimethyl oxygen base butynyl, 1-methyl-2-methyl oxygen base butynyl, 1,3-dimethyl oxygen base butynyl, 2,3-dimethyl oxygen base butynyl, 2-ethyl oxygen base butynyl, 1-methyl oxygen base hexin base, 2-methyl oxygen base hexin base, 3-methyl oxygen base hexin base, 4-methyl oxygen base hexin base, 5-methyl oxygen base hexin base, 1-propyl group oxygen base butynyl, 4-methyl-4-methyl oxygen base pentynyl, 1-methyl oxygen base heptyne base, 2-methyl oxygen base heptyne base, 3-methyl oxygen base heptyne base, 4-methyl oxygen base heptyne base, 5-methyl oxygen base heptyne base, 6-methyl oxygen base heptyne base, 1-propyl group oxygen base pentynyl, 2-ethyl oxygen base hexin base, 5-methyl-5-methyl oxygen base hexin base, 3-methyl oxygen base octyne base, 4-methyl oxygen base octyne base, 5-methyl oxygen base octyne base, 6-methyl oxygen base octyne base, 1-propyl group oxygen base hexin base, 2-ethyl oxygen base heptyne base, 6-methyl-6-methyl oxygen base heptyne base, 1-methyl oxygen base n-heptylacetylene base, 3-methyl oxygen base n-heptylacetylene base, 8-methyl oxygen base n-heptylacetylene base, 3-ethyl oxygen base octyne base, 3-methyl-7-methyl oxygen base octyne base, 7,7-dimethyl oxygen base octyne base, 4-methyl-8-methyl oxygen base n-heptylacetylene base, 3,7-dimethyl-11-methyl oxygen base dodecyne base, 4,8-dimethyl-12-methyl oxygen base tridecyne base, 1-methyl oxygen base 15 alkynyls, 14-methyl oxygen base 15 alkynyls, 13-methyl isophthalic acid 3-methyl oxygen base 14 alkynyls, 15-methyl oxygen base hexadecyne base, 1-methyl oxygen base 17 alkynyls and 3,7,11-trimethylammonium-15-methyl oxygen base hexadecyne base and so on wherein has the alkynyl of the carbonatoms 3-20 of 1 or 2 Sauerstoffatom; 1-(N-methylamino) ethynyl, 2-(N methylamino) ethynyl, 1-(N-methylamino) proyl, 2-(N-methylamino) proyl, 3-(N-methylamino) proyl, 2-(N-ethylamino) ethynyl, 2-(N, the N-dimethylamino) ethynyl, 1-(N-methylamino) butynyl, 2-(N-methylamino) butynyl, 3-(N-methylamino) butynyl, 2-(N-ethylamino) proyl, 3-(N, the N-dimethylamino) proyl, 4-(N-methylamino) pentynyl, 3-(N-methylamino) pentynyl, 2-(N-methylamino) pentynyl, 1-(N-methylamino) pentynyl, 3-(N, the N-dimethylamino) butynyl, 2-(N, the N-dimethylamino) butynyl, 1-(N, the N-dimethylamino) butynyl, 1-methyl-2-(N-methylamino) butynyl, 1,3-two (N-methylamino) butynyl, 2,3-two (N-methylamino) butynyl, 2-(N-ethylamino) butynyl, 1-(N-methylamino) hexin base, 2-(N-methylamino) hexin base, 3-(N-methylamino) hexin base, 4-(N-methylamino) hexin base, 5-(N-methylamino) hexin base, 1-(N-propyl group amino) butynyl, 4-methyl-4-(N-methylamino) pentynyl, 1-(N-methylamino) heptyne base, 2-(N-methylamino) heptyne base, 3-(N-methylamino) heptyne base, 4-(N-methylamino) heptyne base, 5-(N-methylamino) heptyne base, 6-(N-methylamino) heptyne base, 1-(N-propyl group amino) pentynyl, 2-(N-ethylamino) hexin base, 5-methyl-5-(N-methylamino) hexin base, 3-(N methylamino) octyne base, 4-(N-methylamino) octyne base, 5-(N-methylamino) octyne base, 6-(N-methylamino) octyne base, 1-(N-propyl group amino) hexin base, 2-(N-ethylamino) heptyne base, 6-methyl-6-(N-methylamino) heptyne base, 1-(N-methylamino) n-heptylacetylene base, 3-(N-methylamino) n-heptylacetylene base, 8-(N-methylamino) n-heptylacetylene base, 3-(N-ethylamino) octyne base, 3-methyl-7-(N-methylamino) octyne base, 7,7-two (N-methylamino) octyne base, 4-methyl-8-(N-methylamino) n-heptylacetylene base, 3,7-dimethyl-11-(N methylamino) dodecyne base, 4,8-dimethyl-12-(N-methylamino) tridecyne base, 1-(N-methylamino) 15 alkynyls, 14-(N-methylamino) 15 alkynyls, 13-methyl isophthalic acid 3-(N-methylamino) 14 alkynyls, 15-(N-methylamino) hexadecyne base, 1-(N-methylamino) 17 alkynyls and 3,7,11-trimethylammonium-15-(N-methylamino) hexadecyne base and so on wherein has the alkynyl of the carbonatoms 3-20 of 1 or 2 nitrogen-atoms; Heteroatomic C is preferably wherein arranged
3-C
10Alkynyl.
In above-mentioned, R
4aAnd R
11Definition in the " C that is replaced by aryl or aromatic heterocyclic radical
2-C
20Alkynyl " aforementioned " C of expression
2-C
20Alkynyl " by the group of 1 or 3 identical or different aforementioned " aryl " or aforementioned " aromatic heterocyclic radical " replacement.
In above-mentioned, R
4aAnd R
11Definition in " C
2-C
20Alkenyl " example vinyl is arranged; 2-propenyl; 1-methyl-2-propenyl; 2-methyl-2-propenyl; 2-ethyl-2-propenyl; crotyl, 1-methyl-2-butene base, 2-methyl-2-butene base, 1-ethyl-crotyl, the 3-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 1-ethyl-3-butenyl, pentenyl, 1-methyl-pentenyl, 2-methyl-pentenyl, the 3-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, the 4-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, the 2-hexenyl, the 3-hexenyl, the 4-hexenyl, the 5-hexenyl, heptenyl, 1-methyl hexenyl, 2-methyl hexenyl, 3-methyl hexenyl, 4-methyl hexenyl, 5-methyl hexenyl, 1-propyl group butenyl, 4,4-dimethyl-penten thiazolinyl, octenyl, 1-methyl heptenyl, 2-methyl heptenyl, 3-methyl heptenyl, 4-methyl heptenyl, 5-methyl heptenyl, 6-methyl heptenyl, 1-propyl group pentenyl, 2-ethyl hexene base, 5,5-dimethyl hexenyl, the nonene base, 3-methyl octenyl, 4-methyl octenyl, 5-methyl octenyl, 6-methyl octenyl, 1-propyl group hexenyl, 2-ethyl heptenyl, 6,6-dimethyl-g thiazolinyl, the decene base, 1-methyl nonene base, 3-methyl nonene base, 8-methyl nonene base, 3-ethyl octenyl, 3,7-dimethyl-octa thiazolinyl, 7,7-dimethyl-octa thiazolinyl, undecenyl, 4,8-dimethyl nonene base, dodecenyl succinic, the tridecylene base, the tetradecene base, 15 carbene bases, 3,7,11-trimethylammonium dodecenyl succinic, the cetene base, 4,8,12-trimethylammonium tridecylene base, 1-methyl 15 carbene bases, 14-methyl 15 carbene bases, 13,13-dimethyl tetradecene base, the heptadecene base, 15-methyl cetene base, the vaccenic acid base, 1-methyl heptadecene base, 19 carbene bases, eicosylene base and 3,7,11, the straight or branched alkenyl of 15-phytene base and so on carbonatoms 2-20, preferred C
2-C
10Alkenyl.
In above-mentioned, R
4aAnd R
11Definition in " heteroatomic C is arranged wherein
3-C
20Alkenyl " aforementioned " C of expression
2-C
20Alkenyl " in 1 or 2 identical or different sulphur atom is arranged in " alkenyl of carbonatoms 3-20 "; the group of Sauerstoffatom or nitrogen-atoms; its example has 1-methylmercaptan ethyl thiazolinyl; 2-methylmercaptan ethyl thiazolinyl; 1-methylthio group propenyl; 2-methylthio group propenyl, 3-methylthio group propenyl, 2-ethyl vinyl sulfide base, 2-methyl-2-methylmercaptan ethyl thiazolinyl, 1-methylthio group butenyl, 2-methylthio group butenyl, 3-methylthio group butenyl, 2-ethylmercapto group propenyl, 3-methyl-3-methylthio group propenyl, 4-methylthio group pentenyl, 3-methylthio group pentenyl, 2-methylthio group pentenyl, 1-methylthio group pentenyl, 3,3-diformazan sulfenyl butenyl, 2,2-diformazan sulfenyl butenyl, 1,1-diformazan sulfenyl butenyl, 1-methyl-2-methylthio group butenyl, 1,3-diformazan sulfenyl butenyl, 2,3-diformazan sulfenyl butenyl, 2-ethylmercapto group butenyl, 1-methylthio group hexenyl, 2-methylthio group hexenyl, 3-methylthio group hexenyl, 4-methylthio group hexenyl, 5-methylthio group hexenyl, 1-rosickyite base butenyl, 4-methyl-4-methylthio group pentenyl, 1-methylthio group heptenyl, 2-methylthio group heptenyl, 3-methylthio group heptenyl, 4-methylthio group heptenyl, 5-methylthio group heptenyl, 6-methylthio group heptenyl, 1-rosickyite base pentenyl, 2-ethylmercapto group hexenyl, 5-methyl-5-methylthio group hexenyl, 3-methylthio group octenyl, 4-methylthio group octenyl, 5-methylthio group octenyl, 6-methylthio group octenyl, 1-rosickyite base hexenyl, 2-ethylmercapto group heptenyl, 6-methyl-6-methylthio group heptenyl, 1-methylthio group nonene base, 3-methylthio group nonene base, 8-methylthio group nonene base, 3-ethylmercapto group octenyl, 3-methyl-7-methylthio group octenyl, 7,7-diformazan sulfenyl octenyl, 4-methyl-8-methylthio group nonene base, 3,7-dimethyl-11-methylthio group dodecenyl succinic, 4,8-dimethyl-12-methylthio group tridecylene base, 1-methylthio group 15 carbene bases, 14-methylthio group 15 carbene bases, 13-methyl isophthalic acid 3-methylthio group tetradecene base, 15-methylthio group cetene base, 1-methylthio group heptadecene base and 3,7,11-trimethylammonium-15-methylthio group cetene base and so on wherein has the alkenyl of the carbonatoms 3-20 of 1 or 2 sulphur atom; 1-methyl ethoxy ethylene base, 2-methyl ethoxy ethylene base, 1-methyl oxygen base propenyl, 2-methyl oxygen base propenyl, 3-methyl oxygen base propenyl, 2-ethyl ethoxy ethylene base, 2-methyl-2-methyl ethoxy ethylene base, 1-methyl oxygen base butenyl, 2-methyl oxygen base butenyl, 3-methyl oxygen base butenyl, 2-ethyl oxygen base propenyl, 3-methyl-3-methyl oxygen base propenyl, 4-methyl oxygen base pentenyl, 3-methyl oxygen base pentenyl, 2-methyl oxygen base pentenyl, 1-methyl oxygen base pentenyl, 3,3-dimethyl oxygen base butenyl, 2,2-dimethyl oxygen base butenyl, 1,1-dimethyl oxygen base butenyl, 1-methyl-2-methyl oxygen base butenyl, 1,3-dimethyl oxygen base butenyl, 2,3-dimethyl oxygen base butenyl, 2-ethyl oxygen base butenyl, 1-methyl oxygen base hexenyl, 2-methyl oxygen base hexenyl, 3-methyl oxygen base hexenyl, 4-methyl oxygen base hexenyl, 5-methyl oxygen base hexenyl, 1-propyl group oxygen base butenyl, 4-methyl-4-methyl oxygen base pentenyl, 1-methyl oxygen base heptenyl, 2-methyl oxygen base heptenyl, 3-methyl oxygen base heptenyl, 4-methyl oxygen base heptenyl, 5-methyl oxygen base heptenyl, 6-methyl oxygen base heptenyl, 1-propyl group oxygen base pentenyl, 2-ethyl oxygen base hexenyl, 5-methyl-5-methyl oxygen base hexenyl, 3-methyl oxygen base octenyl, 4-methyl oxygen base octenyl, 5-methyl oxygen base octenyl, 6-methyl oxygen base octenyl, 1-propyl group oxygen base hexenyl, 2-ethyl oxygen base heptenyl, 6-methyl-6-methyl oxygen base heptenyl, 1-methyl oxygen base nonene base, 3-methyl oxygen base nonene base, 8-methyl oxygen base nonene base, 3-ethyl oxygen base octenyl, 3-methyl-7-methyl oxygen base octenyl, 7,7-dimethyl oxygen base octenyl, 4-methyl-8-methyl oxygen base nonene base, 3,7-dimethyl-11-methyl oxygen base dodecenyl succinic, 4,8-dimethyl-12-methyl oxygen base tridecylene base, 1-methyl oxygen base 15 carbene bases, 14-methyl oxygen base 15 carbene bases, 13-methyl isophthalic acid 3-methyl oxygen base tetradecene base, 15-methyl oxygen base hexenyl, 1-methyl oxygen base heptadecene base and 3,7,11-trimethylammonium-15-methyl oxygen base cetene base and so on wherein has the alkenyl of the carbonatoms 3-20 of 1 or 2 Sauerstoffatom; 1-(N-methylamino) vinyl, 2-(N-methylamino) vinyl, 1-(N-methylamino) propenyl, 2-(N-methylamino) propenyl, 3-(N-methylamino) propenyl, 2-(N-ethylamino) vinyl, 2-(N, the N-dimethylamino) vinyl, 1-(N-methylamino) butenyl, 2-(N-methylamino) butenyl, 3-(N-methylamino) butenyl, 2-(N-ethylamino) propenyl, 3-(N, the N-dimethylamino) propenyl, 4-(N-methylamino) pentenyl, 3-(N-methylamino) pentenyl, 2-(N-methylamino) pentenyl, 1-(N-methylamino) pentenyl, 3-(N, the N-dimethylamino) butenyl, 2-(N, the N-dimethylamino) butenyl, 1-(N, the N-dimethylamino) butenyl, 1-methyl-2-(N-methylamino) butenyl, 1,3-two (N-methylamino) butenyl, 2,3-two (N-methylamino) butenyl, 2-(N-ethylamino) butenyl, 1-(N-methylamino) hexenyl, 2-(N-methylamino) hexenyl, 3-(N-methylamino) hexenyl, 4-(N-methylamino) hexenyl, 5-(N-methylamino) hexenyl, 1-(N-propyl group amino) butenyl, 4-methyl-4-(N-methylamino) pentenyl, 1-(N-methylamino) heptenyl, 2-(N-methylamino) heptenyl, 3-(N-methylamino) heptenyl, 4-(N-methylamino) heptenyl, 5-(N-methylamino) heptenyl, 6-(N-methylamino) heptenyl, 1-(N-propyl group amino) pentenyl, 2-(N-ethylamino) hexenyl, 5-methyl-5-(N-methylamino) hexenyl, 3-(N-methylamino) octenyl, 4-(N-methylamino) octenyl, 5-(N-methylamino) octenyl, 6-(N-methylamino) octenyl, 1-(N-propyl group amino) hexenyl, 2-(N-ethylamino) heptenyl, 6-methyl-6-(N-methylamino) heptenyl, 1-(N-methylamino) nonene base, 3-(N-methylamino) nonene base, 8-(N-methylamino) nonene base, 3-(N-ethylamino) octenyl, 3-methyl-7-(N-methylamino) octenyl, 7,7-two (N-methylamino) octenyl, 4-methyl-8-(N-methylamino) nonene base, 3,7-dimethyl-11-(N-methylamino) dodecenyl succinic, 4,8-dimethyl-12-(N-methylamino) tridecylene base, 1-(N-methylamino) 15 carbene bases, 14-(N-methylamino) 15 carbene bases, 1 3-methyl isophthalic acid 3-(N-methylamino) tetradecene base, l5-(N-methylamino) cetene base, 1-(N-methylamino) heptadecene base and 3,7,11-trimethylammonium-15-(N-methylamino) cetene base and so on wherein has the alkenyl of the carbonatoms 3-20 of 1 or 2 nitrogen-atoms; Heteroatomic C is preferably wherein arranged
3-C
10Alkenyl.
In above-mentioned, R
4aAnd R
11Definition in the " C that is replaced by aryl or aromatic heterocyclic radical
2-C
20Alkenyl " aforementioned " C of expression
2-C
20Alkenyl " by the group of 1 or 3 identical or different aforementioned " aryl " or aforementioned " aromatic heterocyclic radical " replacement.
In above-mentioned, R
4aAnd R
11Definition in " heteroatomic C wherein arranged by what aryl or aromatic heterocyclic radical replaced
2-C
20Alkyl " expression aforementionedly " wherein has heteroatomic C
2-C
20Alkyl " by the group of 1 or 3 identical or different aforementioned " aryl " or aforementioned " aromatic heterocyclic radical " replacement.
" lipase " used to the present invention is not particularly limited, optimal lipase is different and different with the kind of starting compound, preferably by Rhodopseudomonas (Pseudomonas sp), Pseudomonas fluorescens (Pseudomonas fluorescens), pseudomonas cepacia (Pseudomonascepacia), thickness look bacillus (Chromobacterium viscosum), aspergillus niger (Aspergillusniger), aspergillus oryzae (Aspergillus oryzae), Candida antarctica, Candidacylindracea, Candida lipolytica (Candida lipolytica), candiyeast (Candidarugosa) wrinkles, Candida utilis (Candida utilis), penicillum requeforti (Penicilliumroqueforti), rhizopus arrhizus (Rhizopus arrhizus), Rhizopus delemar, Java head mold (Rhizopus javanicus), Man Hegen Mucor (Rhizomucor miehei), snow-white head mold (Rhizopus niveus), Humicola lanuginosa, mucor javanicus (Mucor javanicus), rice black wool mould (Mucor miehei), thermus aquaticus (Thermus aquaticus), the Huang hot bacterium (Thermus flavus) that dwells, thermus thermophilus (Thermus thermophilus) etc. or human pancreas, pig (hog) pancreas, pig (porcine) pancreas, the lipase that wheatgerm obtains.The use of not only enzyme partly or entirely can being purified, and can use with solid form.The enzyme that Rhodopseudomonas is fixedly obtained (for example from Rhodopseudomonas fixedly lipase (TOYOBA company)) most preferably.
The used generating vinyl carboxylate ester derivative (R of most preferred the present invention with formula (XLIII)
11COOCH-CH
2) different and different with the kind of starting compound, linear aliphatic vinyl carboxylates such as usually preferred n-caproic acid vinyl acetate, positive enanthic acid vinyl acetate, positive valeric acid vinyl acetate, vinyl-acetic ester, most preferably n-caproic acid vinyl acetate.
The compound that " acceptable salt on its pharmacology " expression has a general formula of the present invention (I) under situation with amino and so on basic group by with acid-respons, perhaps salt under situation by forming with alkali reaction with carboxyl and so on acidic-group.
Based on the preferred hydrofluoride of the salt of basic group, hydrochloride, hydrobromate, hydriodate and so on halogen acid salt, nitrate, perchlorate, vitriol, inorganic acid salts such as phosphoric acid salt; Mesylate, fluoroform sulphonate, esilate and so on lower alkane sulfonate, benzene sulfonate, tosilate and so on arylsulphonate, acetate, malate, fumarate, succinate, Citrate trianion, ascorbate salt, tartrate, oxalate, organic acid salts such as maleate; And glycinate, lysine salt, arginic acid salt, ornithine salt, glutaminate, aspartate and so on amino acid salts.Organic acid salt most preferably.
On the other hand, based on an alkali metal salt of the salt particular certain cancers of acidic-group, sylvite, lithium salts and so on, the alkaline earth salt of calcium salt, magnesium salts and so on, metal-salts such as aluminium salt, molysite; The inorganic salt of ammonium salt and so on, tert-Octylamine salt, dibenzyl amine salt, alkylbenzyldimethylasaltsum saltsum, glucosamine salt, phenylglycocoll alkyl ester salt, ethylenediamine salt, N-methylglucosamine salt, guanidinesalt, diethyl amine salt, triethylamine salt, dicyclohexyl amine salt, N, the amine salt such as organic salt of N '-dibenzyl ethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-1-phenylethylamine salt, piperazine salt, tetramethyl ammonium, three (methylol) aminomethane salt and so on; And the amino acid salts of glycinate, lysine salt, arginic acid salt, ornithine salt, glutaminate, aspartate and so on.
On compound with general formula (I) of the present invention, its pharmacology acceptable salt, its ester or other derivative be positioned in the atmosphere or since recrystallization can absorb moisture, be with planar water, form hydrate, such hydrate is also contained in the scope of salt of the present invention.
Have unsymmetrical carbon in acceptable salt, its ester or other derivative molecular on compound with general formula (I) of the present invention, its pharmacology, thereby have optical isomer.It is general formula (I) expression that the optical isomer of The compounds of this invention and the mixture of optical isomer are all used a formula.Therefore, the present invention includes the mixture of the arbitrary ratio of all optical isomers and optical isomer.For example, acceptable salt, its ester or other derivative have following formula on the compound with general formula (I) of the present invention, its pharmacology:
In the following formula ,-NR
1R
2Group links to each other with unsymmetrical carbon, especially preferably has the compound of R absolute configuration.
Above-mentioned " ester " is meant the formed ester of The compounds of this invention (I); the example of such ester has " ester of hydroxyl " and " ester of carboxyl ", and various ester residues are meant " the general protecting group in the reaction " or " can pass through hydrolysis and so on biological method rimose protecting group in vivo ".
" the general protecting group in the reaction " is meant and can passes through hydrogenolysis, hydrolysis, electrolysis, photodissociation and so on chemical process rimose protecting group.
" the general protecting group in the reaction " and " can pass through hydrolysis and so on biological method rimose protecting group in vivo " expression and aforementioned " protecting group of hydroxyl " identical meaning in " ester of hydroxyl ".
In " ester of carboxyl " " the general protecting group in the reaction " preferably aforementioned " low alkyl group "; Vinyl, the 1-propenyl, the 2-propenyl, 1-methyl-2-propenyl, 1-methyl isophthalic acid-propenyl, 2-methyl isophthalic acid-propenyl, the 1-butylene base, crotyl, 1-methyl-2-butene base, 1-methyl isophthalic acid-butenyl, 3-methyl-2-butene base, 1-ethyl-crotyl, the 3-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 1-ethyl-3-butenyl, the 1-pentenyl, pentenyl, 1-methyl-pentenyl, 2-methyl-pentenyl, the 3-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, the 4-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, the 1-hexenyl, the 2-hexenyl, the 3-hexenyl, the 4-hexenyl, the low-grade alkenyl of 5-hexenyl and so on; Ethynyl, 2-propynyl, 1-methyl-2-propynyl, the 2-butyne base, 1-methyl-2-butyne base, 1-ethyl-2-butyne base, the 3-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-ethyl-3-butynyl, the valerylene base, 1-methyl-valerylene base, the 3-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, the 4-pentynyl, 1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 2-hexin base, 3-hexin base, 4-hexin base, the low-grade alkynyl of 5-hexin base and so on; Aforementioned " junior alkyl halides "; 2-hydroxyethyl, 2,3-dihydroxypropyl, 3-hydroxypropyl, 3, the hydroxyl " low alkyl group " of 4-dihydroxyl butyl, 4-hydroxybutyl and so on; " rudimentary aliphatic acidyl " of ethanoyl methyl and so on-" low alkyl group "; Aforementioned " aralkyl "; Aforementioned " silyl ".
" can by hydrolysis and so on biological method rimose protecting group " in vivo be meant by biological methods such as hydrolysis in human body and ftractures; generate the protecting group of free acid or its salt; whether be such derivative; can be through the laboratory animal administration of intravenous injection to rat or mouse and so on; the body fluid of analyzing animal is afterwards determined according to detecting on original compound or its pharmacology acceptable salt." can by hydrolysis and so on biological method rimose protecting group " in vivo preferred methoxy ethyl, 1-ethoxyethyl group, 1-methyl isophthalic acid-methoxy ethyl, 1-(isopropoxy) ethyl, 2-methoxy ethyl, 2-ethoxyethyl group, 1 in " ester of carboxyl ", the lower alkoxy low alkyl group of 1-dimethyl-1-methoxy ethyl, ethoxyl methyl, n-propoxymethyl, isopropoxy methyl, n-butoxy methyl, tert.-butoxy methyl and so on; The lower alkoxy lower alkoxy low alkyl group of 2-methoxy ethoxy methyl and so on; " aryl " oxygen base " low alkyl group " of phenoxymethyl and so on; 2,2, " alkoxyalkyls " such as halogenated lower alkoxy low alkyl groups of 2-trichlorine ethoxyl methyl, two (2-chloroethoxy) methyl and so on; " " lower alkoxy " carbonyl " low alkyl group " " of methoxycarbonyl methyl and so on; " cyano group " low alkyl group " " of cyano methyl, 2-cyano ethyl and so on; " " low alkyl group " sulfenyl methyl " of methylthiomethyl, ethylmercapto group methyl and so on; " " aryl " sulfenyl methyl " of thiophenyl methyl, naphthalene sulfenyl methyl and so on; " " low alkyl group " alkylsulfonyl " low alkyl group " that can be replaced by halogen " of 2-methylsulfonyl ethyl, 2-trifyl ethyl and so on; 2-benzenesulfonyl ethyl, 2-tosyl group ethyl and so on " " aryl " alkylsulfonyl " low alkyl group " "; Aforementioned " 1-(acyloxy) " low alkyl group " "; Aforementioned " phthalidyl "; Aforementioned " aryl "; Aforementioned " low alkyl group "; " carboxyalkyl " of carboxymethyl and so on; And " the amino acid whose acid amides formation residue " of phenylalanine and so on.
" other derivative " is meant compound formed above-mentioned " acceptable salt on the pharmacology " and above-mentioned " its ester " derivative in addition under the situation with amino and/or carboxyl with general formula (I) of the present invention.The example of such derivative has the amide derivatives of acyl group and so on.
Object lesson with compound of general formula (I) of the present invention has following table 1 and the listed compound of table 2, object lesson with general formula (La) and compound (La-1) of the present invention has following table 3 and the listed compound of table 4, but the present invention has more than and is limited to these compounds.
Abbreviation in the table is as follows:
Ac: ethanoyl
Boc: tertbutyloxycarbonyl
Bpyrr: benzopyrrole base
Bu: butyl
IBu: isobutyl-
Bz: benzyl
Bzt: benzothienyl
Et: ethyl
Fur: furyl
CHx: cyclohexyl
Me: methyl
Np (1): naphthalene-1-base
Np (2): naphthalene-2-base
Ph: phenyl
CPn: cyclopentyl
Pr: propyl group
IPr: sec.-propyl
Pyr: pyridyl
TBDMS: t-butyldimethylsilyl
The: thienyl
[table 1]
[table 2]
In the last table 1 and 2,
Preferred The compounds of this invention (I) is the exemplary compounds of following numbering:
1-19，1-23～1-32，1-36～1-45，1-49～1-58，1-62～1-71，1-75～1-84，1-88～1-102，1-106～1-156，1-160～1-214，1-218～1-268，1-272～1-322，1-325～1-334，1-338～1-347，1-351～1-360，1-364～1-373，1-377～1-386，1-390～1-404，1-408～1-458，1-462～1-513，1-517～1-526，1-530～1-544，1-548～1-598，1-602～1-657，1-670，1-674～1-683，1-696，1-700～1-717，1-721～1-730，1-734～1-743，1-747～1-756，1-760～1-774，1-778～1-828，1-832～1-886，1-890～1-940，1-944～1-993，1-997～1-1006，1-1010～1-1019，1-1045，1-1049～1-1058，1-1062～1-1076，1-1080～1-1130，1-1134～1-1185，1-1189～1-1198，1-1202～1-1208，1-1212～1-1216，1-1220～1-1270，1-1274～1-1331，1-1335～1-1344，1-1348～1-1357，1-1361～1-1370，1-1374～1-1387，1-1391～1-1400，1-1404～1-1418，1-1422～1-1472，1-1476～1-1527，1-1531～1-1540，1-1544～1-1558，1-1562～1-1612，1-1616～1-1673，1-1677～1-1686，1-1690～1-1699，1-1703～1-1712，1-1716～1-1729，1-1733～1-1744，1-1748～1-1767，1-1772～1-1793，1-1797～1-1818，1-1824～1-1846，1-1850～1-1869，1-1872，1-1876，1-1880，1-1884，1-1888～1-1892，1-1896，1-1900，1-1908～1-1913，1-1917～1-1939，1-1943～1-1966，1-1970～1-1991，1-1995～1-2013，1-2017，1-2021，1-2025，1-2029，1-2033，1-2037～1-2042，1-2045～1-2068，1-2072～1-2089，1-2093，1-2097，1-2101，1-2105，1-2109，1-2113，1-2117，1-2121，1-2125，1-2129，1-2133，1-2135，1-2139～1-2158，1-2161～1-2164，1-2184～1-2346，
2-9～2-18，2-22～2-43，2-47～2-70，2-74～2-96，2-100～2-119，2-142，2-146，2-150，2-154，2-158～2-163，2-167～2-183，2-185～2-189，2-193～2-216，2-220～2-241，2-245～2-263，2-267，2-271，2-275，2-279，2-283，2-287～2-292，2-296～2-318，2-322～2-338，2-343，2-347，2-351，2-371，2-375～2-377，2-381～2-407
，
More preferably descend the compound of column number:
1-19，1-32，1-36～1-45，1-57，1-62～1-71，1-84，1-88，1-97～1-100，1-152～1-154，1-160～1-214，1-218～1-227，1-264～1-268，1-272～1-322，1-334，1-347，1-360，1-373，1-386，1-390～1-402，1-454～1-458，1-462～1-513，1-526，1-530～1-542，1-594～1-598，1-602～1-653，1-743，1-756，1-760～1-768，1-770～1-774，1-778～1828，1-832～1-886，1-890～1-940，1-944～1-993，1-1045，1-1058，1-1062～1-1074，1-1126～1-1130，1-1134～1-1185，1-1198，1-1202～1-1208，1-1212，1-1213，1-1214，1-1266～1-1270，1-1274～1-1331，1-1344，1-1348～1-1357，1-1370，1-1374～1-1387，1-1400，1-1404～1-1416，1-1468～1-1472，1-1476～1-1527，1-1540，1-1544～1-1556，1-1608～1-1612，1-1616～1-1666，1-1729，1-1742，1-1744，1-1759～1-1767，1-1789～1-1793，1-1797～1-1818，1-1842～1-1846，1-1900，1-1908～1-1913，1-1935～1-1939，1-1943～1-1966，1-1987～1-1991，1-2013，1-2017，1-2029，1-2033，1-2037～1-2042，1-2064～1-2068，1-2072～1-2089，1-2093，1-2097，1-2101，1-2105，1-2109，1-2129，1-2133，1-2135，1-2184～1-2346，
2-11～2-18，2-39～2-43，2-47～2-70，2-185～2-189，2-193～2-216，2-287～2-292，2-338，2-343，2-347，2-351，
Be more preferably down the compound of column number:
1-45，1-71，1-84，1-88，1-97～1-100，1-152～1-154，1-160～1-206，1-209～1-212，1-264～1-266，1-334，1-373，1-386，1-390～1-402，1-454～1-458，1462～1-485，1-509，1-510，1-513，1-526，1-530～1-542，1-594～1-598，1-602～1-613，1-649，1-650，1-743，1-756，1-760～1-768，1-770～1-772，1-824～1-828，1-832～1-884，1-936，1-1045，?1-1058，1-1062～1-1074，1-1126～1-1130，1-1134～1-1145，1-1148～1-1151，1-1162，1-1163，1-1179～1-1182，1-1185，1-1198，1-1202～1-1208，1-1212，1-1213，1-1214，1-1266～1-1270，1-1274～1-1285，1-1288～1-1291，1-1319～1-1322，1-1329～1-1331，1-1344，1-1348～1-1357，1-1370，1-1387，1-1400，1-1404～1-1416，1-1468～1-1472，1-1476～1-1487，1-1490～1-1493，1-1504，1-1505，1-1521～1-1524，1-1527，1-1540，1-1544～1-1556，1-1608～1-1612，1-1616～1-1627，1-1663，1-1664，1-1729，1-1742，1-1744，1-1761～1-1766，1-1789～1-1791，1-1815～1-1818，1-1900，1-1909，1-1962，1-2064～1-2066，1-2089，1-2093，1-2097，1-2105，1-2133，1-2216～1-2288，1-2290～1-2346，
Further preferred exemplary compounds is as follows:
1-71:2-amino-2-methyl-4-[5-(4-cyclohexyl butyl) thiophene-2-yl] fourth-1-alcohol,
1-84:2-amino-2-methyl-4-[5-(4-phenyl butyl) thiophene-2-yl] fourth-1-alcohol,
1-98:2-amino-2-methyl-4-[5-(5-cyclohexyl amyl group) thiophene-2-yl] fourth-1-alcohol,
1-152:2-amino-2-methyl-4-[5-(5-phenylpentyl) thiophene-2-yl] fourth-1-alcohol,
1-210:2-amino-2-methyl-4-[5-(6-cyclohexyl hexyl) thiophene-2-yl] fourth-1-alcohol,
1-264:2-amino-2-methyl-4-[5-(6-phenyl hexyl) thiophene-2-yl] fourth-1-alcohol,
1-373:2-amino-2-methyl-4-[5-(3-cyclohexyloxy propyl group) thiophene-2-yl] fourth-1-alcohol,
1-386:2-amino-2-methyl-4-[5-(3-phenoxy propyl) thiophene-2-yl] fourth-1-alcohol,
1-400:2-amino-2-methyl-4-[5-(4-cyclohexyloxy butyl) thiophene-2-yl] fourth-1-alcohol,
1-454:2-amino-2-methyl-4-[5-(4-phenoxy group butyl) thiophene-2-yl] fourth-1-alcohol,
1-509:2-amino-2-methyl-4-[5-(5-cyclohexyloxy amyl group) thiophene-2-yl] fourth-1-alcohol,
1-510:2-amino-2-methyl-4-[5-(5-phenoxy group amyl group) thiophene-2-yl] fourth-1-alcohol,
1-513:2-amino-2-methyl-4-[5-(3-cyclohexyl methoxy-propyl) thiophene-2-yl] fourth-1-alcohol,
1-743:2-amino-2-methyl-4-[5-(4-cyclohexyl fourth-1-alkynyl) thiophene-2-yl] fourth-1-alcohol,
1-756:2-amino-2-methyl-4-[5-(4-phenyl fourth-1-alkynyl) thiophene-2-yl] fourth-1-alcohol,
1-770:2-amino-2-methyl-4-[5-(5-cyclohexyl penta-1-alkynyl) thiophene-2-yl] fourth-1-alcohol,
1-824:2-amino-2-methyl-4-[5-(5-phenyl penta-1-alkynyl) thiophene-2-yl] fourth-1-alcohol,
1-882:2-amino-2-methyl-4-[5-(6-cyclohexyl oneself-1-alkynyl) thiophene-2-yl] fourth-1-alcohol,
1-936:2-amino-2-methyl-4-[5-(6-phenyl oneself-1-alkynyl) thiophene-2-yl] fourth-1-alcohol,
1-1045:2-amino-2-methyl-4-[5-(3-cyclohexyloxy proyl) thiophene-2-yl] fourth-1-alcohol,
1-1058:2-amino-2-methyl-4-[5-(3-phenoxy group proyl) thiophene-2-yl] fourth-1-alcohol,
1-1072:2-amino-2-methyl-4-[5-(4-cyclohexyloxy fourth-1-alkynyl) thiophene-2-yl] fourth-1-alcohol,
1-1126:2-amino-2-methyl-4-[5-(4-phenoxy group fourth-1-alkynyl) thiophene-2-yl] fourth-1-alcohol,
1-1181:2-amino-2-methyl-4-[5-(5-cyclohexyloxy penta-1-alkynyl) thiophene-2-yl] fourth-1-alcohol,
1-1182:2-amino-2-methyl-4-[5-(5-phenoxy group penta-1-alkynyl) thiophene-2-yl] fourth-1-alcohol,
1-1185:2-amino-2-methyl-4-[5-(3-cyclohexyl methoxy propyl alkynyl) thiophene-2-yl] fourth-1-alcohol,
1-1329:2-amino-2-methyl-4-[5-(4-cyclohexyl butyryl radicals) thiophene-2-yl] fourth-1-alcohol,
1-1330:2-amino-2-methyl-4-[5-(4-phenyl butyryl radicals) thiophene-2-yl] fourth-1-alcohol,
1-1331:2-amino-2-methyl-4-[5-(5-cyclohexyl pentanoyl) thiophene-2-yl] fourth-1-alcohol,
1-1344:2-amino-2-methyl-4-[5-(5-phenyl pentanoyl) thiophene-2-yl] fourth-1-alcohol,
1-1357:2-amino-2-methyl-4-[5-(6-cyclohexyl caproyl) thiophene-2-yl] fourth-1-alcohol,
1-1370:2-amino-2-methyl-4-[5-(6-phenyl caproyl) thiophene-2-yl] fourth-1-alcohol,
1-1387:2-amino-2-methyl-4-[5-(3-cyclohexyloxy propionyl) thiophene-2-yl] fourth-1-alcohol,
1-1400:2-amino-2-methyl-4-[5-(3-phenoxy group propionyl) thiophene-2-yl] fourth-1-alcohol,
1-1414:2-amino-2-methyl-4-[5-(4-cyclohexyloxy butyryl radicals) thiophene-2-yl] fourth-1-alcohol,
1-1468:2-amino-2-methyl-4-[5-(4-phenoxy group butyryl radicals) thiophene-2-yl] fourth-1-alcohol,
1-1523:2-amino-2-methyl-4-[5-(5-cyclohexyloxy pentanoyl) thiophene-2-yl] fourth-1-alcohol,
1-1524:2-amino-2-methyl-4-[5-(5-phenoxy group pentanoyl) thiophene-2-yl] fourth-1-alcohol,
1-1527:2-amino-2-methyl-4-[5-(3-cyclohexyl methoxy propyl acyl group) thiophene-2-yl] fourth-1-alcohol,
1-1729:2-amino-2-methyl-4-[5-(4-cyclohexyl p-methoxy-phenyl) thiophene-2-yl] fourth-1-alcohol,
1-1742:2-amino-2-methyl-4-[5 (4-cyclohexyl ethoxyl phenenyl) thiophene-2-yl] fourth-1-alcohol,
1-1744:2-amino-2-methyl-4-[5-(4-benzyloxy phenyl) thiophene-2-yl] fourth-1-alcohol,
1-1761:2-amino-2-ethyl-4-[5-(4-cyclohexyl butyl) thiophene-2-yl] fourth-1-alcohol,
1-1764:2-amino-2-ethyl-4-[5-(5-cyclohexyl amyl group) thiophene-2-yl] fourth-1-alcohol,
1-1816:2-amino-2-ethyl-4-[5-(6-cyclohexyl hexyl) thiophene-2-yl] fourth-1-alcohol,
1-1900:2-amino-2-ethyl-4-[5-(4-cyclohexyl fourth-1-alkynyl) thiophene-2-yl] fourth-1-alcohol,
1-1909:2-amino-2-ethyl-4-[5-(5-cyclohexyl penta-1-alkynyl) thiophene-2-yl] fourth-1-alcohol,
1-1962:2-amino-2-ethyl-4-[5-(6-cyclohexyl oneself-1-alkynyl) thiophene-2-yl] fourth-1-alcohol,
1-2089:2-amino-2-ethyl-4-[5-(4-cyclohexyl butyryl radicals) thiophene-2-yl] fourth-1-alcohol,
1-2097:2-amino-2-ethyl-4-[5-(5-cyclohexyl pentanoyl) thiophene-2-yl] fourth-1-is pure and mild
1-2105:2-amino-2-ethyl-4-[5-(6-cyclohexyl caproyl) thiophene-2-yl] fourth-1-alcohol and
1-463:2-amino-2-methyl-4-{5-[4-(4-fluorophenoxy) butyl] thiophene-2-yl } fourth-1-alcohol,
1-479:2-amino-2-methyl-4-{5-[4-(4-methoxyl group phenoxy group) butyl] thiophene-2-yl } fourth-1-alcohol,
1-594:2-amino-2-methyl-4-[5-(4-benzyloxy butyl) thiophene-2-yl] fourth-1-alcohol,
1-760:2-amino-2-methyl-4-{5-[4-(4-fluorophenyl) fourth-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-761:2-amino-2-methyl-4-{5-[4-(4-aminomethyl phenyl) fourth-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-762:2-amino-2-methyl-4-{5-[4-(4-ethylphenyl) fourth-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-763:2-amino-2-methyl-4-{5-[4-(4-trifluoromethyl) fourth-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-764:2-amino-2-methyl-4-{5-[4-(4-p-methoxy-phenyl) fourth-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-765:2-amino-2-methyl-4-{5-[4-(4-ethoxyl phenenyl) fourth-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-766:2-amino-2-methyl-4-{5-[4-(4-methylthio group phenyl) fourth-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-832:2-amino-2-methyl-4-{5-[5-(3-fluorophenyl) penta-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-833:2-amino-2-methyl-4-{5-[5-(4-fluorophenyl) penta-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-834:2-amino-2-methyl-4-{5-[5-(4-chloro-phenyl-) penta-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-836:2-amino-2-methyl-4-{5-[5-(3-aminomethyl phenyl) penta-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-837:2-amino-2-methyl-4-{5-[5-(4-aminomethyl phenyl) penta-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-846:2-amino-2-methyl-4-{5-[5-(3-trifluoromethyl) penta-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-847:2-amino-2-methyl-4-{5-[5-(4-trifluorophenyl) penta-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-848:2-amino-2-methyl-4-{5-[5-(3-p-methoxy-phenyl) penta-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-849:2-amino-2-methyl-4-{5-[5-(4-p-methoxy-phenyl) penta-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-860:2-amino-2-methyl-4-{5-[5-(3-methylthio group phenyl) penta-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-861:2-amino-2-methyl-4-{5-[5-(4-aminomethyl phenyl) penta-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-877:2-amino-2-methyl-4-{5-[5-(3, the 4-3,5-dimethylphenyl) penta-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-878:2-amino-2-methyl-4-{5-[5-(3, the 5-3,5-dimethylphenyl) penta-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-1050:2-amino-2-methyl-4-{5-[3-(4-methyl cyclohexane oxygen base) proyl] thiophene-2-yl } fourth-1-alcohol,
1-1062:2-amino-2-methyl-4-{5-[3-(4-fluorophenoxy) proyl] thiophene-2-yl } fourth-1-alcohol,
1-1063:2-amino-2-methyl-4-{5-[3-(4-methylphenoxy) proyl] thiophene-2-yl } fourth-1-alcohol,
1-1064:2-amino-2-methyl-4-{5-[3-(4-ethyl phenoxy group) proyl] thiophene-2-yl } fourth-1-alcohol,
1-1065:2-amino-2-methyl-4-{5-[3-(4-4-trifluoromethylphenopendant) proyl] thiophene-2-yl } fourth-1-alcohol,
1-1066:2-amino-2-methyl-4-{5-[3-(4-methoxyl group phenoxy group) proyl] thiophene-2-yl } fourth-1-alcohol,
1-1067:2-amino-2-methyl-4-{5-[3-(4-ethoxy phenoxy) proyl] thiophene-2-yl } fourth-1-alcohol,
1-1068:2-amino-2-methyl-4-{5-[3-(4-methylthio group phenoxy group) proyl] thiophene-2-yl } fourth-1-alcohol,
1-1134:2-amino-2-methyl-4-{5-[4-(3-fluorophenoxy) fourth-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-1135:2-amino-2-methyl-4-{5-[4-(4-fluorophenoxy) fourth-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-1136:2-amino-2-methyl-4-{5-[4-(4-chlorophenoxy) fourth-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-1138:2-amino-2-methyl-4-{5-[4-(3-methylphenoxy) fourth-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-1139:2-amino-2-methyl-4-{5-[4-(4-methylphenoxy) fourth-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-1148:2-amino-2-methyl-4-{5-[4-(3-4-trifluoromethylphenopendant) fourth-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-1149:2-amino-2-methyl-4-{5-[4-(4-4-trifluoromethylphenopendant) fourth-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-1150:2-amino-2-methyl-4-{5-[4-(3-methoxyl group phenoxy group) fourth-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-1151:2-amino-2-methyl-4-{5-[4-(4-methoxyl group phenoxy group) fourth-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-1162:2-amino-2-methyl-4-{5-[4-(3-methylthio group phenoxy group) fourth-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-1163:2-amino-2-methyl-4-{5-[4-(4-methylthio group phenoxy group) fourth-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-1179:2-amino-2-methyl-4-{5-[4-(3, the 4-dimethyl phenoxy) fourth-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-1180:2-amino-2-methyl-4-{5-[4-(3, the 5-dimethyl phenoxy) fourth-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-1198:2-amino-2-methyl-4-[5-(3-phenyl methoxy propyl alkynyl) thiophene-2-yl] fourth-1-alcohol,
1-1202:2-amino-2-methyl-4-{5-[3-(4-fluorophenyl) methoxy propyl alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-1203:2-amino-2-methyl-4-{5-[3-(4-aminomethyl phenyl) methoxy propyl alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-1204:2-amino-2-methyl-4-{5-[3-(4-ethylphenyl) methoxy propyl alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-1205:2-amino-2-methyl-4-{5-[3-(4-trifluoromethyl) methoxy propyl alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-1206:2-amino-2-methyl-4-{5-[3-(4-p-methoxy-phenyl) methoxy propyl alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-1207:2-amino-2-methyl-4-{5-[3-(4-ethoxyl phenenyl) methoxy propyl alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-1208:2-amino-2-methyl-4-{5-[3-(4-methylthio group phenyl) methoxy propyl alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-1212:2-amino-2-methyl-4-[5-(4-cyclohexyl methoxyl group fourth-1-alkynyl) thiophene-2-yl] fourth-1-alcohol,
1-1266:2-amino-2-methyl-4-[5-(4-phenyl methoxyl group fourth-1-alkynyl) thiophene-2-yl] fourth-1-alcohol,
1-1274:2-amino-2-methyl-4-{5-[4-(3-fluorophenyl) methoxyl group fourth-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-1275:2-amino-2-methyl-4-{5-[4-(4-fluorophenyl) methoxyl group fourth-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-1276:2-amino-2-methyl-4-{5-[4-(4-chloro-phenyl-) methoxyl group fourth-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-1278:2-amino-2-methyl-4-{5-[4-(3-aminomethyl phenyl) methoxyl group fourth-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-1279:2-amino-2-methyl-4-{5-[4-(4-aminomethyl phenyl) methoxyl group fourth-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-1288:2-amino-2-methyl-4-{5-[4-(3-trifluoromethyl) methoxyl group fourth-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-1289:2-amino-2-methyl-4-{5-[4-(4-trifluoromethyl) methoxyl group fourth-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-1290:2-amino-2-methyl-4-{5-[4-(3-p-methoxy-phenyl) methoxyl group fourth-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-1291:2-amino-2-methyl-4-{5-[4-(4-p-methoxy-phenyl) methoxyl group fourth-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-1319:2-amino-2-methyl-4-{5-[4-(3, the 4-3,5-dimethylphenyl) methoxyl group fourth-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-1320:2-amino-2-methyl-4-{5-[4-(3, the 5-3,5-dimethylphenyl) methoxyl group fourth-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-1348:2-amino-2-methyl 4-{5-[5-(4-fluorophenyl) pentanoyl] thiophene-2-yl } fourth-1-alcohol,
1-1349:2-amino-2-methyl-4-{5-[5-(4-aminomethyl phenyl) pentanoyl] thiophene-2-yl } fourth-1-alcohol,
1-1350:2-amino-2-methyl-4-{5-[5-(4-ethylphenyl) pentanoyl] thiophene-2-yl } fourth-1-alcohol,
1-1351:2-amino-2-methyl-4-{5-[5-(4-trifluoromethyl) pentanoyl] thiophene-2-yl } fourth-1-alcohol,
1-1352:2-amino-2-methyl-4-{5-[5-(4-p-methoxy-phenyl) pentanoyl] thiophene-2-yl } fourth-1-alcohol,
1-1353:2-amino-2-methyl-4-{5-[5-(4-ethoxyl phenenyl) pentanoyl] thiophene-2-yl } fourth-1-alcohol,
1-1354:2-amino-2-methyl-4-{5-[5-(4-methylthio group phenyl) pentanoyl] thiophene-2-yl } fourth-1-alcohol,
1-1476:2-amino-2-methyl-4-{5-[4-(3-fluorophenoxy) butyryl radicals] thiophene-2-yl } fourth-1-alcohol,
1-1477:2-amino-2-methyl-4-{5-[4-(4-fluorophenoxy) butyryl radicals] thiophene-2-yl } fourth-1-alcohol,
1-1478:2-amino-2-methyl-4-{5-[4-(4-chlorophenoxy) butyryl radicals] thiophene-2-yl } fourth-1-alcohol,
1-1480:2-amino-2-methyl-4-{5-[4-(3-methylphenoxy) butyryl radicals] thiophene-2-yl } fourth-1-alcohol,
1-1481:2-amino-2-methyl-4-{5-[4-(4-methylphenoxy) butyryl radicals] thiophene-2-yl } fourth-1-alcohol,
1-1490:2-amino-2-methyl-4-{5-[4-(3-4-trifluoromethylphenopendant) butyryl radicals] thiophene-2-yl } fourth-1-alcohol,
1-1491:2-amino-2-methyl-4-{5-[4-(4-4-trifluoromethylphenopendant) butyryl radicals] thiophene-2-yl } fourth-1-alcohol,
1-1492:2-amino-2-methyl-4-{5-[4-(3-methoxyl group phenoxy group) butyryl radicals] thiophene-2-yl } fourth-1-alcohol,
1-1493:2-amino-2-methyl-4-{5-[4-(4-methoxyl group phenoxy group) butyryl radicals] thiophene-2-yl } fourth-1-alcohol,
1-1504:2-amino-2-methyl-4-{5-[4-(3-methylthio group phenoxy group) butyryl radicals] thiophene-2-yl } fourth-1-alcohol,
1-1505:2-amino-2-methyl-4-{5-[4-(4-methylthio group phenoxy group) butyryl radicals] thiophene-2-yl } fourth-1-alcohol,
1-1521:2-amino-2-methyl-4-{5-[4-(3, the 4-dimethyl phenoxy) butyryl radicals] thiophene-2-yl } fourth-1-alcohol,
1-1522:2-amino-2-methyl-4-{5-[4-(3, the 5-dimethyl phenoxy) butyryl radicals] thiophene-2-yl } fourth-1-alcohol,
1-2093:2-amino-ethyl-4-[5-(4-phenyl butyryl radicals) thiophene-2-yl] fourth-1-alcohol,
1-2101:2-amino-ethyl-4-[5-(5-phenyl pentanoyl) thiophene-2-yl] fourth-1-alcohol,
1-2109:2-amino-ethyl-4-[5-(6-phenyl caproyl) thiophene-2-yl] fourth-1-alcohol,
1-2257:2-amino-2-methyl-4-{5-[5-(3, the 4-difluorophenyl) penta-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-2258:2-amino-2-methyl-4-{5-[5-(3, the 5-difluorophenyl) penta-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-2259:2-amino-2-methyl-4-{5-[5-(3-chloro-phenyl-) penta-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-2260:2-amino-2-methyl-4-{5-[5-(3, the 4-dichlorophenyl) penta-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-2261:2-amino-2-methyl-4-{5-[5-(3, the 5-dichlorophenyl) penta-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-2262:2-amino-2-methyl 4-{5-[5-(3,4-two (trifluoromethyl) phenyl) penta-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-2263:2-amino-2-methyl-4-{5-[5-(3,5-two (trifluoromethyl) phenyl) penta-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-2264:2-amino-2-methyl-4-{5-[5-(3, the 4-Dimethoxyphenyl) penta-1 alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-2265:2-amino-2-methyl-4-{5-[5-(3, the 5-Dimethoxyphenyl) penta-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-2266:2-amino-2-methyl-4-{5-[5-(3,4, the 5-trimethoxyphenyl) penta-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-2267:2-amino-2-methyl-4-{5-[5-(3-acetylphenyl) penta-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-2268:2-amino-2-methyl-4-{5-[5-(4-acetylphenyl) penta-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-2269:2-amino-2-methyl-4-{5-[3-(3-fluorophenoxy) proyl] thiophene-2-yl } fourth-1-alcohol,
1-2270:2-amino-2-methyl-4-{5-[3-(3,4-two fluorophenoxies) proyl] thiophene-2-yl } fourth-1-alcohol,
1-2271:2-amino-2-methyl-4-{5-[3-(3,5-two fluorophenoxies) proyl] thiophene-2-yl } fourth-1-alcohol,
1-2272:2-amino-2-methyl-4-{5-[3-(3-chlorophenoxy) proyl] thiophene-2-yl } fourth-1-alcohol,
1-2273:2-amino-2-methyl-4-{5-[3-(4-chlorophenoxy) proyl] thiophene-2-yl } fourth-1-alcohol,
1-2274:2-amino-2-methyl-4-{5-[3-(3, the 4-dichlorophenoxy) proyl] thiophene-2-yl } fourth-1-alcohol,
1-2275:2-amino-2-methyl-4-{5-[3-(3, the 5-dichlorophenoxy) proyl] thiophene-2-yl } fourth-1-alcohol,
1-2276:2-amino-2-methyl-4-{5-[3-(3-methylphenoxy) proyl] thiophene-2-yl } fourth-1-alcohol,
1-2278:2-amino-2-methyl-4-{5-[3-(3,4 dimethyl phenoxy) proyl] thiophene-2-yl } fourth-1-alcohol,
1-2279:2-amino-2-methyl-4-{5-[3-(3, the 5-dimethyl phenoxy) proyl] thiophene-2-yl } fourth-1-alcohol,
1-2280:2-amino-2-methyl-4-{5-[3-(3-4-trifluoromethylphenopendant) proyl] thiophene-2-yl } fourth-1-alcohol,
1-2281:2-amino-2-methyl-4-{5-[3-(3,4-two (trifluoromethyl) phenoxy group) proyl] thiophene-2-yl } fourth-1-alcohol,
1-2282:2-amino-2-methyl-4-{5-[3-(3,5-two (trifluoromethyl) phenoxy group) proyl] thiophene-2-yl } fourth-1-alcohol,
1-2283:2-amino-2-methyl-4-{5-[3-(3-methoxyl group phenoxy group) proyl] thiophene-2-yl } fourth-1-alcohol,
1-2284:2-amino-2-methyl-4-{5-[3-(3,4-dimethoxy phenoxy group) proyl] thiophene-2-yl } fourth-1-alcohol,
1-2285:2-amino-2-methyl-4-{5-[3-(3,5-dimethoxy phenoxy group) proyl] thiophene-2-yl } fourth-1-alcohol,
1-2286:2-amino-2-methyl-4-{5-[3-(3,4,5-trimethoxy phenoxy group) proyl] thiophene-2-yl } fourth-1-alcohol,
1-2287:2-amino-2-methyl-4-{5-[3-(3-ethanoyl phenoxy group) proyl] thiophene-2-yl } fourth-1-alcohol,
1-2288:2-amino-2-methyl-4-{5-[3-(4-ethanoyl phenoxy group) proyl] thiophene-2-yl } fourth-1-alcohol,
1-2290:2-amino-2-methyl-4-{5-[4-(3,4-two fluorophenoxies) fourth-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-2291:2-amino-2-methyl-4-{5-[4-(3,5-two fluorophenoxies) fourth-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-2292:2-amino-2-methyl-4-{5-[4-(3-chlorophenoxy) fourth-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-2293:2-amino-2-methyl-4-{5-[4-(3, the 4-dichlorophenoxy) fourth-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-2294:2-amino-2-methyl-4-{5-[4-(3, the 5-dichlorophenoxy) fourth-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-2295:2-amino-2-methyl-4-{5-[4-(3,4-two (trifluoromethyl) phenoxy group) fourth-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-2296:2-amino-2-methyl-4-{5-[4-(3,5-two (trifluoromethyl) phenoxy group) fourth-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-2297:2-amino-2-methyl-4-{5-[4-(3,4-dimethoxy phenoxy group) fourth-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-2298:2-amino-2-methyl-4-{5-[4-(3,5-dimethoxy phenoxy group) fourth-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-2299:2-amino-2-methyl-4-{5-[4-(3,4,5-trimethoxy phenoxy group) fourth-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-2300:2-amino-2-methyl-4-{5-[4-(3-ethanoyl phenoxy group) fourth-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-2301:2-amino-2-methyl-4-{5-[4-(4-ethanoyl phenoxy group) fourth-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-2328:2-amino-2-methyl-4-{5-[5-(3-fluorophenyl) pentanoyl] thiophene-2-yl } fourth-1-alcohol,
1-2329:2-amino-2-methyl-4-{5-[5-(3, the 4-difluorophenyl) pentanoyl] thiophene-2-yl } fourth-1-alcohol,
1-2330:2-amino-2-methyl-4-{5-[5-(3, the 5-difluorophenyl) pentanoyl] thiophene-2-yl } fourth-1-alcohol,
1-2331:2-amino-2-methyl-4-{5-[5-(3-chloro-phenyl-) pentanoyl] thiophene-2-yl } fourth-1-alcohol,
1-2332:2-amino-2-methyl-4-{5-[5-(4-chloro-phenyl-) pentanoyl] thiophene-2-yl } fourth-1-alcohol,
1-2333:2-amino-2-methyl-4-{5-[5-(3, the 4-dichlorophenyl) pentanoyl] thiophene-2-yl } fourth-1-alcohol,
1-2334:2-amino-2-methyl-4-{5-[5-(3, the 5-dichlorophenyl) pentanoyl] thiophene-2-yl } fourth-1-alcohol,
1-2335:2-amino-2-methyl-4-{5-[5-(3-aminomethyl phenyl) pentanoyl] thiophene-2-yl } fourth-1-alcohol,
1-2336:2-amino-2-methyl-4-{5-[5-(3, the 4-3,5-dimethylphenyl) pentanoyl] thiophene-2-yl } fourth-1-alcohol,
1-2337:2-amino-2-methyl-4-{5-[5-(3, the 5-3,5-dimethylphenyl) pentanoyl] thiophene-2-yl } fourth-1-alcohol,
1-2338:2-amino-2-methyl-4-{5-[5-(3-trifluoromethyl) pentanoyl] thiophene-2-yl } fourth-1-alcohol,
1-2339:2-amino-2-methyl-4-{5-[5-(3,4-two (trifluoromethyl) phenyl) pentanoyl] thiophene-2-yl } fourth-1-alcohol,
1-2340:2-amino-2-methyl-4-{5-[5-(3,5-two (trifluoromethyl) phenyl) pentanoyl] thiophene-2-yl } fourth-1-alcohol,
1-2341:2-amino-2-methyl-4-{5-[5-(3-p-methoxy-phenyl) pentanoyl] thiophene-2-yl } fourth-1-alcohol,
1-2342:2-amino-2-methyl-4-{5-[5-(3, the 4-Dimethoxyphenyl) pentanoyl] thiophene 2-yl } fourth-1-alcohol,
1-2343:2-amino-2-methyl-4-{5-[5-(3, the 5-Dimethoxyphenyl) pentanoyl] thiophene-2-yl } fourth-1-alcohol,
1-2344:2-amino-2-methyl-4-{5-[5-(3,4, the 5-trimethoxyphenyl) pentanoyl] thiophene-2-yl } fourth-1-alcohol,
1-2345:2-amino-2-methyl-4-{5-[5-(3-acetylphenyl) pentanoyl] thiophene-2-yl } fourth-1-is pure and mild
1-2346:2-amino-2-methyl-4-{5-[5-(4-acetylphenyl) pentanoyl] thiophene-2-yl } fourth-1-alcohol.
Most preferred is as follows:
1-71:2-amino-2-methyl-4-[5-(4-cyclohexyl butyl) thiophene-2-yl] fourth-1-alcohol,
1-98:2-amino-2-methyl-4-[5-(5-cyclohexyl amyl group) thiophene-2-yl] fourth-1-alcohol,
1-152:2-amino-2-methyl-4-[5-(5-phenylpentyl) thiophene-2-yl] fourth-1-alcohol,
1-400:2-amino-2-methyl-4-[5-(4-cyclohexyloxy butyl) thiophene-2-yl] fourth-1-alcohol,
1-463:2-amino-2-methyl-4-{5-[4-(4-fluorophenoxy) butyl] thiophene-2-yl } fourth-1-alcohol,
1-479:2-amino-2-methyl-4-{5-[4-(4-methoxyl group phenoxy group) butyl] thiophene-2-yl } fourth-1-alcohol,
1-594:2-amino-2-methyl-4-[5-(4-benzyloxy butyl) thiophene-2-yl] fourth-1-alcohol,
1-743:2-amino-2-methyl-4-[5-(4-cyclohexyl fourth-1-alkynyl) thiophene-2-yl] fourth-1-alcohol,
1-756:2-amino-2-methyl-4-[5-(4-phenyl fourth-1-alkynyl) thiophene-2-yl] fourth-1-alcohol,
1-770:2-amino-2-methyl-4-[5-(5-cyclohexyl penta-1-alkynyl) thiophene-2-yl] fourth-1-alcohol,
1-824:2-amino-2-methyl-4-[5-(5-phenyl penta-1-alkynyl) thiophene-2-yl] fourth-1-alcohol,
1-833:2-amino-2-methyl-4-{5-[5-(4-fluorophenyl) penta-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-849:2-amino-2-methyl-4-{5-[5-(4-p-methoxy-phenyl) penta-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-1050:2-amino-2-methyl-4-{5-[3-(4-methyl cyclohexane oxygen base) proyl] thiophene-2-yl } fourth-1-alcohol,
1-1063:2-amino-2-methyl-4-{5-[3-(4-methylphenoxy) proyl] thiophene-2-yl } fourth-1-alcohol,
1-1064:2-amino-2-methyl-4-{5-[3-(4-ethyl phenoxy group) proyl] thiophene-2-yl } fourth-1-alcohol,
1-1068:2-amino-2-methyl-4-{5-[3-(4-methylthio group phenoxy group) proyl] thiophene-2-yl } fourth-1-alcohol,
1-1072:2-amino-2-methyl-4-[5-(4-cyclohexyloxy fourth-1-alkynyl) thiophene-2-yl] fourth-1-alcohol,
1-1135:2-amino-2-methyl-4-{5-[4-(4-fluorophenoxy) fourth-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-1139:2-amino-2-methyl-4-{5-[4-(4-methylphenoxy) fourth-1-alkynyl] thiophene-2-yl } fourth-1-alcohol,
1-1185:2-amino-2-methyl-4-[5-(3-cyclohexyl methoxy propyl alkynyl) thiophene-2-yl] fourth-1-alcohol,
1-1266:2-amino-2-methyl-4-[5-(4-phenyl methoxyl group fourth-1-alkynyl) thiophene-2-yl] fourth-1-alcohol,
1-1329:2-amino-2-methyl-4-[5-(4-cyclohexyl butyryl radicals) thiophene-2-yl] fourth-1-alcohol,
1-1330:2-amino-2-methyl-4-[5-(4-phenyl butyryl radicals) thiophene-2-yl] fourth-1-alcohol,
1-1331:2-amino-2-methyl-4-[5-(5-cyclohexyl pentanoyl) thiophene-2-yl] fourth-1-alcohol,
1-1344:2-amino-2-methyl-4-[5-(5-phenyl pentanoyl) thiophene-2-yl] fourth-1-alcohol,
1-1348:2-amino-2-methyl-4-{5-[5-(4-fluorophenyl) pentanoyl] thiophene-2-yl } fourth-1-alcohol,
1-1764:2-amino-2-ethyl-4-[5-(5-cyclohexyl amyl group) thiophene-2-yl] fourth-1-alcohol,
1-1909:2-amino-2-ethyl-4-[5-(5-cyclohexyl penta-1-alkynyl) thiophene-2-yl] fourth-1-alcohol,
1-2097:2-amino-2-ethyl-4-[5-(5-cyclohexyl pentanoyl) thiophene-2-yl] fourth-1-alcohol,
1-2273:2-amino-2-methyl-4-{5-[3-(4-chlorophenoxy) proyl] thiophene-2-yl } fourth-1-alcohol,
1-2276:2-amino-2-methyl-4-{5-[3-(3-methylphenoxy) proyl] thiophene-2-yl } fourth-1-alcohol,
1-2278:2-amino-2-methyl-4-{5-[3-(3, the 4-dimethyl phenoxy) proyl] thiophene-2-yl } fourth-1-alcohol,
1-2283:2-amino-2-methyl-4-{5-[3-(3-methoxyl group phenoxy group) proyl] thiophene-2-yl } fourth-1-alcohol,
1-2284:2-amino-2-methyl-4-{5-[3-(3,4-dimethoxy phenoxy group) proyl] thiophene-2-yl } fourth-1-alcohol,
1-2285:2-amino-2-methyl-4-{5-[3-(3,5-dimethoxy phenoxy group) proyl] thiophene-2-yl } fourth-1-alcohol,
1-2287:2-amino-2-methyl-4-{5-[3-(3-ethanoyl phenoxy group) proyl] thiophene-2-yl fourth-1-alcohol and
1-2288:2-amino-2-methyl-4-{5-[3-(4-ethanoyl phenoxy group) proyl] thiophene-2-yl } fourth-1-alcohol.
[table 3]
[table 4]
In the last table 3 and 4, the compound of preferred 3-5,3-6,3-7,3-8,3-11,3-12,4-4,4-5,4-6,4-7,4-8,4-9,4-10,4-11,4-12,4-13,4-17,4-23,4-24,4-27,4-28,4-31 and 4-32.
Most preferred is the compound of following numbering:
4-4:4-methyl-4-[(thiene-3-yl-) ethyl] oxazolidine-ketone,
4-5:4-methyl-4-[(thiene-3-yl-) ethyl] oxazolidine-ketone,
4-8:4-methyl-4-[(5-bromothiophene-3-yl) ethyl] oxazolidine-ketone and
4-9:4-methyl-4-[(5-bromothiophene-3-yl) ethyl] oxazolidine-ketone.
Compound of the present invention (I), (XLIVa), (XLIVb), (La) and (Lb) can be according to following method preparation.
Method A is the method for preparing compound (I) and compound (Ic), and compound (Ic) is R in the compound (I)
1Be hydrogen atom; R
2The compound of the aralkyl oxy carbonyl that replaces for lower alkoxycarbonyl, aralkyl oxy carbonyl or by 1-3 substituting group that is selected from substituting group group a.
Method A
In the following formula, R
1, R
2, R
3, R
4, R
5, R
6, R
7, X, Y and n represent meaning same as described above; R
8Expression formyl radical, carboxyl or lower alkoxycarbonyl; R
9And R
9aIdentical or different, expression hydrogen atom or low alkyl group; R
10Expression low alkyl group, aralkyl or the aralkyl that is replaced by the individual group that is selected from substituting group group a of 1-3; R
5a, R
6aAnd R
7aRepresent each R
5, R
6And R
7In the group contained substituting group amino, hydroxyl and/or carboxyl be can protected amino, the group of hydroxyl and/or carboxyl, and and R
5, R
6And R
7The group that group in the group definition is identical.
Above-mentioned R
5a, R
6aAnd R
7aDefinition in " protecting group " of " can protected amino " so long as the protecting group of the used amino in Synthetic Organic Chemistry field gets final product, it is not particularly limited, represent implication same as described above, preferred lower alkoxycarbonyl, most preferably tertbutyloxycarbonyl.
Above-mentioned R
5a, R
6aAnd R
7aDefinition in " can protected hydroxyl " " protecting group " so long as the protecting group of the used hydroxyl in Synthetic Organic Chemistry field get final product; it is not particularly limited; for example expression and aforementioned " the general protecting group described in the ester of hydroxyl in the reaction " identical implication; preferred rudimentary aliphatic acidyl, aromatic acyl group, lower alkoxycarbonyl or (lower alkoxy) methyl; more preferably rudimentary aliphatic acidyl or (lower alkoxy) methyl, most preferably ethanoyl or methoxymethyl.
Above-mentioned R
5a, R
6aAnd R
7aDefinition in " can protected carboxyl " " protecting group " so long as the protecting group of the used carboxyl in Synthetic Organic Chemistry field get final product; it is not particularly limited; for example expression and aforementioned " the general protecting group described in the ester of carboxyl in the reaction " identical implication; preferred low alkyl group, most preferable.
Steps A 1 is the step of compound that preparation has general formula (III), by in inert solvent, in the existence of alkali or not (in the presence of preferred), the have general formula compound of (II) and reductive agent is reacted carry out.
Used inert solvent in the above-mentioned reaction is not particularly limited it as long as this reaction is inertia, can be the aliphatic hydrocarbon of hexane, heptane, raw gasline, sherwood oil and so on for example; The aromatic hydrocarbons of benzene,toluene,xylene and so on; Chloroform, methylene dichloride, 1, the halogenated hydrocarbon of 2-ethylene dichloride, tetracol phenixin and so on; The ester class of acetate, methyl acetate, ethyl acetate, propyl acetate, butylacetate, diethyl carbonate and so on; The ethers of diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether, diglyme and so on; The alcohols of methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, primary isoamyl alcohol, glycol ether, glycerine, octanol, hexalin, methylcyclohexane and so on; The amides of methane amide, dimethyl formamide, N,N-DIMETHYLACETAMIDE, hexamethyl phosphoric triamide and so on; Water; The perhaps mixed solvent of water or above-mentioned solvent.Preferred ethers (most preferably tetrahydrofuran (THF)).
Used reductive agent is the alkali metal borohydride class of for example sodium borohydride, lithium borohydride, sodium cyanoborohydride and so in the above-mentioned reaction; The aluminum hydride compound of diisobutylaluminium hydride, lithium aluminum hydride, hydrogenation aluminum ethylate lithium and so on.Preferred as alkali hydroborate class (most preferably sodium borohydride).
Temperature of reaction is different and different with starting compound, used reductive agent, solvent types etc., is generally-50 ℃ to 100 ℃ (preferred 0 ℃ to 50 ℃).
Reaction times is different and different with starting compound, used reductive agent, solvent, temperature of reaction etc., is generally 15 minutes to 150 hours (preferred 1 hour to 100 hours).
Reaction can be collected the target compound (III) of this reaction according to ordinary method after finishing from reaction mixture.For example can obtain target compound: reaction mixture is suitably neutralized by following operation, perhaps when having insolubles, it is removed by filter, add the immiscible organic solvent of entry and ethyl acetate and so on afterwards, separate the organic layer that contains target compound, after the washing such as water, through dryings such as anhydrous magnesium sulfate, anhydrous sodium sulphate, anhydrous sodium bicarbonates, heat up in a steamer afterwards and desolvate.If desired, can also be by with ordinary method, for example customary way appropriate combination in the separation and purification of organic compound usually such as recrystallization, redeposition is carried out chromatography, with suitable eluent wash-out separate, purifying gained target compound.
Steps A 2 is steps of compound that preparation has general formula (IV), by in inert solvent, in the presence of alkali, the hydroxyl of compound (III) changed into leavings group after, itself and iodinating agent are reacted and the leavings group iodate are carried out.
The reagent that forms leavings group has: the sulfonic acid halide of methylsulfonyl chloride, Tosyl chloride and so on, the thionyl halide class of thionyl chloride, thionyl bromide, sulfurous acyl iodides and so on, the sulfonyl halides of SULPHURYL CHLORIDE, sulfuryl bromide, sulfonic acid iodide and so on, the phosphorus trihalide class of phosphorus trichloride, phosphorus tribromide, phosphorus triiodide and so on, the phosphorus pentahalides class of phosphorus pentachloride, phosphorus pentabromide, pentaiodo phosphorus and so on, the halogenating agents such as phosphoryl halogen class of phosphoryl chloride, phosphoryl bromide, phosphinylidyne iodine and so on; And the rhenium reagent of methyl trioxy-rhenium (VII) and so on.Preferred sulfonic acid halide.
The example of used alkali had the alkaline carbonate class of Quilonum Retard, yellow soda ash, salt of wormwood and so on when hydroxyl was changed into leavings group; The alkali metal hydrocarbonate class of lithium bicarbonate, sodium bicarbonate, saleratus and so on; The alkalimetal hydride class of lithium hydride, sodium hydride, potassium hydride KH and so on; The alkali metal hydroxide of lithium hydroxide, sodium hydroxide, potassium hydroxide and so on; The alkali metal alcohol salt of lithium methoxide, sodium methylate, sodium ethylate, potassium tert.-butoxide and so on; Triethylamine, Tributylamine, diisopropyl ethyl amine, N-methylmorpholine, pyridine, 4-(N, the N-dimethylamino) pyridine, N, accelerine, N, N-Diethyl Aniline, 1,5-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene, 1,4-diazabicyclo [2.2.2] octane (DABCO), 1, the organic amine of 8-diazabicyclo [5.4.0]-7-undecylene (DBU) and so on.Preferred organic amine (most preferably triethylamine).
Used inert solvent when hydroxyl is changed into leavings group is not particularly limited it as long as this reaction is inertia, can be the aliphatic hydrocarbon of hexane, heptane, raw gasline, sherwood oil and so on for example; The aromatic hydrocarbons of benzene,toluene,xylene and so on; Chloroform, methylene dichloride, 1, the halogenated hydrocarbon of 2-ethylene dichloride, tetracol phenixin and so on; The ethers of diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether, diglyme and so on; The ketone of acetone, 2-butanone and so on; The amides of methane amide, dimethyl formamide, N,N-DIMETHYLACETAMIDE, hexamethyl phosphoric triamide and so on; The sulfoxide class of dimethyl sulfoxide (DMSO) and so on; Tetramethylene sulfone.Preferred halogenated hydrocarbon (most preferably methylene dichloride).
Temperature of reaction when hydroxyl is changed into leavings group is different and different with starting compound, agents useful for same, solvent types etc., is generally-50 ℃ to 200 ℃ (preferred-10 ℃ to 150 ℃).
Reaction times when hydroxyl is changed into leavings group is different and different with starting compound, agents useful for same, solvent, temperature of reaction etc., is generally 15 minutes to 24 hours (preferred 30 minutes to 12 hours).
Iodinating agent used in the above-mentioned reaction is for example pentaiodo phosphorus, phosphinylidyne iodine, sodium iodide, potassiumiodide, preferred sodium iodide.
Temperature of reaction during with the leavings group iodate is different and different with starting compound, agents useful for same, solvent types etc., is generally 0 ℃ to 200 ℃ (preferred 10 ℃ to 150 ℃).
Reaction times during with the leavings group iodate is different and different with starting compound, agents useful for same, solvent, temperature of reaction etc., is generally 15 minutes to 24 hours (preferred 30 minutes to 12 hours).
Reaction can be collected the target compound (IV) of this reaction according to ordinary method after finishing from reaction mixture.For example can obtain target compound: reaction mixture is suitably neutralized by following operation, perhaps when having insolubles, it is removed by filter, add the immiscible organic solvent of entry and ethyl acetate and so on afterwards, separate the organic layer that contains target compound, after the washing such as water, through dryings such as anhydrous magnesium sulfate, anhydrous sodium sulphate, anhydrous sodium bicarbonates, heat up in a steamer afterwards and desolvate.If desired, can also be by with ordinary method, for example customary way appropriate combination in the separation and purification of organic compound usually such as recrystallization, redeposition is carried out chromatography, with suitable eluent wash-out separate, purifying gained target compound.
Steps A 3 is steps that preparation has the compound of general formula (VI), by in inert solvent, in the presence of alkali, compound (IV) is reacted with the compound with logical formula V carry out.
Used inert solvent in the above-mentioned reaction is not particularly limited it as long as this reaction is inertia, can be the ethers of diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether, diglyme and so on for example; The alcohols of methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, primary isoamyl alcohol, glycol ether, glycerine, octanol, hexalin, methylcyclohexane and so on; The amides of methane amide, dimethyl formamide, N,N-DIMETHYLACETAMIDE, hexamethyl phosphoric triamide and so on; Water; The perhaps mixed solvent of water or above-mentioned solvent.Preferred alcohols or amides (most preferably dimethyl formamide).
In the above-mentioned reaction used alkali for example have with preceding method A steps A 2 in the used identical alkali of alkali when hydroxyl changed into leavings group, preferred as alkali hydride class or alkali metal alcohol salt (most preferably sodium hydride).
Temperature of reaction is different and different with starting compound, alkali, solvent types etc., is generally-78 ℃ to 100 ℃ (preferred 0 ℃ to 50 ℃).
Reaction times is different and different with starting compound, alkali, solvent, temperature of reaction etc., is generally 15 minutes to 48 hours (preferred 30 minutes to 12 hours).
Reaction can be collected the target compound (VI) of this reaction according to ordinary method after finishing from reaction mixture.For example can obtain target compound: reaction mixture is suitably neutralized by following operation, perhaps when having insolubles, it is removed by filter, add the immiscible organic solvent of entry and ethyl acetate and so on afterwards, separate the organic layer that contains target compound, after the washing such as water, through dryings such as anhydrous magnesium sulfate, anhydrous sodium sulphate, anhydrous sodium bicarbonates, heat up in a steamer afterwards and desolvate.If desired, can also be by with ordinary method, for example customary way appropriate combination in the separation and purification of organic compound usually such as recrystallization, redeposition is carried out chromatography, with suitable eluent wash-out separate, purifying gained target compound.
Steps A 4 is steps that preparation has the compound of general formula (VII), by in inert solvent, makes compound (VI) and alkali reaction, hydrolysis of ester group is become carboxyl carry out.
Used inert solvent in the above-mentioned reaction is not particularly limited it as long as this reaction is inertia, can be the aliphatic hydrocarbon of hexane, heptane, raw gasline, sherwood oil and so on for example; The aromatic hydrocarbons of benzene,toluene,xylene and so on; The ethers of diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether, diglyme and so on; The alcohols of methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, primary isoamyl alcohol, glycol ether, glycerine, octanol, hexalin, methylcyclohexane and so on; The perhaps mixed solvent of water or above-mentioned solvent.Preferred alcohols (most preferred ethanol).
In the above-mentioned reaction used alkali for example have with preceding method A steps A 2 in the used identical alkali of alkali when hydroxyl changed into leavings group, preferred alkali metal hydroxide class (most preferably potassium hydroxide).
Temperature of reaction is different and different with starting compound, alkali, solvent types etc., is generally-20 ℃ to 200 ℃ (preferred 0 ℃ to 50 ℃).
Reaction times is different and different with starting compound, alkali, solvent, temperature of reaction etc., is generally 30 minutes to 120 hours (preferred 1 hour to 80 hours).
Reaction can be collected the target compound (VII) of this reaction according to ordinary method after finishing from reaction mixture.For example can obtain target compound: reaction mixture is suitably neutralized by following operation, perhaps when having insolubles, it is removed by filter, add the immiscible organic solvent of entry and ethyl acetate and so on afterwards, separate the organic layer that contains target compound, after the washing such as water, through dryings such as anhydrous magnesium sulfate, anhydrous sodium sulphate, anhydrous sodium bicarbonates, heat up in a steamer afterwards and desolvate.If desired, can also be by with ordinary method, for example customary way appropriate combination in the separation and purification of organic compound usually such as recrystallization, redeposition is carried out layer and is prayed, with suitable eluent wash-out separate, purifying gained target compound.
Steps A 5 is steps that preparation has the compound of general formula (IX), this step makes the carboxyl of compound (VII) change into carbamate through the Ku Ertisi rearrangement reaction, it is by in inert solvent, in the presence of alkali, make the diaryl phosphoryl azide derivatives reaction of compound (VII) and diphenylphosphine acylazide and so on, itself and the compound reacting by heating with general formula (VIII) are carried out.
Used inert solvent in the above-mentioned reaction is not particularly limited it as long as this reaction is inertia, can be the aliphatic hydrocarbon of hexane, heptane, raw gasline, sherwood oil and so on for example; The aromatic hydrocarbons of benzene,toluene,xylene and so on; Chloroform, methylene dichloride, 1, the halogenated hydrocarbon of 2-ethylene dichloride, tetracol phenixin and so on; The ethers of diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether, diglyme and so on; The perhaps mixed solvent of water or above-mentioned solvent.Aromatic hydrocarbons class (most preferably benzene).
In the above-mentioned reaction used alkali for example have with preceding method A steps A 2 in the used identical alkali of alkali when hydroxyl changed into leavings group, preferred organic amine (most preferably triethylamine).
Temperature of reaction when making compound (VII) with diaryl phosphoryl azide derivatives reaction and the temperature of reaction when reacting with compound (VIII) are all different and different with starting compound, alkali, solvent types etc., are generally 0 ℃ to 200 ℃ (preferred 20 ℃ to 150 ℃).
Reaction times when making compound (VII) with diaryl phosphoryl azide derivatives reaction and the reaction times when reacting with compound (VIII) are all different and different with starting compound, alkali, solvent, temperature of reaction etc., are generally 15 minutes to 24 hours (preferred 30 minutes to 12 hours).
When making compound (VII) with diaryl phosphoryl azide derivatives reaction, react by making the material one that is difficult in the compound (VIII) with diaryl phosphoryl azide derivative direct reaction, can a gas carboxyl be changed into carbamate.
Reaction can be collected the target compound (IX) of this reaction according to ordinary method after finishing from reaction mixture.For example can obtain target compound: reaction mixture is suitably neutralized by following operation, perhaps when having insolubles, it is removed by filter, add the immiscible organic solvent of entry and ethyl acetate and so on afterwards, separate the organic layer that contains target compound, after the washing such as water, through dryings such as anhydrous magnesium sulfate, anhydrous sodium sulphate, anhydrous sodium bicarbonates, heat up in a steamer afterwards and desolvate.If desired, can also be by with ordinary method, for example customary way appropriate combination in the separation and purification of organic compound usually such as recrystallization, redeposition is carried out chromatography, with suitable eluent wash-out separate, purifying gained target compound.
Steps A 6 is steps of compound that preparation has general formula (X), and the ester by reducing compound (IX) carries out, and by in inert solvent, compound (IX) and reductive agent is reacted carry out.
Used inert solvent in the above-mentioned reaction is not particularly limited it as long as this reaction is inertia, can be the aliphatic hydrocarbon of hexane, heptane, raw gasline, sherwood oil and so on for example; The aromatic hydrocarbons of benzene,toluene,xylene and so on; Chloroform, methylene dichloride, 1, the halogenated hydrocarbon of 2-ethylene dichloride, tetracol phenixin and so on; The ethers of diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether, diglyme and so on; The alcohols of methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, primary isoamyl alcohol, glycol ether, glycerine, octanol, hexalin, methylcyclohexane and so on or the mixed solvent of above-mentioned solvent.The mixed solvent (mixed solvent of most preferred ethanol and tetrahydrofuran (THF)) of preferred alcohols and ethers.
In the above-mentioned reaction used reductive agent for example have with preceding method A steps A 1 in the identical reductive agent of used reductive agent, preferred as alkali hydroborate class (most preferably sodium borohydride or lithium borohydride).
Temperature of reaction is different and different with starting compound, solvent types etc., is generally-78 ℃ to 150 ℃ (preferred-20 ℃ to 50 ℃).
Reaction times is different and different with starting compound, solvent, temperature of reaction etc., is generally 5 minutes to 48 hours (preferred 30 minutes to 24 hours).
Reaction can be collected the target compound (X) of this reaction according to ordinary method after finishing from reaction mixture.For example can obtain target compound: reaction mixture is suitably neutralized by following operation, perhaps when having insolubles, it is removed by filter, add the immiscible organic solvent of entry and ethyl acetate and so on afterwards, separate the organic layer that contains target compound, after the washing such as water, through dryings such as anhydrous magnesium sulfate, anhydrous sodium sulphate, anhydrous sodium bicarbonates, heat up in a steamer afterwards and desolvate.If desired, can also be by with ordinary method, for example customary way appropriate combination in the separation and purification of organic compound usually such as recrystallization, redeposition is carried out chromatography, with suitable eluent wash-out separate, purifying gained target compound.
Steps A 7 is steps that preparation has the compound of general formula (XI), is undertaken by making compound (X) and alkali reaction closed loop form the oxazolidine ring.
Used inert solvent in the above-mentioned reaction is not particularly limited it as long as this reaction is inertia, can be the ethers of diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether, diglyme and so on for example; The alcohols of methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, primary isoamyl alcohol, glycol ether, glycerine, octanol, hexalin, methylcyclohexane and so on; The amides of methane amide, dimethyl formamide, N,N-DIMETHYLACETAMIDE, hexamethyl phosphoric triamide and so on; Water; The perhaps mixed solvent of water or above-mentioned solvent.Preferred alcohols or amides (most preferably dimethyl formamide).
In the above-mentioned reaction used alkali for example have with preceding method A steps A 2 in the used identical alkali of alkali when hydroxyl changed into leavings group, preferred as alkali alcohol salt (most preferably potassium tert.-butoxide).
Temperature of reaction is different and different with starting compound, alkali, solvent types etc., is generally-78 ℃ to 100 ℃ (preferred-50 ℃ to 50 ℃).
Reaction times is different and different with starting compound, alkali, solvent, temperature of reaction etc., is generally 15 minutes to 48 hours (preferred 30 minutes to 12 hours).
Reaction can be collected the target compound (XI) of this reaction according to ordinary method after finishing from reaction mixture.For example can obtain target compound: reaction mixture is suitably neutralized by following operation, perhaps when having insolubles, it is removed by filter, add the immiscible organic solvent of entry and ethyl acetate and so on afterwards, separate the organic layer that contains target compound, after the washing such as water, through dryings such as anhydrous magnesium sulfate, anhydrous sodium sulphate, anhydrous sodium bicarbonates, heat up in a steamer afterwards and desolvate.If desired, can also be by with ordinary method, for example customary way appropriate combination in the separation and purification of organic compound usually such as recrystallization, redeposition is carried out chromatography, with suitable eluent wash-out separate, purifying gained target compound.
Steps A 8 is steps that preparation has the compound of general formula (I), by in inert solvent, compound (XI) is taken place after the hydrolysis with alkali reaction, removes R as required
1, R
2, R
3, R
5a, R
6aAnd R
7aThe protecting group of middle amino, hydroxyl and/or carboxyl, protection R
1And/or R
2In amino, and/or the protection R
3In hydroxyl carry out.
Used inert solvent be as long as this reaction is inertia can be not particularly limited it when making compound (XI) and alkali reaction, can be the aliphatic hydrocarbon of hexane, heptane, raw gasline, sherwood oil and so on for example; The aromatic hydrocarbons of benzene,toluene,xylene and so on; Chloroform, methylene dichloride, 1, the halogenated hydrocarbon of 2-ethylene dichloride, tetracol phenixin and so on; The ethers of diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether, diglyme and so on: the alcohols of methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, primary isoamyl alcohol, glycol ether, glycerine, octanol, hexalin, methylcyclohexane and so on; Water; The perhaps mixed solvent of above-mentioned solvent.The mixed solvent (the most preferably mixed solvent of methyl alcohol and tetrahydrofuran (THF)) of preferred alcohols and ethers.
When making compound (XI) with alkali reaction used alkali for example have with preceding method A steps A 2 in the used identical alkali of alkali when hydroxyl changed into leavings group, preferred alkali metal hydroxide class (most preferably potassium hydroxide).
Temperature of reaction is different and different with starting compound, alkali, solvent types etc., is generally-20 ℃ to 200 ℃ (preferred 0 ℃ to 100 ℃).
Reaction times is different and different with starting compound, alkali, solvent types, temperature of reaction etc., is generally 30 minutes to 48 hours (preferred 1 hour to 24 hours).
Removing with its kind of the protecting group of amino, hydroxyl and carboxyl is different and different, usually can be by well-known method in the Synthetic Organic Chemistry technology, T.W.Green for example, (Protective Groups in Organic Synthesis), John Wiley ﹠amp; Sons:J.F.W.McOmis, (Protective Groups in Organic Chemistry), the method that Plenum Press is put down in writing is following carries out.
When the protecting group of amino is the silyl time-like, remove by handling usually with the compound of tetrabutylammonium, hydrofluoric acid, hydrofluoric acid-pyridine, Potassium monofluoride and so on generation fluorine anion.
Used solvent only otherwise hindering reaction get final product is not particularly limited it in the above-mentioned reaction, for example the preferred ethers of diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether, diglyme and so on.
Temperature of reaction and reaction times are not particularly limited, and carry out 10 minutes to 18 hours at 0 ℃ to 50 ℃ usually.
When the protecting group of amino is the substituted methylene of aliphatic acyl class, aromatic acyl group class, carbalkoxy class or formation Schiff's base group, can remove with acid or alkaline purification by in the presence of aqueous solvent.
Used acid in the above-mentioned reaction does not have special restriction to it so long as do not hinder the common used acid of reaction and get final product, and for example can be the mineral acid of Hydrogen bromide, hydrochloric acid, sulfuric acid, perchloric acid, phosphoric acid, nitric acid and so on, preferred hydrochloric acid.
Used alkali needs only the not influence of other parts to compound in the above-mentioned reaction, and it is not had special the restriction, preferably uses the alkaline carbonate class of Quilonum Retard, yellow soda ash, salt of wormwood and so on; The alkali metal hydroxide of lithium hydroxide, sodium hydroxide, potassium hydroxide and so on; The metal alkoxide class of lithium methoxide, sodium methylate, sodium ethylate, potassium tert.-butoxide and so on; The Ammonia of ammoniacal liquor, dense ammonia-methyl alcohol and so on.
Used solvent in the above-mentioned reaction is so long as be used for the solvent of common hydrolysis reaction and get final product, it is not had special restriction, can be the alcohols of methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, primary isoamyl alcohol, glycol ether, glycerine, octanol, hexalin, methylcyclohexane and so on for example; The ethers of diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether, diglyme and so on; Water; The mixed solvent of water and above-mentioned organic solvent.Preferred ethers (most preferably diox).
Temperature of reaction and reaction times with starting compound, solvent is different with used acid or alkali etc. and different, and it is not had special restriction, in order to suppress side reaction, makes it 0 ℃ to 150 ℃ reaction 1 hour to 10 hours usually.
When the protecting group of amino is aralkyl base class or aralkyl oxy carbonyl time-like, usually preferably in inert solvent, by contact (preferably at catalytic reduction in the presence of the catalyzer, under the normal temperature) method of removing or method of removing with reductive agent with oxygenant.
Used solvent when removing by catalytic reduction is not particularly limited it as long as this reaction is inertia, can be the aliphatic hydrocarbon of hexane, heptane, raw gasline, sherwood oil and so on for example; The aromatic hydrocarbons of toluene, benzene, dimethylbenzene and so on; The ester class of methyl acetate, ethyl acetate, propyl acetate, butylacetate, diethyl carbonate and so on; The ethers of diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether, diglyme and so on; The alcohols of methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, primary isoamyl alcohol, glycol ether, glycerine, octanol, hexalin, methylcyclohexane and so on; The organic acid of acetate and so on; Water; The mixed solvent of above-mentioned solvent and water.Preferred alcohols, ethers, organic acid or water (most preferably alcohols or organic acid).
Catalyst system therefor when removing by catalytic reduction does not have special restriction to it so long as be generally used for the catalyzer of catalytic reduction reaction and get final product, and preferably uses palladium on carbon, Raney nickel, platinum oxide, platinum black, rhodium-aluminum oxide, triphenyl phosphine-rhodium chloride, palladium-barium sulfate.
Pressure is not particularly limited, under the 1-10 normal atmosphere, carries out usually.
Temperature of reaction is different and different with starting compound, catalyzer, solvent etc. with the reaction times, carries out 5 minutes to 24 hours at 0 ℃ to 100 ℃ usually.
Used solvent only otherwise participating in this reaction get final product does not have especially it and limits, preferably water-containing organic solvent when removing by oxidation.
Such representative examples of organic has chloroform, methylene dichloride, 1, the halogenated hydrocarbon of 2-ethylene dichloride, tetracol phenixin and so on; The nitrile of acetonitrile and so on; The ethers of diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether, diglyme and so on; The ketone of acetone and so on; The amides of methane amide, dimethyl formamide, N,N-DIMETHYLACETAMIDE, hexamethyl phosphoric triamide and so on; And the sulfoxide class of dimethyl sulfoxide (DMSO) and so on; Tetramethylene sulfone.Preferred halogenated hydrocarbon, ethers or sulfoxide class (most preferably halogenated hydrocarbon or sulfoxide class).
Used oxygenant does not have special restriction to it so long as can be used for the compound of oxidation and get final product, and preferably uses Potassium Persulphate, Sodium Persulfate, ceric ammonium nitrate (CAN), 2,3-two chloro-5,6-dicyano-right-benzoquinones (DDQ).
Temperature of reaction is different and different with starting compound, catalyzer, solvent etc. with the reaction times, carries out 10 minutes to 24 hours at 0 ℃ to 150 ℃ usually.
When the protecting group of amino is the aralkyl time-like, also can remove protecting group with acid.
Used acid in the above-mentioned reaction does not have special restriction to it so long as can be used as the acid of acid catalyst get final product in common reaction, can be the mineral acid of hydrochloric acid, Hydrogen bromide, sulfuric acid, perchloric acid, phosphoric acid and so on for example; The Bronsted acids such as organic acid of acetate, formic acid, oxalic acid, methylsulfonic acid, tosic acid, camphorsulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid and so on; The Lewis acid of zinc chloride, tin tetrachloride, boron trichloride, boron trifluoride, boron tribromide and so on; Acidic ion exchange resin.Preferred mineral acid or organic acid (most preferably hydrochloric acid, acetate or trifluoroacetic acid).
Used inert solvent is not particularly limited it as long as this reaction is inertia in the reaction of above-mentioned leading portion, can be the aliphatic hydrocarbon of hexane, heptane, raw gasline, sherwood oil and so on for example; The aromatic hydrocarbons of benzene,toluene,xylene and so on; Chloroform, methylene dichloride, 1, the halogenated hydrocarbon of 2-ethylene dichloride, tetracol phenixin and so on; The ester class of methyl acetate, ethyl acetate, propyl acetate, butylacetate, diethyl carbonate and so on; The ethers of diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether, diglyme and so on; The alcohols of methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, primary isoamyl alcohol, glycol ether, glycerine, octanol, hexalin, methylcyclohexane and so on; The amides of methane amide, dimethyl formamide, N,N-DIMETHYLACETAMIDE, hexamethyl phosphoric triamide and so on; Water; The perhaps mixed solvent of water or above-mentioned solvent.Preferred ethers, alcohols or water (most preferably diox, tetrahydrofuran (THF), ethanol or water).
Temperature of reaction is different and different with starting compound, used acid, solvent etc., is generally-20 ℃ to boiling temperature (preferred 0 ℃ to 100 ℃).
Reaction times is different and different with starting compound, used acid, solvent, temperature of reaction etc., is generally 15 minutes to 48 hours (preferred 30 minutes to 20 hours).
When the protecting group of amino is an alkenyloxy carbonyl time-like; removing under the reacting phase condition together, in the time of can being aforementioned aliphatic acyl class, aromatic acyl group class, carbalkoxy class or the substituted methylene that forms Schiff's base usually in protecting group with aforementioned amino by removing with alkaline purification.
In addition, when protecting group is allyloxy carbonyl, particularly can under less generation side reaction, use palladium and triphenyl phosphine or nickel tetracarbonyl to remove easily.
When using the silicomethane base class as the protecting group of hydroxyl; usually can handle by the compound that generates fluorine anion with tetrabutylammonium, hydrofluoric acid, hydrofluoric acid-pyridine, Potassium monofluoride and so on, perhaps handle and remove with the organic acid of the mineral acid of hydrochloric acid, Hydrogen bromide, sulfuric acid, perchloric acid, phosphoric acid and so on or acetate, formic acid, oxalic acid, methylsulfonic acid, tosic acid, camphorsulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid and so on.
In addition, when removing, can promote reaction by the organic acid that adds formic acid, acetate, propionic acid and so on by fluorine anion.
Used inert solvent is not particularly limited it as long as this reaction is inertia in the above-mentioned reaction, the ethers of preferred diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether, diglyme and so on; The nitrile of acetonitrile, isopropyl cyanide and so on; The organic acid of acetate and so on; Water; The mixed solvent of above-mentioned solvent.
Temperature of reaction is different and different with starting compound, catalyzer, solvent etc. with the reaction times, carries out 1 hour to 24 hours at 0 ℃ to 100 ℃ (preferred 10 ℃ to 50 ℃) usually.
When the protecting group of hydroxyl is aralkyl base class or aromatic alkoxy carbonyl time-like, preferred usually by in inert solvent, contacting (preferably at catalytic reduction in the presence of the catalyzer, under the normal temperature) method of removing or method of removing with oxygenant with reductive agent.
Used solvent only otherwise participating in this reaction gets final product is not particularly limited it when removing by catalytic reduction, can be the aliphatic hydrocarbon of hexane, heptane, raw gasline, sherwood oil and so on for example; The aromatic hydrocarbons of toluene, benzene, dimethylbenzene and so on; The ester class of ethyl acetate, propyl acetate and so on; The ethers of diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether, diglyme and so on; The alcohols of methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, primary isoamyl alcohol, glycol ether, glycerine, octanol, hexalin, methylcyclohexane and so on; The amides of methane amide, dimethyl formamide, N,N-DIMETHYLACETAMIDE, N-N-methyl-2-2-pyrrolidone N-, hexamethyl phosphoric triamide and so on; The fatty acid of formic acid, acetate and so on; Water; The mixed solvent of above-mentioned solvent.Preferred alcohols (most preferably methyl alcohol).
Catalyst system therefor when removing by catalytic reduction is so long as be generally used for the catalyzer of catalytic reduction reaction and get final product, it there is not special restriction, can be for example palladium on carbon, palladium black, Raney nickel, platinum oxide, platinum black, rhodium-aluminum oxide, triphenyl phosphine-rhodium chloride, palladium-barium sulfate, preferred palladium on carbon.
Pressure is not particularly limited, under the 1-10 normal atmosphere, carries out usually.
Temperature of reaction is different and different with starting compound, catalyzer, solvent etc. with the reaction times, carries out 5 minutes to 48 hours (preferred 1 hour to 24 hours) at 0 ℃ to 100 ℃ (preferred 20 ℃ to 70 ℃) usually.
Used solvent only otherwise participating in this reaction get final product does not have especially it and limits, preferably water-containing organic solvent when removing by chlorination.
Such representative examples of organic has the ketone of acetone and so on; The halogenated hydrocarbon of methylene dichloride, chloroform, tetracol phenixin and so on; The nitrile of acetonitrile and so on; The ethers of diethyl ether, tetrahydrofuran (THF), diox and so on; The amides of dimethyl formamide, N,N-DIMETHYLACETAMIDE, hexamethyl phosphoric triamide and so on; And the sulfoxide class of dimethyl sulfoxide (DMSO) and so on.
Used oxygenant does not have special restriction to it so long as can be used for the compound of oxidation and get final product, and preferably uses Potassium Persulphate, Sodium Persulfate, ceric ammonium nitrate (CAN), 2,3-two chloro-5,6-dicyano-right-benzoquinones (DDQ).
Temperature of reaction is different and different with starting compound, catalyzer, solvent etc. with the reaction times, carries out 10 minutes to 24 hours at 0 ℃ to 150 ℃ usually.
In addition, also can be by in liquid ammonia or in the alcohols of methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, primary isoamyl alcohol, glycol ether, glycerine, octanol, hexalin, methylcyclohexane and so on, at-78 ℃ to 0 ℃, with the basic metal class of metallic lithium, sodium Metal 99.5 and so on it is handled and to remove.
Can also in solvent, remove with the halogenated alkyl silicane of ammonium chloride-sodium iodide or iodate trimethyl silane and so on.
Solvent for use only otherwise participating in this reaction get final product does not have especially it and limits, preferably the halogenated hydrocarbon of methylene dichloride, chloroform, tetracol phenixin and so on; The nitrile of acetonitrile and so on; The mixed solvent of above-mentioned solvent.
Temperature of reaction is different and different with starting compound, solvent etc. with the reaction times, carries out 5 minutes to 72 hours at 0 ℃ to 50 ℃ usually.
In addition, when reactant has sulphur atom, preferably use ammonium chloride-sodium iodide.
When the protecting group of hydroxyl is aliphatic acyl class, aliphatic acyl class or carbalkoxy time-like, can be by in solvent, removing with alkaline purification.
Used alkali needs only the not influence of other parts to compound in the above-mentioned reaction, and it is not had special the restriction, can be the alkaline carbonate class of for example Quilonum Retard, yellow soda ash, salt of wormwood and so on; The alkali metal hydrocarbonate class of lithium bicarbonate, sodium bicarbonate, saleratus and so on; The alkali metal hydroxide of lithium hydroxide, sodium hydroxide, potassium hydroxide and so on; The metal alkoxide class of lithium methoxide, sodium methylate, sodium ethylate, potassium tert.-butoxide and so on; The Ammonia of ammoniacal liquor, dense ammonia-methyl alcohol and so on.Preferred alkali metal hydroxide class, metal alkoxide class or Ammonia (most preferably alkali metal hydroxide or metal alkoxide class).
Solvent for use so long as in the common hydrolysis reaction used solvent get final product, it is not had special restriction, the ethers of preference such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, two-methyl ethyl ether, diglyme and so on; The alcohols of methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, primary isoamyl alcohol, glycol ether, glycerine, octanol, hexalin, methylcyclohexane and so on; Water; The mixed solvent of above-mentioned solvent.
Temperature of reaction is different and different with starting compound, used alkali, solvent etc. with the reaction times, and it is not had special restriction, in order to suppress side reaction, answers 1 hour to 10 hours at-20 ℃ to 150 ℃ usually.
When the protecting group of hydroxyl is (alkoxymethyl)-2 base class, tetrahydropyrans base class, tetrahydric thiapyran base class, tetrahydrofuran (THF) base class, tetramethylene sulfide base class or substituted ethyl time-like, usually by in solvent, removing with acid treatment.
Used acid is so long as get final product as Bronsted acid or lewis acidic acid usually, it is not particularly limited, the preferred hydrogenchloride that uses, the mineral acid of hydrochloric acid, sulfuric acid, nitric acid and so on, or the Bronsted acids such as organic acid of acetate, trifluoroacetic acid, methylsulfonic acid, tosic acid and so on; The Lewis acid of boron trifluoride and so on.Also can use the highly acid Zeo-karb of Dowex 50W and so on.
Used solvent in the above-mentioned reaction is not particularly limited it as long as this reaction is inertia, can be the aliphatic hydrocarbon of hexane, heptane, raw gasline, sherwood oil and so on for example; The aromatic hydrocarbons of benzene,toluene,xylene and so on; The halogenated hydrocarbon of methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, chlorobenzene, dichlorobenzene and so on; The ester class of ethyl formate, ethyl acetate, propyl acetate, butylacetate, diethyl carbonate and so on; The ethers of diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether, diglyme and so on; The alcohols of methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, primary isoamyl alcohol, glycol ether, glycerine, octanol, hexalin, methylcyclohexane and so on; The ketone of acetone, methyl ethyl ketone, methyl iso-butyl ketone (MIBK), isophorone, pimelinketone and so on; Water; The mixed solvent of above-mentioned solvent.Preferred ethers (most preferably tetrahydrofuran (THF)) or alcohols (most preferably methyl alcohol).
Temperature of reaction and reaction times are different and different with starting compound, used acid, solvent etc., carry out 5 minutes to 48 hours (preferred 30 minutes to 10 hours) at-10 ℃ to 200 ℃ (preferred 0 ℃ to 150 ℃) usually.
When the protecting group of hydroxyl is an alkenyloxy carbonyl time-like, can be in protecting group usually with aforementioned hydroxyl aforementioned aliphatic acyl class, aromatic acyl group class or carbalkoxy time-like remove reacting phase with condition under, by removing with alkaline purification.
In addition, when protecting group is allyloxy carbonyl, particularly can under less generation side reaction, use palladium and triphenyl phosphine or two (methyldiphenyl base phosphine) (1, the 5-cyclooctadiene) iridium (I) hexafluorophosphate to remove easily.
When the protecting group of carboxyl is C
1-C
6Alkyl or can be through C by 1-3
1-C
6Alkyl, C
1-C
6The C that alkoxyl group, nitro, halogen or cyano group replace
6-C
10The C that aryl replaced
1-C
6During alkyl, can be in protecting group usually with aforementioned hydroxyl aforementioned aliphatic acyl class, aromatic acyl group class or carbalkoxy time-like remove reacting phase with condition under, by removing with alkaline purification.
In addition, the protecting group of amino, hydroxyl and/or carboxyl remove can be different order implement the required dereaction of removing in turn.
Protection is amino different and different with the kind of its protecting group with the method for hydroxyl, can be undertaken by well-known method in the Synthetic Organic Chemistry technology is following usually.
The amino method of protection can followingly be carried out: at the inert solvent (ethers of preferred diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether, diglyme and so on; The alcohols of methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, primary isoamyl alcohol, glycol ether, glycerine, octanol, hexalin, methylcyclohexane and so on) in, in the existence of alkali (organic amine of triethylamine, Tributylamine, diisopropyl ethyl amine, N-methylmorpholine, pyridine and so on) or not, make R in the compound (I)
1And R
2Compound and following formula: compound for hydrogen atom
R
1a-Z (XII)
[in the following formula, R
1aThe protecting group (expression implication as hereinbefore) that expression is amino, Z represents halogen atom.]
Near 0 ℃ to 50 ℃ (the preferred room temperature) 30 minutes to 10 hours (preferred 1 hour to 5 hours) of reaction.
The method of protection hydroxyl can followingly be carried out: at inert solvent (preferred chloroform, methylene dichloride, 1, the halogenated hydrocarbon of 2-ethylene dichloride, tetracol phenixin and so on; The amides of methane amide, dimethyl formamide, N,N-DIMETHYLACETAMIDE, hexamethyl phosphoric triamide and so on; The sulfoxide class of dimethyl sulfoxide (DMSO) and so on) in, in alkali (the alkalimetal hydride class of preferred lithium hydride, sodium hydride, potassium hydride KH and so on; The organic amine of triethylamine, Tributylamine, diisopropyl ethyl amine, N-methylmorpholine, pyridine and so on) under the existence, makes R in the compound (I)
3Compound and following formula: compound for hydrogen atom
R
3a-Z (XIII)
[in the following formula, R
3aThe protecting group of expression hydroxyl (expression implication as hereinbefore), Z represents implication as hereinbefore.]
Near 0 ℃ to 50 ℃ (the preferred room temperature) 30 minutes to 24 hours (preferred 1 hour to 24 hours) of reaction.
In addition, the order that the reaction of removing and protect amino and/or hydroxyl of the protecting group of amino, hydroxyl and/or carboxyl can be different is implemented required reaction in turn.
Reaction can be collected the target compound (I) of this reaction according to ordinary method after finishing from reaction mixture.For example can obtain target compound: reaction mixture is suitably neutralized by following operation, perhaps when having insolubles, it is removed by filter, add the immiscible organic solvent of entry and ethyl acetate and so on afterwards, separate the organic layer that contains target compound, after the washing such as water, through dryings such as anhydrous magnesium sulfate, anhydrous sodium sulphate, anhydrous sodium bicarbonates, heat up in a steamer afterwards and desolvate.If desired, can also be by with ordinary method, for example customary way appropriate combination in the separation and purification of organic compound usually such as recrystallization, redeposition is carried out chromatography, with suitable eluent wash-out separate, purifying gained target compound.
Steps A 9 is to have the step of the compound of logical penta (I) by compound (X) preparation, by in inert solvent, makes compound (X) after hydrolysis takes place, remove R with alkali reaction as required
1, R
2, R
3, R
5a, R
6aAnd R
7aThe protecting group of middle amino, hydroxyl and/or carboxyl, protection R
1And/or R
2In amino, and/or the protection R
3In hydroxyl carry out, this step and preceding method A steps A 8 are carried out equally.
Steps A 10 is steps of preparation compound (Ic), by after the ester of reducing compound (IX), removes R as required
1, R
2, R
3, R
5a, R
6aAnd R
7aThe protecting group of middle amino, hydroxyl and/or carboxyl, protection R
1And/or R
2In amino, and/or the protection R
3In hydroxyl carry out, the method for the ester of reducing compound (IX) can be carried out equally with preceding method A steps A 6.
Method B is that X is the compound (Id) of ethynylene, compound (Ie) that X is vinylidene in preparation compound (I), X is ethylidene compound (If), X are for having-CO-CH
2-the compound (Ig), X of group for having-CO-CH
2-group and R
1For-CO
2R
10Compound (Ig-1), X for having-CH (OH)-CH
2-compound (Ih), the X of group be the compound (Ii) of aryl or the aryl that replaced by 1-3 group that is selected from substituting group group a and the method for the compound (Ij) that X is Sauerstoffatom or sulphur atom.
Method B
In the following formula, R
1, R
2, R
3, R
4, R
5, R
5a, R
6, R
6a, R
7, R
7a, R
10, Y and n represent meaning same as described above; X
aExpression Sauerstoffatom or sulphur atom; Ya is C
1-C
10Alkylidene group or the C that is replaced by the individual group that is selected from substituting group group a and b of 1-3
1-C
10Alkylidene group; Ring A represents aryl or the aryl that is replaced by the individual group that is selected from substituting group group a of 1-3; W represents to have the group that shows general formula down:
[in the following formula, R
4And R
10Represent implication same as described above; R ' and R " identical or different, expression low alkyl group, aryl or the aryl that is replaced by the individual group that is selected from substituting group group a of 1-3].
Step B1 is the step of compound that preparation has general formula (XVI), by in inert solvent, in the presence of alkali and palladium catalyst, makes the have general formula compound of (XIV) with the compound with general formula (XV) the Sonogashira linked reaction take place and carries out.
Used solvent in the above-mentioned reaction is not particularly limited it as long as this reaction is inertia, can be the aliphatic hydrocarbon of hexane, heptane, raw gasline, sherwood oil and so on for example; The aromatic hydrocarbons of benzene,toluene,xylene and so on; The halogenated hydrocarbon of methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, chlorobenzene, dichlorobenzene and so on; The ester class of ethyl formate, ethyl acetate, propyl acetate, butylacetate, diethyl carbonate and so on; The ethers of diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether, diglyme and so on; The ketone of acetone, methyl ethyl ketone, methyl iso-butyl ketone (MIBK), isophorone, pimelinketone and so on; The nitrile of acetonitrile, isopropyl cyanide and so on; The amides of methane amide, dimethyl formamide, N,N-DIMETHYLACETAMIDE, hexamethyl phosphoric triamide and so on; The sulfoxide class of dimethyl sulfoxide (DMSO), tetramethylene sulfone and so on.Preferred ethers, amides or sulfoxide class (most preferably amides or ethers).In addition, in reaction solvent, add less water and can promote the carrying out that react.
In the above-mentioned reaction used alkali for example can have with preceding method A steps A 2 in the used identical alkali of alkali when hydroxyl changed into leavings group, preferred organic amine (most preferably triethylamine).
Used palladium catalyst in the above-mentioned reaction is not particularly limited it so long as be used for the catalyzer of common Sonogashira linked reaction and get final product, and can be the palladium salt of for example acid chloride, Palladous chloride, carbonate palladium and so on; Form the palladium complex class that the dichloro two (triphenyl phosphine) of complex compound closes palladium and so on part.
By using additive cuprous iodide, benzyltriethylammonium chloride can improve yield.
Temperature of reaction is different and different with starting compound, alkali, solvent types etc., is generally-20 ℃ to 200 ℃ (preferred 0 ℃ to 120 ℃).
Reaction times is different and different with starting compound, alkali, solvent, temperature of reaction etc., is generally 5 minutes to 48 hours (preferred 15 minutes to 24 hours).
Reaction can be collected the target compound (XVI) of this reaction according to ordinary method after finishing from reaction mixture.For example can obtain target compound: reaction mixture is suitably neutralized by following operation, perhaps when having insolubles, it is removed by filter, add the immiscible organic solvent of entry and ethyl acetate and so on afterwards, separate the organic layer that contains target compound, after the washing such as water, through dryings such as anhydrous magnesium sulfate, anhydrous sodium sulphate, anhydrous sodium bicarbonates, heat up in a steamer afterwards and desolvate.If desired, can also be by with ordinary method, for example customary way appropriate combination in the separation and purification of organic compound usually such as recrystallization, redeposition is carried out chromatography, with suitable eluent wash-out separate, purifying gained target compound.
Step B2 is the step of compound that preparation has general formula (Id), when the W of compound (XVI) be (W-1) when basic, can be by making itself and preceding method A steps A 7 and steps A 8, and perhaps preceding method A steps A 9 is equally reacted and is prepared.Perhaps, when the W of compound (XVI) is (W-2) or (W-3) when base, itself and preceding method A steps A 8 are reacted equally prepare the have general formula compound of (Id).
Step B3 is the step that preparation has the compound of general formula (XVII), by making compound (XV) and catecholborane reaction, carries out the Suzuki linked reaction with compound (XIV) afterwards and carries out.
Temperature of reaction when compound (XV) is reacted with catecholborane is different and different with starting compound, alkali, solvent types etc., is generally 0 ℃ to 150 ℃ (preferred 10 ℃ to 100 ℃).
Reaction times when compound (XV) is reacted with catecholborane is different and different with starting compound, alkali, solvent, temperature of reaction etc., is generally 15 minutes to 24 hours (preferred 30 minutes to 12 hours).
Afterwards, carry out the Suzuki linked reaction method can with the same the carrying out of Sonogashira linked reaction of preceding method B step B1.
In the above-mentioned reaction used solvent for example have with preceding method B step B1 in the identical solvent of solvent for use, aromatic hydrocarbons class (most preferably toluene).
In the above-mentioned reaction used alkali for example have with preceding method A steps A 2 in the used identical alkali of alkali when hydroxyl changed into leavings group, preferred as alkali alcohol salt (most preferred ethanol sodium).
Used palladium catalyst has for example used with the preceding method B step B1 identical catalyzer of catalyzer in the above-mentioned reaction, preferred palladium complex class (most preferably dichloro two (triphenyl phosphine) closes palladium).
Step B4 is the step of compound that preparation has general formula (Ie), when the W of compound (XVII) be (W-1) when basic, can be by making itself and preceding method A steps A 7 and steps A 8, and perhaps preceding method A steps A 9 is equally reacted and is prepared.Perhaps, when the W of compound (XVII) is (W-2) or (W-3) when base, itself and preceding method A steps A 8 are reacted equally prepare the have general formula compound of (Ie).
Step B5 is the step of compound that preparation has general formula (XVIII), and by in inert solvent, reducing compound (XVI) (preferably in the presence of catalyzer, under normal temperature catalytic reduction) carries out.
Used solvent when removing by catalytic reduction is not particularly limited it as long as this reaction is inertia, can be the aliphatic hydrocarbon of hexane, heptane, raw gasline, sherwood oil and so on for example; The aromatic hydrocarbons of toluene, benzene, dimethylbenzene and so on; The halogenated hydrocarbon of methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, chlorobenzene, dichlorobenzene and so on; The ester class of methyl acetate, ethyl acetate, propyl acetate, butylacetate, diethyl carbonate and so on; The ethers of diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether, diglyme and so on; The alcohols of methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, primary isoamyl alcohol, glycol ether, glycerine, octanol, hexalin, methylcyclohexane and so on; The organic acid of acetate, hydrochloric acid and so on; Water; The mixed solvent of above-mentioned solvent and water.Preferred alcohols or ethers (most preferably methyl alcohol).
Used catalyzer when removing by catalytic reduction is so long as be generally used for the catalyzer of catalytic reduction reaction and get final product, it is not particularly limited, preferably uses palladium on carbon, Raney nickel, platinum oxide, platinum black, rhodium-aluminum oxide, triphenyl phosphine-rhodium chloride, palladium-barium sulfate.
Temperature of reaction is different and different with starting compound, alkali, solvent types etc., is generally-20 ℃ to 200 ℃ (preferred 0 ℃ to 100 ℃).
Reaction times is different and different with starting compound, alkali, solvent, temperature of reaction etc., is generally 5 minutes to 96 hours (preferred 15 minutes to 72 hours).
Reaction can be collected the target compound (XVIII) of this reaction according to ordinary method after finishing from reaction mixture.For example can obtain target compound: reaction mixture is suitably neutralized by following operation, perhaps when having insolubles, it is removed by filter, add the immiscible organic solvent of entry and ethyl acetate and so on afterwards, separate the organic layer that contains target compound, after the washing such as water, through dryings such as anhydrous magnesium sulfate, anhydrous sodium sulphate, anhydrous sodium bicarbonates, heat up in a steamer afterwards and desolvate.If desired, can also be by with ordinary method, for example customary way appropriate combination in the separation and purification of organic compound usually such as recrystallization, redeposition is carried out chromatography, with suitable eluent wash-out separate, purifying gained target compound.
Step B6 is the step of compound that preparation has general formula (If), when the W of compound (XVIII) be (W-1) when basic, can be by making itself and preceding method A steps A 7 and steps A 8, and perhaps preceding method A steps A 9 is equally reacted and is prepared.Perhaps, when the W of compound (XVIII) is (W-2) or (W-3) when base, itself and preceding method A steps A 8 are reacted equally prepare the have general formula compound of (If).
Step B7 is the step of compound that preparation has general formula (XIX), when the W of compound (XVI) be (W-1) when basic, can be by making itself and preceding method A steps A 7 and steps A 8, and perhaps preceding method A steps A 9 is equally reacted and is prepared.Perhaps, when the W of compound (XVI) is (W-2) or (W-3) when base, itself and preceding method A steps A 8 are reacted equally prepare the have general formula compound of (XIX).
Step B8 is the step of compound that preparation has general formula (Ig), can be in inert solvent, by make compound (XIX) through using acid catalyst the water addition reaction or use the oxymercuration of red precipitate to react and carry out, remove R as required
1, R
2, R
3, R
5a, R
6aAnd R
7aThe protecting group of middle amino, hydroxyl and/or carboxyl, protection R
1And/or R
2In amino, and/or the protection R
3In hydroxyl carry out.
Used solvent in the above-mentioned reaction is not particularly limited it as long as this reaction is inertia, can be the aliphatic hydrocarbon of hexane, heptane, raw gasline, sherwood oil and so on for example; The aromatic hydrocarbons of benzene,toluene,xylene and so on; The halogenated hydrocarbon of methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, chlorobenzene, dichlorobenzene and so on; The ester class of ethyl formate, ethyl acetate, propyl acetate, butylacetate, diethyl carbonate and so on; The ethers of diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether, diglyme and so on; The alcohols of methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, primary isoamyl alcohol, glycol ether, glycerine, octanol, hexalin, methylcyclohexane and so on; The ketone of acetone, methyl ethyl ketone, methyl iso-butyl ketone (MIBK), isophorone, pimelinketone and so on; Water; The mixed solvent of above-mentioned solvent.Preferred alcohols (most preferably methyl alcohol).
Used acid catalyst in the above-mentioned reaction is so long as be used as the acid catalyst of acid catalyst and get final product in common reaction, it is not particularly limited, can be for example mineral acid of hydrochloric acid, Hydrogen bromide, sulfuric acid, perchloric acid, phosphoric acid and so on, the perhaps Bronsted acids such as organic acid of acetate, formic acid, oxalic acid, methylsulfonic acid, tosic acid, camphorsulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid and so on; The perhaps Lewis acid of zinc chloride, tin tetrachloride, boron trichloride, boron trifluoride, boron tribromide and so on; Perhaps acidic ion exchange resin.Preferred mineral acid (most preferably sulfuric acid).
Temperature of reaction is different and different with starting compound, alkali, solvent types etc., is generally-20 ℃ to 200 ℃ (preferred 0 ℃ to 100 ℃).
Reaction times is different and different with starting compound, alkali, solvent, temperature of reaction etc., is generally 5 minutes to 96 hours (preferred 15 minutes to 72 hours).
Remove R as required
1, R
2, R
3, R
5a, R
6aAnd R
7aThe method of the protecting group of middle amino, hydroxyl and/or carboxyl, protection R
1And/or R
2In amino and/or protection R
3In the method for hydroxyl can carry out equally with preceding method A steps A 8.
Step B9 is the step of compound that preparation has general formula (Ig-1), in inert solvent, by make compound (XVIa) through using acid catalyst the water addition reaction or use the method for the oxymercuration reaction of red precipitate to carry out, remove R as required
1, R
2, R
3, R
5a, R
6aAnd R
7aIn the protecting group of amino, hydroxyl and/or carboxyl, and/or protection R
3In hydroxyl carry out, this step and preceding method B step B8 carry out equally.
Step B10 is the step of compound that preparation has general formula (XX), in inert solvent, by make compound (XIX) through using acid catalyst the water addition reaction or use the oxymercuration of red precipitate to react and carry out, remove R as required
1, R
2, R
3, R
5a, R
6aAnd R
7aThe protecting group of middle amino, hydroxyl and/or carboxyl, protection R
1And/or R
2In amino, and/or the protection R
3In hydroxyl carry out, this step and preceding method B step B8 carry out equally.
Step B11 is the step that preparation has the compound of general formula (Ih), by in inert solvent compound (XX) being reduced, removes R afterwards as required
1, R
2, R
3, R
5a, R
6aAnd R
7aThe protecting group of middle amino, hydroxyl and/or carboxyl, protection R
1And/or R
2In amino, and/or the protection R
3In hydroxyl carry out.
Used inert solvent in the above-mentioned reaction is not particularly limited it as long as this reaction is inertia, can be the aliphatic hydrocarbon of hexane, heptane, raw gasline, sherwood oil and so on for example; The aromatic hydrocarbons of benzene toluene, dimethylbenzene and so on; Chloroform, methylene dichloride, 1, the halogenated hydrocarbon of 2-ethylene dichloride, tetracol phenixin and so on; The ethers of diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether, diglyme and so on; The alcohols of methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, primary isoamyl alcohol, glycol ether, glycerine, octanol, hexalin, methylcyclohexane and so on; The perhaps mixed solvent of above-mentioned solvent.Preferred ethers or alcohols (most preferably methyl alcohol or ethanol).
Used reductive agent can be the alkali metal borohydride class of for example sodium borohydride, lithium borohydride, sodium cyanoborohydride and so in the above-mentioned reaction; The aluminum hydride compound of diisobutylaluminium hydride, lithium aluminum hydride, hydrogenation aluminum ethylate lithium and so on.Preferred as alkali hydroborate class (sodium cyanoborohydride).
Temperature of reaction is different and different with starting compound, alkali, solvent types etc., is generally-10 ℃ to 100 ℃ (preferred-20 ℃ to 20 ℃).
Reaction times is different and different with starting compound, alkali, solvent, temperature of reaction etc., is generally 10 minutes to 48 hours (preferred 30 minutes to 12 hours).
Remove R as required
1, R
2, R
3, R
5a, R
6aAnd R
7aThe method of the protecting group of middle amino, hydroxyl and/or carboxyl, protection R
1And/or R
2In amino and/or protection R
3In the method for hydroxyl can carry out equally with preceding method A steps A 8.
Reaction can be collected the target compound (Ih) of this reaction according to ordinary method after finishing from reaction mixture.For example can obtain target compound: reaction mixture is suitably neutralized by following operation, perhaps when having insolubles, it is removed by filter, add the immiscible organic solvent of entry and ethyl acetate and so on afterwards, separate the organic layer that contains target compound, after the washing such as water, through dryings such as anhydrous magnesium sulfate, anhydrous sodium sulphate, anhydrous sodium bicarbonates, heat up in a steamer afterwards and desolvate.If desired, can also be by with ordinary method, for example customary way appropriate combination in the separation and purification of organic compound usually such as recrystallization, redeposition is carried out chromatography, with suitable eluent wash-out separate, purifying gained target compound.
Step B12 is the step that preparation has the compound of general formula (XXII), is undertaken by making compound (XXI) and compound (XIV) that the Suzuki linked reaction take place, and this step is carried out equally with the Sonogashira linked reaction part of preceding method B step B3.
Step B13 is the step of compound that preparation has general formula (Ii), when the W of compound (XXII) be (W-1) when basic, can be by making itself and preceding method A steps A 7 and steps A 8, and perhaps preceding method A steps A 9 is equally reacted and is prepared.Perhaps, when the W of compound (XXII) is (W-2) or (W-3) when base, itself and preceding method A steps A 8 are reacted equally prepare the have general formula compound of (Ii).
Step B14 is the step that preparation has the compound of general formula (XXIV), by solvent-free down or in inert solvent, in the presence of copper catalyst, the have general formula compound of (XIV) is reacted with an alkali metal salt with compound of general formula (XXII) carry out.This step can be utilized for example JHeterocyclic.Chem., the method for being put down in writing in 20,1557 (1983).
Used solvent in the above-mentioned reaction is not particularly limited it as long as this reaction is inertia, can be the ethers of diethyl ether, diox, tetrahydrofuran (THF), glycol dimethyl ether, diglyme and so on for example; The pyridines of pyridine, picoline, lutidine, collidine and so on.Preferably do not use solvent.The copper catalyst that uses in above-mentioned reaction can be for example cuprous iodide, cuprous bromide, Red copper oxide, cupric oxide, preferred Red copper oxide.
An alkali metal salt of used compound (XXIII) can be made by general formula (XXIII) and basic metal or alkali metal compound in the above-mentioned reaction.Alkali-metal example has lithium, sodium, potassium, and the example of alkali metal compound has the alkalimetal hydride of lithium hydride, sodium hydride, potassium hydride KH and so on.Preferably prepare with sodium Metal 99.5.In addition, by using the additive potassiumiodide can improve yield.
Temperature of reaction is different and different with starting compound, catalyzer, solvent types, is generally room temperature to 150 ℃ (preferred 60 ℃ to 120 ℃).
Reaction times is different and different with starting compound, catalyzer, solvent types, is generally 1 hour to 7 days (preferred 3 hours to 72 hours).
Reaction can be collected the target compound (XXIV) of this reaction according to ordinary method after finishing from reaction mixture.For example can obtain target compound: reaction mixture is suitably neutralized by following operation, perhaps when having insolubles, it is removed by filter, add the immiscible organic solvent of entry and ethyl acetate and so on afterwards, separate the organic layer that contains target compound, after the washing such as water, through dryings such as anhydrous magnesium sulfate, anhydrous sodium sulphate, anhydrous sodium bicarbonates, heat up in a steamer afterwards and desolvate.If desired, can also be by with ordinary method, for example customary way appropriate combination in the separation and purification of organic compound usually such as recrystallization, redeposition is carried out chromatography, with suitable eluent wash-out separate, purifying gained target compound.
Step B15 is the step of compound that preparation has general formula (Ij), when the W of compound (XXIV) be (W-1) when basic, can be by making itself and preceding method A steps A 7 and steps A 8, and perhaps preceding method A steps A 9 is equally reacted and is prepared.Perhaps, when the W of compound (XXIV) is (W-2) or (W-3) when base, itself and preceding method A steps A 8 are reacted equally prepare the have general formula compound of (Ij).
Step B16 is the step of compound that preparation has general formula (XXVI), is undertaken by the have general formula compound of (XIV) is reacted with the compound with general formula (XXV), and this step is carried out equally with preceding method B step B1.
Step B17 is that Y is the step of compound (XVIb) with group of formula-Ya-O-in preparation compound (XVI), by in inert solvent, make compound (XXVI) prolong reaction (Mitsunobu reaction) condensation through light and carry out with compound with general formula (XXVII).
Light prolongs reagent used in the reaction so long as can be used for the reagent that light prolongs reaction usually and get final product, it is not particularly limited, preferred diethylazodicarboxylate, diisopropyl azo-2-carboxylic acid and so on azo-2-carboxylic acid's two lower alkyl esters classes or 1, the combination of the phosphine classes such as three low alkyl group phosphine classes of the triaryl phosphine class of azo-compounds such as the azo dicarbapentaborane class of 1 '-(azo dicarbapentaborane) two piperidines and so on and triphenyl phosphine and so on or tri-n-butyl phosphine and so on, the more preferably combination of azo-2-carboxylic acid's two lower alkyl esters classes and triaryl phosphine class.
Solvent for use only otherwise hinder reaction, dissolving raw material get final product to a certain extent, it is not particularly limited, preferably the aromatic hydrocarbons of benzene,toluene,xylene and so on; The halogenated hydrocarbon of methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, chlorobenzene, dichlorobenzene and so on; The ester class of ethyl formate, ethyl acetate, propyl acetate, butylacetate, diethyl carbonate and so on; The ethers of diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether, diglyme and so on; The nitrile of acetonitrile, isopropyl cyanide and so on; Methane amide, N, the amides of dinethylformamide, N,N-dimethylacetamide, N-N-methyl-2-2-pyrrolidone N-, N-Methyl pyrrolidone, hexamethyl phosphoric triamide and so on; The sulfoxide class of dimethyl sulfoxide (DMSO), tetramethylene sulfone and so on.Aromatic hydrocarbons class and ethers.
Temperature of reaction is-20 ℃ to 100 ℃, preferred 0 ℃ to 50 ℃.
Reaction times is mainly different and different with the kind of temperature of reaction starting compound, reaction reagent or solvent for use, be generally 10 minutes to 3 days, preferred 30 minutes to 12 hours.
Reaction can be collected the target compound (XVIb) of this reaction according to ordinary method after finishing from reaction mixture.For example can obtain target compound: reaction mixture is suitably neutralized by following operation, perhaps when having insolubles, it is removed by filter, add the immiscible organic solvent of entry and ethyl acetate and so on afterwards, separate the organic layer that contains target compound, after the washing such as water, through dryings such as anhydrous magnesium sulfate, anhydrous sodium sulphate, anhydrous sodium bicarbonates, heat up in a steamer afterwards and desolvate.If desired, can also be by with ordinary method, for example customary way appropriate combination in the separation and purification of organic compound usually such as recrystallization, redeposition is carried out chromatography, with suitable eluent wash-out separate, purifying gained target compound.
Can also use other method different, after the hydrolysis of the W of compound (XIV) base,, prepare compound (Id)-(Ij) by making itself and compound (XV), (XXI), (XXIII) or (XXV) reaction with present method.
Starting compound (II), (V), (VIII), (XII), (XIII), (XIV), (XV), (XXI), (XXIII), (XXV) and (XXVII) be known or can easily make according to currently known methods or its similar approach.
Starting compound (II) and (XIV) also can be by the preparation of following method.
Method C is the method for preparing compound (XIV) and compound (XIVa), and compound (XIVa) is to have-(CH on 5 that have on 2 of thienyl in the compound (XIV) as substituent bromine atoms, thienyl
2)
nThe compound of-W group.
Method C
In the following formula, R
4, R
6a, R
7a, R
8, R
9, R
9a, R
10, n is identical with aforementioned implication with W.
Step C1 is the step that preparation has the compound of general formula (XXIX), by in inert solvent, in the existence of alkali or not (preferred in the presence of), the have general formula compound of (XXVIII) and reductive agent are reacted carry out, this step and preceding method A steps A 1 are carried out equally.
Step C2 is the step of compound that preparation has general formula (XXX), by in inert solvent, in the presence of alkali, the hydroxyl of compound (XXIX) changed into leavings group after, its iodate is carried out, this step is carried out equally with preceding method A steps A 2.
Step C3 is the step that preparation has the compound of general formula (XXXI), by in inert solvent, in the presence of alkali, compound (XXX) and compound (V) reaction is carried out, and this step is carried out equally with preceding method A steps A 3.
Step C4 is the step that preparation has the compound of general formula (XXXII), by in inert solvent, compound (XXXI) and alkali reaction generation hydrolysis is carried out, and this step is carried out equally with preceding method A steps A 4.
Step C5 is the step that preparation has the compound of general formula (XXXIII), this step makes the carboxyl of compound (XXXII) change into carbamate through the Ku Ertisi rearrangement reaction, it is by in inert solvent, in the presence of alkali, make the diaryl phosphoryl azide derivatives reaction of compound (XXXII) and diphenylphosphine acylazide and so on, itself and compound (VIII) reaction are carried out, and this step is carried out equally with preceding method A steps A 5.
Step C6 be preparation compound (XIV) step, the ester by reducing compound (XXXIII) carries out, this step is carried out equally with preceding method A steps A 6.
Reaction can be collected the target compound (XIV) of this reaction according to ordinary method after finishing from reaction mixture.For example can obtain target compound: reaction mixture is suitably neutralized by following operation, perhaps when having insolubles, it is removed by filter, add the immiscible organic solvent of entry and ethyl acetate and so on afterwards, separate the organic layer that contains target compound, after the washing such as water, through dryings such as anhydrous magnesium sulfate, anhydrous sodium sulphate, anhydrous sodium bicarbonates, heat up in a steamer afterwards and desolvate.If desired, can also be by with ordinary method, for example customary way appropriate combination in the separation and purification of organic compound usually such as recrystallization, redeposition is carried out chromatography, with suitable eluent wash-out separate, purifying gained target compound.
Step C7 is the step that preparation has the compound of general formula (XXXV), by in inert solvent, in the existence of alkali or not (preferred in the presence of), the have general formula compound of (XXXIV) and reductive agent are reacted carry out, this step and preceding method A steps A 1 are carried out equally.
Step C8 is the step of compound that preparation has general formula (XXXVI), by in inert solvent, in the presence of alkali, the hydroxyl of compound (XXXV) changed into leavings group after, its iodate is carried out, this step is carried out equally with preceding method A steps A 2.
Step C9 is the step that preparation has the compound of general formula (XXXVII), by in inert solvent, in the presence of alkali, compound (XXXVI) and compound (V) reaction is carried out, and this step is carried out equally with preceding method A steps A 3.
Step C10 is the step that preparation has the compound of general formula (XXXVIII), by in inert solvent, compound (XXXVII) and alkali reaction generation hydrolysis is carried out, and this step is carried out equally with preceding method A steps A 4.
Step C11 is the step that preparation has the compound of general formula (XXXIX), this step makes the carboxyl of compound (XXXVIII) change into carbamate through the Ku Ertisi rearrangement reaction, by in inert solvent, in the presence of alkali, make the diaryl phosphoryl azide derivatives reaction of compound (XXXVIII) and diphenylphosphine acylazide and so on, itself and compound (VIII) reaction are carried out, and this step is carried out equally with preceding method A steps A 5.
Step C12 is the step of compound that preparation has general formula (XL), and the ester by reducing compound (XXXIX) carries out, and this step is carried out equally with preceding method A steps A 6.
Step C13 is the step of preparation compound (XIVa), by in inert solvent, compound (XL) and bromizating agent is reacted carry out.
Used solvent in the above-mentioned reaction is not particularly limited it as long as this reaction is inertia, can be the halogenated hydrocarbon of methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, chlorobenzene, dichlorobenzene and so on for example; The ethers of diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether, diglyme and so on; The amides of methane amide, dimethyl formamide, N,N-DIMETHYLACETAMIDE, hexamethyl phosphoric triamide and so on.Preferred amide class (most preferably dimethyl formamide).
Bromizating agent used in the above-mentioned reaction is not particularly limited, and can be the bromizating agent described in " Comprehensive Organic Transformations " (Larock, VCH, 316-317 page or leaf) for example.Preferred N-bromine succinimide or bromine.
Temperature of reaction is different and different with starting compound, bromizating agent, solvent types etc., is generally-78 ℃ to 150 ℃ (preferred-20 ℃ to 100 ℃).
Reaction times is different and different with starting compound, bromizating agent, solvent, temperature of reaction etc., is generally 5 minutes to 48 hours (preferred 30 minutes to 24 hours).
Reaction can be collected the target compound (XIVa) of this reaction according to ordinary method after finishing from reaction mixture.For example can obtain target compound: reaction mixture is suitably neutralized by following operation, perhaps when having insolubles, it is removed by filter, add the immiscible organic solvent of entry and ethyl acetate and so on afterwards, separate the organic layer that contains target compound, after the washing such as water, through dryings such as anhydrous magnesium sulfate, anhydrous sodium sulphate, anhydrous sodium bicarbonates, heat up in a steamer afterwards and desolvate.If desired, can also be by with ordinary method, for example customary way appropriate combination in the separation and purification of organic compound usually such as recrystallization, redeposition is carried out chromatography, with suitable eluent wash-out separate, purifying gained target compound.
Method D is that X is the compound (IIa) of ethynylene, compound (IIb) that X is ethylidene in preparation compound (II), X is vinylidene compound (IIc), X are for having-CO-CH
2-the compound (IId), X of group for having-CH (OH)-CH
2-compound (IIe), the X of group be the compound (IIf) of aryl or the aryl that replaced by 1-3 group that is selected from substituting group group a and the method for the compound (IIg) that X is Sauerstoffatom or sulphur atom.
Method D
In the following formula, R
5a, R
6a, R
7a, R
8, n, X
a, Y, Y
aA is identical with aforementioned implication with ring.
Step D1 is the step of preparation compound (IIa), by in inert solvent, in the presence of alkali and palladium catalyst, make compound (XXVIII) and compound that the Sonogashira linked reaction take place and carry out with general formula (XV), this step is carried out equally with preceding method B step B1.
Step D2 is the step of preparation compound (IIb), is undertaken by reducing compound in inert solvent (IIa) (preferably at catalytic reduction in the presence of the catalyzer, under normal temperature), and this step is carried out equally with preceding method B step B5.
Step D3 is the step of preparation compound (IIc), after compound (XV) and catecholborane are reacted, with compound (XXVIII) the Suzuki linked reaction takes place and carries out, and this step is carried out equally with preceding method B step B3.
Step D4 is the step of preparation compound (IId), by in inert solvent, with compound (IIa) through using acid catalyst the water addition reaction or use the oxymercuration of red precipitate to react and carry out, this step is carried out equally with preceding method B step B8.
Step D5 is the step of preparation compound (IIe), and (IId) carries out by reducing compound in inert solvent, and this step is carried out equally with preceding method B step B11.
Step D6 is the step of preparation compound (IIf), is undertaken by making compound (XXI) and compound (XXVIII) that the Suzuki linked reaction take place, and this step is carried out equally with preceding method B step B3.
Step D7 is the step of preparation compound (IIg), by solvent-free down or in inert solvent, in the presence of copper catalyst, an alkali metal salt of compound (XXVIII) and compound (XXIII) is reacted carry out, this step is carried out equally with preceding method B step B14.
Step D8 is the step that preparation has the compound of general formula (XLI), is undertaken by making compound (XXVIII) and compound (XXV) reaction, and this step is carried out equally with preceding method B step B1.
Step D9 is that Y has-step of the compound (IIa-1) of the group of Ya-O-in preparation compound (IIa), is undertaken by making compound (XLI) and compound (XXVII) reaction, and this step is carried out equally with preceding method B step B17.
Method E is midbody compound (XLIVa), (XLIVb), (La) and the method (Lb) of the compound (I) of preparation the present application.
Method E
In the following formula, R
1, R
2, R
3, R
4a, R
11, Ar, m be identical with aforementioned implication with Z.
Step e 1 is preparation general formula (XLIVa) or step (XLIVb); by in the existence of solvent or not; in the presence of lipase, the acylated hydroxy on one side that will have the compound of general formula (XLII) with the compound selective ground with general formula (XLIII) carries out.
Solvent used among the present invention is not particularly limited, it can only be compound (XLIII), optimal solvent is different and different with the kind of starting compound, can use various organic solvents, water-containing organic solvent, the ethers of preferred diisopropyl ether, t-butyl methyl ether, diethyl ether, tetrahydrofuran (THF) and so on; The aliphatic hydrocarbon of normal hexane, Skellysolve A and so on; The aromatic hydrocarbons of benzene, toluene and so on; And methylene dichloride, 1, the halogenated hydrocarbon of 2-ethylene dichloride and so on.More preferably ethers, most preferably diisopropyl ether.
Temperature of reaction is different and different with kind of starting compound, solvent for use, used lipase and compound (XLIII) etc., is generally-50 ℃ to 50 ℃, preferred 0 ℃ to 40 ℃.
Reaction times is also different and different with kind of starting compound, solvent for use, used lipase and compound (XLIII) etc., is generally 15 minutes to 150 hours, preferred 30 minutes to 24 hours.
After reaction finishes, can from reaction mixture, collect the target compound (XLIVa) of this reaction or (XLIVb) according to ordinary method.For example can obtain target compound: when having insolubles, it is removed by filter by following operation, former state concentrates or adds the immiscible organic solvent of entry and ethyl acetate and so on afterwards, separate the organic layer that contains target compound, through dryings such as anhydrous sodium sulphate, anhydrous magnesium sulfates, heat up in a steamer afterwards and desolvate.
If desired, can also perhaps carry out chromatography by ordinary method for example recrystallization, redeposition etc., with suitable eluent wash-out separate, purifying gained target compound.
Step e 2 is steps of compound that preparation has general formula (XLV), by in inert solvent, in the presence of oxygenant, the alcohol moiety of compound (XLIVa) is oxidized to aldehyde carries out.
As long as the used oxidizing reaction of this step can generate aldehyde by primary alconol, it is not particularly limited, its example has: the Collins oxidation of carrying out with pyridine and chromic acid in methylene dichloride; The PCC oxidation of in methylene dichloride, carrying out with pyridinium chlorochromate (PCC); The PDC oxidation of in methylene dichloride, carrying out with dichromic acid pyridine (PDC); The DMSO oxidation of Swern oxidation of in methylene dichloride, carrying out and so on electrophilic reagent (for example diacetyl oxide, trifluoroacetic anhydride, thionyl chloride, SULPHURYL CHLORIDE, oxalyl chloride, dicyclohexylcarbodiimide, diphenyl ketene-right-tolyl imines, N, N-diethyl amino ethyl-acetylene, sulfur trioxide pyridine complex etc.) and dimethyl sulfoxide (DMSO) (DMSO); And the Manganse Dioxide oxidation of in methylene dichloride or benzene, carrying out with Manganse Dioxide etc.
PCC oxidation of preferably in methylene dichloride, carrying out or Swern oxidation.
Temperature of reaction is different and different with the kind of starting compound, solvent, oxygenant etc., is generally-50 ℃ to 50 ℃, preferred-10 ℃ to 30 ℃.
Reaction times is different and different with the kind of starting compound, solvent, oxygenant, temperature of reaction etc., is generally 10 minutes to 2 days, preferred 30 minutes to 24 hours.
For example can obtain target compound: with in the sodium bisulfite water etc. and oxygenant by following operation, when having insolubles, it is removed by filter, former state concentrates or adds the immiscible organic solvent of entry and ethyl acetate and so on afterwards, separate the organic layer that contains target compound, through dryings such as anhydrous sodium sulphate, anhydrous magnesium sulfates, heat up in a steamer afterwards and desolvate.
If desired, can also perhaps carry out chromatography by ordinary method for example recrystallization, redeposition etc., with suitable eluent wash-out separate, purifying gained target compound.
Step e 3 is steps of compound that preparation has general formula (XLVII), by in inert solvent, in the presence of alkali, the aldehyde of compound (XLV) is reacted with the compound with general formula (XLVI) carry out.
Solvent for use only otherwise hinder reaction, dissolving raw material get final product to a certain extent, it is not particularly limited, preferably the aromatic hydrocarbons of benzene,toluene,xylene and so on; Methylene dichloride, chloroform, tetracol phenixin, 1, the halogenated hydrocarbon of 2-ethylene dichloride, chlorobenzene, dichlorobenzene and so on; The ethers of diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran (THF) and so on; The nitrile of acetonitrile, isopropyl cyanide and so on; Methane amide, N, the amides of dinethylformamide, N,N-dimethylacetamide, hexamethyl phosphoric triamide and so on; The sulfone class of dimethyl sulfoxide (DMSO), tetramethylene sulfone and so on.More preferably ethers.
Used alkali is not particularly limited it so long as the alkali that uses in reacting usually gets final product, the alkaline carbonate class of preferred yellow soda ash, salt of wormwood, Quilonum Retard and so on; The alkali metal hydrocarbonate class of sodium bicarbonate, saleratus, lithium bicarbonate and so on; The alkalimetal hydride class of lithium hydride, sodium hydride, potassium hydride KH and so on; The alkali metal hydroxide of sodium hydroxide, potassium hydroxide, hydrated barta, lithium hydroxide and so on; Inorganic bases such as the alkaline metal fluoride cpd class of Sodium Fluoride, Potassium monofluoride and so on; The alkali metal alcohol salt of sodium methylate, sodium ethylate, potassium methylate, potassium ethylate, potassium tert.-butoxide, lithium methoxide and so on; N-methylmorpholine, triethylamine, tripropyl amine, Tributylamine, diisopropyl ethyl amine, dicyclohexyl amine, N-methyl piperidine, 4-tetramethyleneimine pyridine, picoline, 4-(N, the N-dimethylamino) pyridine, 2,6-di-t-butyl-4-picoline, N, accelerine, N, N-Diethyl Aniline, 1,4-diazabicyclo [4.3.0] octane (DABCO), 1,8-diazabicyclo [5.4.0]-7-undecylene (DBU), 1, the organic amine of 5-diazabicyclo [4.3.0]-5-nonene (DBN) and so on; The perhaps organo-metallic bases of butyllithium, diisopropylaminoethyl lithium, two (trimethyl silyl) lithium amide and so on.More preferably alkali metal alcohol salt, alkalimetal hydride class and organo-metallic bases.
Temperature of reaction is different and different with starting compound, the kind of solvent, phosphonium salt, the kind of alkali etc., is generally-80 ℃ to 100 ℃, preferred-20 ℃ to 50 ℃.
Reaction times is different and different with starting compound, the kind of solvent, phosphonium salt, the kind of alkali etc., is generally 10 minutes to 2 days, preferred 30 minutes to 12 hours.
For example can obtain target compound: with neutralization reaction liquid such as dilute hydrochloric acid by following operation, when having insolubles, it is removed by filter, former state concentrates or adds the immiscible organic solvent of entry and ethyl acetate and so on afterwards, separate the organic layer that contains target compound, through dryings such as anhydrous sodium sulphate, anhydrous magnesium sulfates, heat up in a steamer afterwards and desolvate.
If desired, can also perhaps carry out chromatography by ordinary method for example recrystallization, redeposition etc., with suitable eluent wash-out separate, purifying gained target compound.
Step e 4 is steps that preparation has the compound of general formula (XLVIII), by in inert solvent, in the presence of alkali, compound (XLVII) hydrolysis is carried out.
Solvent for use only otherwise hinder reaction, dissolving raw material gets final product to a certain extent, it is not particularly limited the alcohols of particular methanol, ethanol and so on; The aromatic hydrocarbons of benzene,toluene,xylene and so on; The halogenated hydrocarbon of methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride and so on; The ethers of diethyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether, diglyme and so on; The perhaps mixed solvent of the mixed solvent of these solvents or these solvents and water.More preferably alcohols and ethers.
Used alkali is not particularly limited it so long as the alkali that uses in reacting usually gets final product, alkali metal hydroxides such as preferred sodium hydroxide, potassium hydroxide, lithium hydroxide, hydrated barta.
Temperature of reaction is different and different with the kind of starting compound, solvent, alkali etc., is generally-20 ℃ to 200 ℃, preferred 0 ℃ to 20 ℃.
Reaction times is different and different with the kind of starting compound, temperature of reaction, solvent, alkali etc., is generally 30 minutes to 48 hours, preferred 1 hour to 24 hours.
For example can obtain target compound: with neutralization reaction liquid such as dilute hydrochloric acid by following operation, when having insolubles, it is removed by filter, former state concentrates or adds the immiscible organic solvent of entry and ethyl acetate and so on afterwards, separate the organic layer that contains target compound, through dryings such as anhydrous sodium sulphate, anhydrous magnesium sulfates, heat up in a steamer afterwards and desolvate.
If desired, can also perhaps carry out chromatography by ordinary method for example recrystallization, redeposition etc., with suitable eluent wash-out separate, purifying gained target compound.
Step e 5 is steps that preparation has the compound of general formula (IL), and this step in the presence of alkali, changes into compound (IL) with compound (XLVIII) in inert solvent.
Solvent for use only otherwise hinder reaction, dissolving raw material get final product to a certain extent, it is not particularly limited, preferably the ethers of diethyl ether, diox, tetrahydrofuran (THF), glycol dimethyl ether, diglyme and so on; N, the amides of dinethylformamide, N,N-dimethylacetamide, N-N-methyl-2-2-pyrrolidone N-, N-Methyl pyrrolidone, hexamethyl phosphoric triamide and so on; The aromatic hydrocarbons of benzene,toluene,xylene and so on.More preferably ethers, amides.
Used alkali is not particularly limited it so long as the alkali that common reaction is used gets final product, the alkalimetal hydride class of preferred lithium hydride, sodium hydride, potassium hydride KH and so on; Inorganic bases such as the alkaline metal fluoride cpd class of Sodium Fluoride, Potassium monofluoride and so on; The alkali metal alcohol salt of sodium methylate, sodium ethylate, potassium methylate, potassium ethylate, potassium tert.-butoxide, lithium methoxide and so on; The perhaps organo-metallic bases of butyllithium, diisopropylaminoethyl lithium, two (trimethyl silyl) lithium amide and so on.More preferably alkali metal alcohol salt, alkalimetal hydride class.
Temperature of reaction is different and different with the kind of starting compound, solvent, alkali etc., is generally-80 ℃ to 100 ℃, preferred 0 ℃ to 50 ℃.
Reaction times is different and different with the kind of starting compound, temperature of reaction, solvent, alkali, is generally 5 minutes to 48 hours.
For example can obtain target compound: with neutralization reaction liquid such as dilute hydrochloric acid by following operation, when having insolubles, it is removed by filter, former state concentrates or adds the immiscible organic solvent of entry and ethyl acetate and so on afterwards, separate the organic layer that contains target compound, through dryings such as anhydrous sodium sulphate, anhydrous magnesium sulfates, heat up in a steamer afterwards and desolvate.
If desired, can also perhaps carry out chromatography by ordinary method for example recrystallization, redeposition etc., with suitable eluent wash-out separate, purifying gained target compound.
Step e 6 is R in the preparation compound (La)
1Be hydrogen atom and R
2And R
3aBe the step of compound (La-1) of the group of formula ((C=O)-) together, this step in the presence of reductive agent, changes into target compound (La-1) with compound (IL) in inert solvent.
Solvent for use only otherwise hinder reaction, dissolving raw material gets final product to a certain extent, it is not particularly limited the alcohols of preference such as methyl alcohol, ethanol, Virahol and so on; The ethers of diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran (THF), diox and so on; The aromatic hydrocarbons of benzene,toluene,xylene and so on; The aliphatic hydrocarbon of hexane, hexanaphthene and so on; The ester class of ethyl acetate, propyl acetate and so on.More preferably alcohols.
Used reductive agent does not have special restriction to it so long as be generally used for the reductive agent of catalytic reduction reaction and get final product, and preferably uses palladium on carbon, platinum oxide, platinum black, rhodium-aluminum oxide, triphenyl phosphine-rhodium chloride (Wilkinson complex), palladium-barium sulfate, Raney nickel.More preferably palladium on carbon.
Pressure is not particularly limited, under the 1-10 normal atmosphere, carries out usually.
Temperature of reaction is different and different with the kind of starting compound, solvent, alkali etc., is generally 0 ℃ to 100 ℃.
Reaction times is different and different with the kind of starting compound, temperature of reaction, solvent, alkali, is generally 5 minutes to 48 hours.
For example can obtain target compound: after removing by filter catalyzer by following operation, former state concentrates or adds the immiscible organic solvent of entry and ethyl acetate and so on, separate the organic layer that contains target compound,, heat up in a steamer afterwards and desolvate through dryings such as anhydrous sodium sulphate, anhydrous magnesium sulfates.
If desired, can also perhaps carry out chromatography by ordinary method for example recrystallization, redeposition etc., with suitable eluent wash-out separate, purifying gained target compound.
Step e 7 is steps that preparation has the compound of general formula (LI), and this step in the presence of reductive agent, changes into compound (LI) with compound (XLVII) in inert solvent, can carry out according to preceding method E step e 6.
Step e 8 is R in the preparation compound (La)
3aBe the step of the compound (La-2) of hydrogen atom, this step in inert solvent, in the presence of alkali, hydrolysis compound (LI), preparation compound (La-2) can carry out according to preceding method E step e 4.
Step e 9 is steps of preparation compound (La-1), and this step in the presence of alkali, by compound (La-2) preparation target compound (La-1), can be carried out according to preceding method E step e 5 in inert solvent.
Step e 10 is R in the preparation compound (La)
2And R
3aThe step of the compound (La-3) of expression ((C=O)-) group not together, hydroxyl by protection compound (La-2) carries out as required, this step is different and different with the protecting group of hydroxyl, can pass through for example Protective Groups in Organic Synthesis (third edition of used usually method, 1999, John Wiley ﹠amp; Sons, Inc. company distribution) method of describing in is carried out.
By replacing compound (XLIVa) with compound (XLIVb), carry out aforesaid method E step e 2-E10, can prepare compound (Lb).
Method F
In the following formula, Ar is identical with aforementioned implication with Z.
Step F 1 is the step of preparation compound (XLVI), by in inert solvent, the have general formula compound of (LII) and triphenyl phosphine is reacted carry out.
Used inert solvent in the above-mentioned reaction is not particularly limited it as long as this reaction is inertia, can be the aliphatic hydrocarbon of hexane, heptane, raw gasline, sherwood oil and so on for example; The aromatic hydrocarbons of benzene,toluene,xylene and so on; The halogenated hydrocarbon of methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, chlorobenzene, dichlorobenzene and so on; The ethers of diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether, diglyme and so on.Aromatic hydrocarbons class (most preferably benzene).
Temperature of reaction is different and different with starting compound, solvent types etc., ℃ carries out preferred 0 ℃ to 150 ℃ (most preferably 110 ℃) in room temperature to 200 usually.
Reaction times is mainly different and different with the kind of temperature of reaction, starting compound, solvent for use etc., is generally 5 minutes to 96 hours, preferred 15 minutes to 48 hours (most preferably 24 hours).
The target compound of each step of present method F can be as required, by with ordinary method, for example recrystallization, redeposition or customary way in the separation and purification of organic compound usually, for example using silica gel, aluminum oxide, magnesium-silicon glue is the adsorpting column chromatography method of Florisil and so on carrier; Use Sephadex LH-20 (manufacturing of Pharmaciaization department), Amberlite XAD-11 (Rohm ﹠amp; The manufacturing of Haas company), the method for the use synthetic adsorbents such as partition column chromatography of Diaion HP-20 (Mitsubishi changes into company and makes) and so on carrier, ion exchange chromatography, perhaps use the anti-phase column chromatography of positive (preferred high performance liquid chromatography (HPLC)) appropriate combination of silica gel or alkylated silica gel, separate with suitable eluent wash-out, purifying.
In addition, when needs separating isomerism body, after can finishing in the reaction of above steps, perhaps the suitable period after required step finishes, undertaken by above-mentioned separation purification method.
Starting compound (XXVIII), (XXXIV), (XLII), (XLIII) and (LII) be known or can easily prepare by currently known methods or similar approach.
The effect of invention
Aminoalcohol derivative with general formula (I) of the present invention, acceptable salt on its pharmacology, its ester or other derivative toxicity are low, have good immunosuppressive action, contain the compound with general formula (I) of the present invention, acceptable salt or its ester or other derivative can be used as systemic lupus erythematosus especially as the medicinal compositions of effective constituent on its pharmacology, rheumatoid arthritis, polymyositis, dermatomyositis, scleroderma, the Behcet disease, the Chron disease, ulcerative colitis, lupoid hepatitis, aplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, multiple sclerosis, the autoimmune bleb generates, psoriasis, vasculitis syndrome, the Wegener granuloma, uveitis, idiopathic interstitial pneumonia, Goodpasture syndrome, sarcoidosis, the allergic granuloma vasculitis, bronchial asthma, myocarditis, myocardosis, aortitis syndrome, postmyocardial infarction syndrome, primary pulmonary hypertension, microvariations type nephrosis, membranous nephropathy, the film proliferative glomerulonephritis, focal glomerular sclerosis, crescent one-tenth nephritis, myasthenia gravis, the inflammatory neuropathy, atopic dermatitis, chronic actinic dermatitis, acute polyarthritis, the Sydenham tarantism, Sjogren's syndrome, the adult diabetes mellitus, insulin-dependent diabetes, juvenile diabetes, atherosclerosis, glomerulonephritis, the uriniferous tubules interstitial nephritis, primary biliary cirrhosis, primary sclerosing cholangitis, fulminant hepatitis, viral hepatitis, GVHD, the immunological rejection that various organ transplantations cause, contact dermatitis, the preventive or the therapeutical agent of autoimmune disorderss such as septicemia or other immune correlated disease.
The new opticity amino alcohol compound of the present invention (La) and (Lb) the preparation intermediate of useful as drug.
As above-mentioned opticity amino alcohol compound (La) and synthetic intermediate (Lb); preferred opticity 2-replacement-2-amino-1; ammediol monoester derivates (XLIVa) or (XLIVb); described opticity 2-replacement-2-amino-1; ammediol monoester derivates (XLIVa) and (XLIVb) can be by with 2-replacement-2-amino-1; ammediol derivative (XLII) is as raw material; in the presence of lipase; use generating vinyl carboxylate ester derivative (XLIII) only with hydroxyl selectively acylating on one side, make with good yield easily and easily.
Utilizability on the industry
When acceptable salt or its ester are as above-mentioned therapeutical agent or preventive on the compound with general formula (I) of the present invention, its pharmacology, can mix with itself or with acceptable vehicle, thinner etc. on the suitable pharmacology, give with per os such as tablet, capsule, granule, powder or syrups, perhaps give with non-per os such as injection or suppositorys.
These preparations can use additives such as vehicle, lubricant, tackiness agent, disintegrating agent, stablizer, drug flavoring, thinner to prepare by well-known method, described vehicle has for example sugar derivativess such as lactose, sucrose, glucose, mannitol, Sorbitol Powder, starch derivative such as W-Gum, yam starch, α starch, dextrin, derivatived celluloses such as crystalline cellulose, Sudan Gum-arabic, dextran, amylopectin organic excipients such as (pullulan); And silicate derivative such as light silicon anhydride, synthetic aluminium silicate, Calucium Silicate powder, silicoaluminate magnesium, phosphoric acid salt such as secondary calcium phosphate, carbonate such as lime carbonate, inorganic excipients such as vitriol such as calcium sulfate.Described lubricant has for example Metallic stearates such as stearic acid, calcium stearate, Magnesium Stearate; Talcum; Colloided silica; Propolis; Wax classes such as spermaceti; Boric acid; Hexanodioic acid; Vitriol such as sodium sulfate; Glycol; Fumaric acid; Sodium Benzoate; The DL leucine; Fatty acid sodium salt; Lauryl sulfate such as Sodium Lauryl Sulphate BP/USP, lauryl magnesium sulfate; Silicic acid such as silicic anhydride, hydrate of silicic acid class; And above-mentioned starch derivative.Described tackiness agent has for example hydroxypropylcellulose, hypromellose, Polyvinylpyrolidone (PVP), polyoxyethylene glycol and the compound same with above-mentioned vehicle.Described disintegrating agent has for example derivatived celluloses such as low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethylcellulose, interior croscarmellose sodium; The farinose class of chemical modifications such as carboxymethyl starch, sodium starch glycolate, cross-linking polyethylene pyrrolidone.Described stablizer has for example parabens such as methyl p-hydroxybenzoate, propylparaben; Alcohols such as butylene-chlorohydrin, benzylalcohol, phenylethyl alcohol; Benzalkonium chloride; Phenols such as phenol, cresols; Thiomersalate; Dehydroacetic acid (DHA) and Sorbic Acid.Described drug flavoring has for example used usually sweeting agent, acidic flavoring agent, spices etc.
Its consumption is different and different with symptom, age etc., for the adult, gives lower limit 0.05mg every day (preferred 5mg), upper limit 200mg (preferred 40mg) during oral administration at every turn; When intravenous administration, give lower limit 0.01mg every day (preferred 1mg), upper limit 100mg (preferred 10mg) at every turn, divide every day according to symptom and carry out administration 1-6 time.
[best mode that carries out an invention]
The present invention will be described in more detail to provide embodiment and test case below, but scope of the present invention is not limited to this.
Embodiment 1
(2R)-and amino-2-methyl-4-[5-(5-cyclohexyl penta-1-alkynyl) thiophene-2-yl] fourth-1-alcohol
(exemplary compounds 1-770)
Embodiment 1 (a)
2-methyl-2-(2-thienyl) ethyl malonic acid diethylester
18.8g (0.43mol) sodium hydride (55%) is suspended in the dimethyl formamide (200ml), under ice-cooled condition, with 30 minutes slow 50.0g (0.29mol) methyl-malonic ester, restir 30 minutes of adding.Under nitrogen atmosphere,, under room temperature, stirred 4 hours more subsequently with dimethyl formamide (200ml) solution that added 75.2g (0.32mol) 2-(2-iodine ethyl) thiophene in 15 minutes.Reaction mixture is injected ice-cooled 10% hydrochloric acid (500ml), use ethyl acetate extraction.Wash organic layer with saturated brine, then through anhydrous magnesium sulfate drying.The concentrating under reduced pressure solvent passes through quick silica gel column chromatography (eluting solvent with resistates; Hexane: ethyl acetate=10: 1-5: 1) carry out purifying, obtain 53.1g (65%) and be the title compound of colorless oil.
Infrared absorption spectrum v
MaxCm
-1(CHCl
3): 2986,1726,1271,1252
Mass spectrum (FAB) m/z:285 ((M+H)
+).
Embodiment 1 (b)
2-methyl-2-(2-thienyl) ethyl malonic acid one ethyl ester
2-methyl-2-(2-thienyl) ethyl malonic acid diethylester that obtains among 52.7g (0.19mol) embodiment 1 (a) is dissolved in ethanol (240ml) and the water (80ml), under ice-cooled condition, adds 11.4g (0.20mol) potassium hydroxide, stirred 2 hours.Divided at interval with 1 hour again and add 5.7g (0.1mol) potassium hydroxide 3 times, stirred altogether 6 hours.Add entry (300ml) and ice-cooled 10% hydrochloric acid (500ml), use ethyl acetate extraction.Wash organic layer with saturated brine, then through anhydrous magnesium sulfate drying.The concentrating under reduced pressure solvent passes through quick silica gel column chromatography (eluting solvent with resistates; Hexane: ethyl acetate=2: 1-0: 1) carry out purifying, obtain 28.6g (60%) and be the title compound of faint yellow oily thing.
Infrared absorption spectrum v
MaxCm
-1(CHCl
3): 2987,1732,1712,1251,1109
Mass spectrum (FAB) m/z:257 ((M+H)
+).
Embodiment 1 (c)
2-first hydrogen carbonylamino-2-methyl-4-(2-thienyl) ethyl butyrate
2-methyl-2-(2-thienyl) ethyl malonic acid one ethyl ester that obtains among 19.0g (74.3mmol) embodiment 1 (b) is dissolved in the benzene (450ml), add 11.4ml (81.7mmol) triethylamine and 17.6ml (81.7mmol) diphenylphosphine acylazide, at room temperature stirred 10 minutes, and then stirred 1.5 hours in 80 ℃.Subsequently under same temperature, with 30 minutes slow 60.3ml (1.49mol) methyl alcohol, restir 8 hours of dripping.Reaction mixture is injected water (500ml), use ethyl acetate extraction.Wash organic layer with saturated brine, then through anhydrous magnesium sulfate drying.The concentrating under reduced pressure solvent passes through quick silica gel column chromatography (eluting solvent with resistates; Hexane: ethyl acetate=8: 1-4: 1) carry out purifying, obtain 14.7g (69%) and be the title compound of colorless oil.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3) δ ppm:7.11 (1H, d, J=5.1Hz), 6.90 (1H, dd, J=5.1,3.5Hz), 6.77 (1H, d, J=3.5Hz), 5.69 (1H, brs), 4.19 (2H, q.J=7.3Hz), 3.66 (3H, s), 2.84 (2H, dd, J=10.5,10.5Hz), 2.64 (2H, m), 2.20 (2H, dd, J=10.5,8.4Hz), 1.61 (3H, s), 1.28 (3H, t, J=7.3Hz)
Infrared absorption spectrum v
MaxCm
-1(CHCl
3); 3417,2987,1719,1503,1453,1081
Mass spectrum (FAB) m/z:286 ((M+H)
+).
Embodiment 1 (d)
2-methoxycarbonyl amino-2-methyl-4-(2-thienyl) fourth-1-alcohol
2-methoxycarbonyl amino-2-methyl-4-(2-thienyl) ethyl butyrate that obtains among 14.7g (51.6mmol) embodiment 1 (c) is dissolved in ethanol (150ml) and the tetrahydrofuran (THF) (100ml), add 5.07g (0.13mol) sodium borohydride and 5.68g (0.13mol) lithium chloride, under nitrogen atmosphere, room temperature, stir and spend the night.Add 5.07g (0.13mol) sodium borohydride and 5.68g (0.13mol) lithium chloride the next morning equally, and restir spends the night under nitrogen atmosphere, room temperature.Identical operations was carried out 2 more therewith.Reaction mixture is injected ice-cooled 10% hydrochloric acid (500ml), use ethyl acetate extraction.Wash organic layer with saturated brine, then through anhydrous magnesium sulfate drying.The concentrating under reduced pressure solvent passes through quick silica gel column chromatography (eluting solvent with resistates; Hexane: ethyl acetate=2: 1-1: 5) carry out purifying, obtain 11.7g (93%) and be the title compound of white crystals.
Infrared absorption spectrum v
MaxCm
-1(KBr): 3406,3244,1687,1562,1264,1089
Mass spectrum (FAB) m/z:244 ((M+H)
+)
The ultimate analysis value; (with respect to C
11H
17NO
3The % of S)
Calculated value: C:54.30, H:7.04, N:5.76, S:13.18
Measured value: C:54.18, H:6.98, N:5.78, S:13.34.
Embodiment 1 (e)
2-methoxycarbonyl amino-2-methyl-4-(5-bromothiophene-2-yl) fourth-1-alcohol
2-methoxycarbonyl amino-2-methyl-4-(2-thienyl) fourth-1-alcohol that obtains among 11.7g (48.0mmol) embodiment 1 (d) is dissolved in the dimethyl formamide (120ml), at ice-cooled 10.8g (60.8mmol) the N-bromine succinimide that adds down, under nitrogen atmosphere, room temperature, stirred 4 hours.Reaction mixture is injected ice-cooled 10% hydrochloric acid (300ml), use ethyl acetate extraction.Wash organic layer with saturated brine, then through anhydrous magnesium sulfate drying.The concentrating under reduced pressure solvent passes through quick silica gel column chromatography (eluting solvent with resistates; Hexane: ethyl acetate=4: 1-1: 3) carry out purifying, obtain 12.4g (80%) and be the title compound of faint yellow oily thing.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3) δ ppm:6.84 (1H, d, J=3.7Hz), 6.57 (1H, d, J=3.7Hz), 4.80 (1H, brs), 3.68 (2H, m), 3.64 (3H, s), 2.80 (2H, m), 1.9-2.2 (2H, m), 1.24 (3H, s)
Infrared absorption spectrum v
MaxCm
-1(CHCl
3): 3627,3436,2956,1722,1711,1513,1259,1087,1048
Mass spectrum (FAB) m/z:322 ((M+H)
+).
Embodiment 1 (f)
4-[2-(5-bromothiophene-2-yl)] ethyl-4-Jia Ji oxazolidine-2-ketone
2-methoxycarbonyl amino-2-methyl-4-(5-bromothiophene-2-yl) fourth-1-alcohol that obtains among 12.4g (38.6mmol) embodiment 1 (e) is dissolved in the dimethyl formamide (125ml), under ice-cooled, nitrogen atmosphere, add 6.50g (57.9mmol) potassium tert.-butoxide, stirred 3 hours down in uniform temp again.Reaction mixture is injected ice-cooled 10% hydrochloric acid (300ml), use ethyl acetate extraction.Wash organic layer with saturated brine, then through anhydrous magnesium sulfate drying.The concentrating under reduced pressure solvent passes through quick silica gel column chromatography (eluting solvent with resistates; Hexane: ethyl acetate=4: 1-1: 2) carry out purifying, obtain 10.7g (95%) and be the title compound of white crystals.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3) δ ppm:6.86 (1H, d, J=3.7Hz), 6.58 (1H, d, J=3.7Hz), 5.73 (1H, brs), 4.18 (1H, d, J=8.6Hz), 4.08 (1H, d, J=8.6Hz), 2.84 (2H, m), 1.94 (2H, m), 1.41 (3h, s)
Infrared absorption spectrum v
MaxCm
-1(KBr): 3211,1749,1399,1037,798
Mass spectrum (FAB) m/z:290 ((M+H)
+)
The ultimate analysis value; (with respect to C
10H
12NO
2The % of SBr)
Calculated value: C:41.39, H:4.17, N:4.83, S:11.05, Br:27.54
Measured value: C:41.36, H:4.04, N:4.82, S:11.08, Br:27.29.
Embodiment 1 (g)
(4R)-[2-(5-bromothiophene-2-yl)] ethyl-4-Jia Ji oxazolidine-2-ketone and (4S)-[2-(the 5-bromothiophene-
The 2-yl)] ethyl-4-Jia Ji oxazolidine-2-ketone
With the 4-[2-(5-bromothiophene-2-yl) that obtains among the embodiment 1 (f)] ethyl-4-Jia Ji oxazolidine-2-ketone carries out optical resolution (post, ChiralCel OD (2cm φ * 25cm) by preparation optically-active HPLC post (ChiralCel OD, Daicel); Eluting solvent, hexane: 2-propyl alcohol=70: 30; Flow velocity, 5ml/ minute).(55 minutes) of elder generation's wash-out are the 4S bodies, and (77 minutes) of back wash-out are the 4R bodies.In addition, determine absolute configuration by X ray analysis of crystal structure.
(4S) body; [α]
D 24-4.2 (c1.03, methyl alcohol)
(4R) body; [α]
D 24+ 4.2 (c1.00, methyl alcohol).
Embodiment 1 (h)
(4R)-2-[5-(5-cyclohexyl penta-1-alkynyl) thiophene-2-yl] } ethyl-4-Jia Ji oxazolidine-2-ketone
(4R)-[2-(5-bromothiophene-2-yl)] ethyl-4-Jia Ji oxazolidine-2-ketone that obtains among 450mg (1.55mmol) embodiment 1 (g) is dissolved in the 4.5ml dimethyl formamide, add 1.40g (4.65mmol) 5-cyclohexyl penta-1-alkynes (50% xylene solution), 2.16ml (15.5mmol) triethylamine, 30mg (0.16mmol) cupric iodide (I) and 109mg (0.16mmol) dichloro two (triphenyl phosphines) and close palladium, nitrogen atmosphere, 80 ℃ of following stirrings 2 hours.Reaction solution is poured in the water, used ethyl acetate extraction.Wash ethyl acetate layer with saturated brine, then with ethyl acetate layer through anhydrous sodium sulfate drying, decompression is afterwards heated up in a steamer and is desolvated.Resistates is passed through silica gel column chromatography (eluting solvent; Hexane: ethyl acetate=4: 1-3: 2) carry out purifying, obtain 456mg (82%) title compound.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3) δ ppm:6.92 (1H, d, J=3.6Hz), 6.63 (1H, d, J=3.6Hz), 5.45 (1H, brs), 4.18 (1H, d, J=8.6Hz), 4.07 (1H, d, J=8.6Hz), 2.78-2.90 (2H, m), 2.38 (2H, t, J=7.2Hz), 1.92-2.00 (2H, m), 1.55-1.75 (7H, m), 1.40 (3H, s), 1.10-1.35 (6H, m), 0.83-0.95 (2H, m)
Infrared absorption spectrum v
MaxCm
-1(KBr:3450,2925,2852,1758,1382,1046.
Embodiment 1 (i)
(2R)-and amino-2-methyl-4-[5-(5-cyclohexyl penta-1-alkynyl) thiophene-2-yl] fourth-1-alcohol
With (4R) that obtain among 456mg (1.27mmol) embodiment 1 (h)-(2-[5-(5-cyclohexyl penta-1-alkynyl) thiophene-2-yl] } ethyl-4-Jia Ji oxazolidine-2-ketone is dissolved in 1ml tetrahydrofuran (THF), the 2ml methyl alcohol, under ice-cooled, add 2ml 5N potassium hydroxide aqueous solution, reflux 18 hours.In reaction solution, add entry, use dichloromethane extraction.Through anhydrous sodium sulfate drying, decompression is heated up in a steamer and is desolvated then with dichloromethane layer.Resistates is passed through silica gel column chromatography (eluting solvent; Methylene dichloride: methyl alcohol=20: 1-methylene dichloride: methyl alcohol: ammoniacal liquor=10: 1: 0.1) carry out purifying, obtain 353mg (83%) title compound.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3) δ ppm:6.92 (1H, d, J=3.5Hz), 6.62 (1H, d, J=3.5Hz), 3.37 (1H, d, J=10.5Hz), 3.32 (1H, d, J=10.5Hz), 2.75-2.90 (2H, m), 2.38 (2H, t, J=7.1Hz), 1.52-1.79 (9H, m), 1.12-1.33 (6H, m), 1.11 (3H, s), 0.81-0.96 (2H, m)
Infrared absorption spectrum v
MaxCm
-1(CHCl
3): 2925,2852,1449,1041
Mass spectrum (FAB) m/z:334 ((M+H)
+)
The ultimate analysis value; (with respect to C
20H
31NOS0.3H
2The % of O)
Calculated value: C:70.87, H:9.40, N:4.13, S:9.46
Measured value: C:70.83, H:9.21, N:4.22, S:9.64
[α]
D 24-2.0 (c0.60, methyl alcohol).
Embodiment 2
(2R)-and amino-2-methyl-4-[5-(6-cyclohexyl oneself-1-alkynyl) thiophene-2-yl] fourth-1-alcohol
(exemplary compounds 1-882)
Operation obtains title compound similarly to Example 1.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3) δ ppm:6.91 (1H, d, J=3.6Hz), 6.62 (1H, d, J=3.6Hz), 3.39 (1H, d, J=10.7Hz), 3.34 (1H, d, J=10.7Hz), 2.82 (2H, t, J=8.5Hz), 2.40 (2H, t, J=6.9Hz), 2.18-1.92 (4H, m), 1.88-1.51 (8H, m), 1.47-1.38 (2H, m), 1.28-1.07 (9H, m), 0.93-0.78 (2H, m)
Infrared absorption spectrum v
MaxCm
-1(KBr): 3327,3275,2922,2850,1611,1563,1539,1447,1065,1040,803,521
Embodiment 3
2-amino-2-methyl-4-[5-(5-phenyl penta-1-alkynyl) thiophene-2-yl] fourth-1-alcohol
(exemplary compounds 1-824)
With racemic modification 4-[2-(5-bromothiophene-2-yl)] ethyl-4-Jia Ji oxazolidine-2-ketone makes raw material, and operation obtaining title compound similarly to Example 1.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3) δ ppm:7.32-7.26 (2H, m), 7.25-7.16 (3H, m), 6.94 (1H, d, J=3.6Hz), 6.93 (1H, d, J=3.6Hz), 3.37 (1H, d, J=10.8Hz), 3.31 (1H, d, J=10.4Hz), 2.83 (2H, t, J=8.4Hz), 2.77 (2H, t, J=7.6Hz), 2.42 (2H, t, J=7.2Hz), 1.96-1.85 (2H, m), 1.84-164 (2H, m), 1.50 (3H, brs), 1.11 (3H, s)
Infrared absorption spectrum v
MaxCm
-1(liquid film): 2931,2859,1748,1602,1584,1538,1496,1455,1191,1053,908,804,747,700,573.
Embodiment 4
2-amino-2-methyl-4-{5-[5-(4-p-methoxy-phenyl) penta-1-alkynyl] thiophene-2-yl } fourth-1-alkoxide
Hydrochlorate
(exemplary compounds 1-849)
With racemic modification 4-[2-(5-bromothiophene-2-yl)] ethyl-4-Jia Ji oxazolidine-2-ketone makes raw material, and operation obtaining title compound similarly to Example 1.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3) δ ppm:8.07 (3H, brs), 7.10 (2H, d, J=8.6Hz), 6.89 (1H, d, J=3.5Hz), 6.81 (2H, d, J=8.6Hz), 6.65 (1H, d, J=3.5Hz), 4.72 (1H, brs), 3.77 (3H, s), 3.65 (2H, s), 2.78-2.97 (2H, m), 2.66 (2H, t, J=7.5Hz), 2.36 (2H, t, J=7.1Hz), 1.77-2.20 (4H, m), 1.36 (3H, s)
Infrared absorption spectrum v
MaxCm
-1(KBr): 3370,3009,2932,1589,1511,1245,1070,1036.
Embodiment 5
2-amino-2-methyl-4-{5-[5-(4-fluorophenyl) penta-1-alkynyl] thiophene-2-yl } fourth-1-alcohol toxilic acid
Salt
(exemplary compounds 1-833)
With racemic modification 4-[2-(5-bromothiophene-2-yl)] ethyl-4 Jia Ji oxazolidine-2-ketone makes raw material, and operation obtaining title compound similarly to Example 1.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CD
3OD) δ ppm:7.18-7.25 (2H, m), 6.95-7.03 (2H, m), 6.94 (1H, d, J=3.6Hz), 6.73 (1H, d, J=3.6Hz), 6.26 (2H, and s) 3.61 (1H, d, J=11.6Hz), 3.52 (1H, d, J=11.6Hz), 2.80-2.95 (2H, m), 2.74 (2H, t, J=7.8Hz), 2.40 (2H, t, J=7.0Hz), 1.80-2.10 (4H, m), 1.31 (3H, s)
Infrared absorption spectrum v
MaxCm
-1(KBr): 3352,2940,1578,1509,1385,1367,1221,1194.
Embodiment 6
2-amino-2-methyl-4-[5-(biphenyl-4-yl) thiophene acetylene-2-yl] fourth-1-alcohol
(exemplary compounds 1-742)
With racemic modification 4-[2-(5-bromothiophene-2-yl)] ethyl-4-Jia Ji oxazolidine-2-ketone makes raw material, and operation obtaining title compound similarly to Example 1.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3) δ ppm:7.55-7.65 (6H, m), 7.43-7.50 (2H, m), 7.33-7.40 (1H, m), 7.11 (1H, d, J=3.6Hz), 6.72 (1H, d, J=3.6Hz), 3.39 (1H, d, J=10.4Hz), 3.34 (1H, d, J=10.4Hz), 2.80-2.95 (2H, m), 1.70-1.90 (2H, m), 1.13 (3H, s)
Infrared absorption spectrum v
MaxCm
-1(KBr): 3335,3075,2924,1485,1463,1051,837,809,764,698.
Embodiment 7
2-amino-2-methyl-4-[5-(4-butyl phenyl) thiophene acetylene-2-yl] fourth-1-alcohol
(exemplary compounds 1-737)
With racemic modification 4-[2-(5-bromothiophene-2-yl)] ethyl-4-Jia Ji oxazolidine-2-ketone makes raw material, and operation obtaining title compound similarly to Example 1.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3) δ ppm:7.42 (2H, d, J=8.1Hz), 7.36-7.15 (5H, m), 7.16 (2H, d, J=8.1Hz), 7.07 (1H, d, J=3.3Hz), 6.70 (1H, d, J=3.3Hz), 3.99 (2H, s), 3.36-3.24 (2H, m), 2.92-2.81 (2H, m), 201-1.95 (2H, m), 2.65-2.26 (3H, m), 1.11 (3H, s)
Infrared absorption spectrum v
MaxCm
-1(KBr): 3326,3264,2926,2904,1603,1541,1468,1454,1211,1063,1033,803,701.
Embodiment 8
2-amino-2-methyl-4-[5-(4-cyclohexyl phenyl) thiophene acetylene-2-yl] fourth-1-alcohol
(exemplary compounds 1-741)
With racemic modification 4-[2-(5-bromothiophene-2-yl)] ethyl-4-Jia Ji oxazolidine-2-ketone makes raw material, and operation obtaining title compound similarly to Example 1.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, DMSO-d
6) δ ppm:7.42 (2H, d, J=8.2Hz), 7.26 (2H, d, J=8.2Hz), 7.20 (1H, d, J=3.6Hz), 6.83 (1H, d, J=3.6Hz), 3.66-3.24 (5H, m), 2.88-2.70 (2H, m), 1.89-1.52 (7H, m), 1.43-1.21 (6H, m), 0.97 (3H, s)
Infrared absorption spectrum v
MaxCm
-1(KBr): 3326,3279,2924,2850,1645,1567,1539,1448,1385,1055,826,547.
Embodiment 9
2-amino-2-methyl-4-[5-(4-propyl group phenyl) thiophene acetylene-2-yl] fourth-1-alcohol
(exemplary compounds 1-736)
With racemic modification 4-[2-(5-bromothiophene-2-yl)] ethyl-4-Jia Ji oxazolidine-2-ketone makes raw material, and operation obtaining title compound similarly to Example 1.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CD
3OD) δ ppm:7.36 (2H, d, J=8.2Hz), 7.18 (2H, d, J=8.2Hz), 7.06 (1H, d, J=3.5Hz), 6.76 (1H, d, J=3.5Hz), 3.39 (1H, d, J=10.7Hz), 3.38 (1H, d, J=10.7Hz), 2.93-2.80 (2H, m), 2.69-2.58 (2H, m), 1.83-1.59 (4H, m), 1.10 (3H, s), 0.94 (3H, t, J=7.3Hz)
Infrared absorption spectrum v
MaxCm
-1(KBr): 3323,3267,2959,2929,2869,1611,1540,1510,1468,1213,1066,1035,816,804,510.
Embodiment 10
2-amino-2-methyl-4-[5-(4-propoxy-phenyl) thiophene acetylene-2-yl] fourth-1-alcohol
(exemplary compounds 1-740)
With racemic modification 4-[2-(5-bromothiophene-2-yl)] ethyl-4-Jia Ji oxazolidine-2-ketone makes raw material, and operation obtaining title compound similarly to Example 1.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CD
3OD) δ ppm:7.37 (2H, d, J=8.9Hz), 7.03 (1H, d, J=3.6Hz), 6.89 (2H, d, J=8.9Hz), 6.75 (1H, d, J=3.6Hz), 3.95 (2H, t, J=6.3Hz), 3.39 (1H, d, J=10.7Hz), 3.35 (1H, d, J=107Hz), and 2.92-2.78 (2H, m), 1.86-1.72 (4H, m), 1.09 (3H, s), 1.04 (3H, t, J=7.6Hz)
Infrared absorption spectrum v
MaxCm
-1(KBr): 3329,3275,2964,2936,1604,1509,1466,1249,1065,975,832,807.
Embodiment 11
(2R)-and amino-2-methyl-4-[5-(5-cyclohexyl amyl group) thiophene-2-yl] fourth-1-alcohol
(exemplary compounds 1-98)
With (2R)-amino-2-methyl-4-[5-(the 5-cyclohexyl penta-1-alkynyl) thiophene-2-yl that obtains among 175mg (0.53mmol) embodiment 1] fourth-1-alcohol is dissolved in the 9ml ethanol, adds the palladium on carbon of 90mg10%, under hydrogen atmosphere, stirred 2 days.Use the diatomite filtration palladium on carbon, filtrate is heated up in a steamer in decompression then, obtains 150mg (85%) title compound.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3) δ ppm:6.58 (1H, d, J=3.2Hz), 6.55 (1H, d, J=3.2Hz), 3.36 (1H, d, J=10.5Hz), 3.31 (1H, d, J=10.5Hz), 2.75-2.90 (2H, m), 2.73 (2H, t, J=7.6Hz), 1.59-1.83 (9H, m), 1.12-1.32 (10H, m), 1.11 (3H, s), 0.81-0.89 (2H, m)
Infrared absorption spectrum v
MaxCm
-1(CHCl
3): 2926,2853,1440,1042
Mass spectrum (FAB) m/z:338 ((M+H)
+)
The ultimate analysis value; (with respect to C
20H
35NOSH
2The % of O)
Calculated value: C:67.56, H:10.49, N:3.94, S:9.01
Measured value: C:67.11, H:10.03, N:3.93, S:8.88
[α]
D 24-0.7 (c3.03, methyl alcohol).
Embodiment 12
(2R)-and amino-2-methyl-4-[5-(6-cyclohexyl hexyl) thiophene-2-yl] fourth-1-alcohol
(exemplary compounds 1-210)
Use (2R)-amino-2-methyl-4-[5-of obtaining among the embodiment 2 (6-cyclohexyl oneself-1-alkynyl) thiophene-2-yl] fourth-1-alcohol, operation obtains title compound similarly to Example 11.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3) δ ppm:6.58 (1H, d, J=3.3Hz), 6.55 (1H, d, J=3.3Hz), 3.37 (1H, d, J=10.4Hz), 3.32 (1H, d, J=10.4Hz), 2.68-2.93 (4H, m), 1.05-1.85 (24H, m), 0.77-0.93 (2H, m)
Infrared absorption spectrum v
MaxCm
-1(KBr): 3334,3269,3159,2922,2850,1465,1448,1060
Mass spectrum (EI) m/z:351 (M
+)
The ultimate analysis value; (with respect to C
21H
37The % of NOS)
Calculated value: C:71.74, H:10.61, N:3.98, S:9.12
Measured value: C:71.47, H:10.48, N:3.98, S:9.37
[α]
D 24-1.3 (c1.15, methyl alcohol).
Embodiment 13
2-amino-2-methyl-4-[5-(5-phenylpentyl) thiophene-2-yl] fourth-1-alcohol
(exemplary compounds 1-152)
Use 2-amino-2-methyl-4-[5-(the 5-phenyl penta-1-alkynyl) thiophene-2-yl that obtains among the embodiment 3] fourth-1-alcohol, operation obtains title compound similarly to Example 11.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3) δ ppm:7.31-7.24 (2H, m), 7.20-7.14 (3H, m), 6.68 (1H, d, J=2.8Hz), 6.54 (1H, d, J=3.6Hz), 3.36 (1H, d, J=10.8Hz), 3.31 (1H, d, J=10.4Hz), 2.81 (2H, t, J=8.4Hz), 2.74 (2H, t, J=7.6Hz), 2.61 (2H, t, J=7.6Hz), 1.84-1.56 (6H, m), 1.52 (3H, brs), 1.46-1.37 (2H, m), 1.11 (3H, s)
Infrared absorption spectrum v
MaxCm
-1(KBr): 3333,3263,2927,2852,1496,1453,1059,969,928,798,747,699,569.
Embodiment 14
2-amino-2-methyl-4-{5-[5-(4-p-methoxy-phenyl) amyl group] thiophene-2-yl } fourth-1-alcohol
(exemplary compounds 1-177)
Use 2-amino-2-methyl-4-{5-[5-(4-p-methoxy-phenyl) penta-1-alkynyl that obtains among the embodiment 4] thiophene-2-yl } fourth-1-alcohol, operation obtains title compound similarly to Example 11.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3) δ ppm:7.08 (2H, d, J=8.5Hz), 6.82 (2H, d, J=8.5Hz), 6.58 (1H, d, J=3.3Hz), 6.54 (1H, d, J=3.3Hz), 3.79 (3H, s), 3.36 (1H, d, J=10.5Hz), 3.31 (1H, d, J=10.5Hz), 2.70-2.85 (4H, m), 2.55 (2H, t, J=7.7Hz), 1.55-1.85 (6H, m), 1.35-1.45 (2H, m), 1.11 (3H, s)
Infrared absorption spectrum v
MaxCm
-1(KBr): 3333,3263,3103,2926,2852,1514,1247,1061,1029.
Embodiment 15
2-amino-2-methyl-4-{5-[5-(4-fluorophenyl) amyl group] thiophene-2-yl } fourth-1-alcohol
(exemplary compounds 1-161)
Use 2-amino-2-methyl-4-{5-[5-(4-fluorophenyl) penta-1-alkynyl that obtains among the embodiment 5] thiophene-2-yl } fourth-1-alcohol, operation obtains title compound similarly to Example 11.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CD
3OD) δ ppm:7.12-7.18 (2H, m), 6.92-6.98 (2H, m), 6.63 (1H, d, J=3.5Hz), 6.56 (1H, d, J=3.5Hz), 6.25 (2H, s), 3.61 (1H, d, J=11.6Hz), 3.51 (1H, d, J=11.6Hz), 2.70-2.90 (4H, m), 2.58 (2H, t, J=7,6Hz), 1.88-2.03 (2H, m), and 1.57-1.70 (4H, m), 1.28-1.42 (5H, m)
Infrared absorption spectrum v
MaxCm
-1(KBr): 2929,2854,1578,1509,1464,1387,1356,1223.
Embodiment 16
2-amino-2-methyl-4-{5-[2-(biphenyl-4-yl) ethyl] thiophene-2-yl } fourth-1-alcohol
(exemplary compounds 1-44)
Use 2-amino-2-methyl-4-[5-(biphenyl-4-yl) thiophene acetylene-2-yl that obtains among the embodiment 6] fourth-1-alcohol, operation obtains title compound similarly to Example 11.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3) δ ppm:7.25-7.65 (9H, m), 6.60 (1H, d, J=3.5Hz), 6.59 (1H, d, J=3.5Hz), 3.37 (1H, d, J=10.5Hz), 3.32 (1H, d, J=10.5Hz), 3.06-3.15 (2H, m), 2.95-3.04 (2H, m), 2.75-2.90 (2H, m), 1.65-1.85 (2H, m), 1.12 (3H, s)
Infrared absorption spectrum v
MaxCm
-1(KBr): 3333,3265,2924,2852,1598,1486,1448,1059,798,695.
Embodiment 17
(2R)-and amino-2-methyl-4-[5-(5-cyclohexyl pentanoyl) thiophene-2-yl] fourth-1-alcohol
(exemplary compounds 1-1331)
With (2R)-amino-2-methyl-4-[5-(the 5-cyclohexyl penta-1-alkynyl) thiophene-2-yl that obtains among 126mg (0.41mmol) embodiment 1] fourth-1-alcohol is dissolved in the 2ml methyl alcohol, adds 2ml6N sulfuric acid, reflux 4 hours.After with the 1N aqueous sodium hydroxide solution reaction solution being adjusted to alkalescence, use dichloromethane extraction.Use the anhydrous sodium sulfate drying dichloromethane layer, decompression is heated up in a steamer and is desolvated then, obtains 130mg (91%) title compound.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3) δ 99m:7.54 (1H, d, J=3.7Hz), 6.84 (1H, d, J=3.7Hz), 3.39 (1H, d, J=10.4Hz), 3.34 (1H, d, J=10.4Hz), 2.78-2.98 (4H, m), 1.13 (3H, brs), 0.8-1.9 (19H, m)
Infrared absorption spectrum v
MaxCm
-1(KBr): 3332,3267,3134,2922,2851,1647,1 457,1057
Mass spectrum (EI) m/z:351 (M
+)
The ultimate analysis value; (with respect to C
20H
33NO
2The % of S)
Calculated value: C:68.33, H:9.46, N:3.98, S:9.12
Measured value: C:67.99, H:9.48, N:3.92, S:9.11
[α]
D 24-2.1 (c1.03, methyl alcohol).
Embodiment 18
(2R)-and amino-2-methyl-4-[5-(6-cyclohexyl caproyl) thiophene-2-yl] fourth-1-alcohol
(exemplary compounds 1-1357)
Use (2R)-amino-2-methyl-4-[5-of obtaining among the embodiment 2 (6-cyclohexyl oneself-1-alkynyl) thiophene-2-yl] fourth-1-alcohol, operation obtains title compound similarly to Example 17.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3) δ ppm:7.53 (1H, d, J=3.9Hz), 6.63 (1H, d, J=3.9Hz), 3.39 (1H, d, J=10.5Hz), 3.34 (1H, d, J=10.5Hz), 2.80-2.95 (4H, m), 1.33 (3H, brs), 0.8-1.9 (21H, m)
Infrared absorption spectrum v
MaxCm
-1(KBr): 3149,2922,2851,1654,1460,1059,922
Mass spectrum (BI) m/z:365 (M
+)
The ultimate analysis value; (with respect to C
21H
35NO
2The % of S)
Calculated value: C:69.00, H:9.65, N:3.83, S:8.77
Measured value: C:68.74, H:9.50, N:3.83, S:8.85
[α]
D 24-1.3 (c1.15, methyl alcohol).
Embodiment 19
2-amino-2-methyl-4-[5-(5-phenyl pentanoyl) thiophene-2-yl] fourth-1-alcohol hydrochloride
(exemplary compounds 1-1344)
Use 2-amino-2-methyl-4-[5-(the 5-phenyl penta-1-alkynyl) thiophene-2-yl that obtains among the embodiment 3] fourth-1-alcohol, operation obtains title compound similarly to Example 17.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CD
3OD) δ ppm:7.71 (1H, d, J=4.0Hz), 7.28-7.20 (2H, m), 7.20-7.10 (3H, m), 6.98 (1H, d, J=3.6Hz), 3.62 (1H, d, J=7.6Hz), 3.53 (1H, d, J=12.0Hz), and 3.04-2.88 (4H, m), 2.64 (2H, t, J=7.2Hz), and 2.15-2.04 (1H, m), 2.04-1.92 (1H, m), 1.78-1362 (4H, m), 1.32 (3H, s)
Infrared absorption spectrum v
MaxCm
-1(KBr): 3378,2927,1648,1588,1562,1504,1456,1230,1067,827,748,698,578.
Embodiment 20
2-amino-2-methyl-4-{5-[5-(4-fluorophenyl) pentanoyl] thiophene-2-yl } fourth-1-alcohol
(exemplary compounds 1-1348)
Use 2-amino-2-methyl-4-{5-[5-(4-fluorophenyl) penta-1-alkynyl that obtains among the embodiment 6] thiophene-2-yl } fourth-1-alcohol, operation obtains title compound similarly to Example 17.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3) δ ppm; 7.51 (1H, d, J=3.7Hz), 7.08-7.17 (2H, m), 6.90-7.00 (2H, m), 6.83 (1H, d, J=3.7Hz), 3.39 (1H, d, J=10.4Hz), 3.33 (1H, d, J=10.4Hz), 2.80-2.98 (4H, m), 2.62 (2H, t, J=7.5Hz), 1.60-1.90 (6H, m), 1.12 (3H, s)
Infrared absorption spectrum v
MaxCm
-1(KBr): 3178,2935,2858,1645,1455,1218,1058.
Embodiment 21
2-amino-2-methyl-4-[5-(biphenyl-4-yl) acetyl thiophene-2-yl] fourth-1-alcohol
(exemplary compounds 1-1326)
Use 2-amino-2-methyl-4-[5-(biphenyl-4-yl) thiophene acetylene-2-yl that obtains among the embodiment 6] fourth-1-alcohol, operation obtains title compound similarly to Example 17.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3) δ ppm:7.64 (1H, d, J=3.7Hz), 7.52-7.60 (4H, m), and 7.30-7.47 (5H, m), 6.86 (1H, d, J=3.7Hz), 4.18 (2H, s), 3.38 (1H, d, J=10.3Hz), 3.33 (1H, d, J=10.3Hz), 2.84-2.98 (2H, m) 1.70-1.87 (2H, m), 1.12 (3H, s)
Infrared absorption spectrum v
MaxCm
-1(KBr): 3420,2927,1654,1488,1455,1234,1058,751.
Embodiment 22
2-amino-2-methyl-4-[5-(5-phenyl penta-1-thiazolinyl) thiophene-2-yl] fourth-1-alcohol maleate
(exemplary compounds 1-670)
Embodiment 22 (a)
4-methyl-4-{2-[5-(5-phenyl penta-1-thiazolinyl) thiophene-2-yl] } Yi Ji oxazolidine-2-ketone
At room temperature, in 0.38ml (2.58mmol) 5-phenyl penta-1-alkynes, add 500mg (1.72mmol) catecholborane after, stirred 3 hours at 60 ℃.After reaction solution is cooled to room temperature, at room temperature in this reaction solution, adding synthetic 4-[2-(5-bromothiophene-2-yl) among 5.0ml toluene, 500mg (1.72mmol) embodiment 1 (f)] ethyl-4-Jia Ji oxazolidine-2-ketone, 119mg (0.17mmol) dichloro two (triphenyl phosphines) close palladium, 0.83ml (20% ethanolic soln) sodium ethylate.It was stirred 2 hours at 60 ℃.After reaction solution is cooled to room temperature, add 1N sodium hydroxide.It is used ethyl acetate extraction, water, saturated brine washing.Use the anhydrous sodium sulfate drying ethyl acetate layer, decompression is heated up in a steamer and is desolvated then.Resistates is passed through preparation thin-layer chromatography (eluting solvent; Hexane: ethyl acetate=1: 1) purifying obtains 378mg (68%) title compound.
Embodiment 22 (b)
2-amino-2-methyl-4-[5-(5-phenyl penta-1-thiazolinyl) thiophene-2-yl] fourth-1-alcohol maleate
By 4-methyl-4-{2-[5-(the 5-phenyl penta-1-thiazolinyl) thiophene-2-yl that will obtain among 370mg (1.15mmol) embodiment 22 (a)] } Yi Ji oxazolidine-2-ketone and the same being hydrolyzed of embodiment 1 (i), obtain 205mg (0.69mmol) 2-amino-2-methyl-4-[5-(5-phenyl penta-1-thiazolinyl) thiophene-2-yl] fourth-1-alcohol.With its making method, make the title compound of 160mg (34%) maleate form according to common maleate.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, DMSO-d
6) δ ppm; 7.83-7.70 (2H, m), 7.38-7.12 (5H, m), 6.78 (1H, d, J=3.5Hz), 6.71 (1H, d, J=3.5Hz), 6.50 (1H, d, J=15.6Hz), 6.02 (2H, s), 5.96-5.83 (1H, m), 5.52 (2H, brs), 5.36-5.10 (1H, m), 3.51-3.38 (2H, m), 2.83-2.58 (4H, m), 2.28-2.15 (2H, m), 1.88-1.63 (4H, m), 1.18 (3H, s)
Infrared absorption spectrum v
MaxCm
-1(KBr): 3026,2932,1579,1497,1386,1357,1194,1075,1012,865,699,570.
Embodiment 23
2-amino-2-methyl-4-[5-(5-cyclohexyl penta-1-thiazolinyl) thiophene-2-yl] fourth-1-alcohol
(exemplary compounds 1-657)
Operation obtains title compound similarly to Example 22.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3) δ ppm:6.64 (1H, d, J=3.5Hz), 6.61 (1H, d, J=3.5Hz), 6.41 (1H, d, J=15.7Hz), 5.95-5.88 (1H, m), 3.36 (1H, d, J=10.5Hz), 3.31 (1H, d, J=10.5Hz), and 2.86-2.73 (2H, m), 2.29-2.08 (2H, m), 1.83-1.55 (8H, m), 1.52-1.33 (4H, m), 1.30-1.12 (6H, m), 1.11 (3H, s), 0.92-0.79 (2H, m)
Infrared absorption spectrum v
MaxCm
-1(KBr): 3328,3275,2921,2850,1610,1447,1225,1066,1038,957,804,504.
Embodiment 24
2-amino-2-methyl-4-[5-(6-cyclohexyl oneself-1-thiazolinyl) thiophene-2-yl] fourth-1-alcohol maleate
(exemplary compounds 1-683)
Operation obtains title compound similarly to Example 22.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, DMSO-d
6) δ ppm:7.90-7.69 (2H, m), 6.77 (1H, d, J=3.4Hz), 6.70 (1H, d, J=3.4Hz), 6.47 (1H, d, J=15.8Hz), 6.04 (2H, s), 5.92-5.84 (1H, m), 5.55 (1H, brs), 3.49-3.32 (2H, m), 2.85-2.71 (2H, m), and 2.18-2.06 (2H, m), 1.96-1.53 (8H, m), 1.42-1.03 (14H, m), 0.93-0.78 (2H, m)
Infrared absorption spectrum v
MaxCm
-1(KBr): 3042,2924,2851,1695,1577,1533,1493,1477,1387,1362,1351,1210,1074,866.
Embodiment 25
2-amino-2-methyl-4-[4-(5-phenyl penta-1-alkynyl) thiophene-2-yl] fourth-1-alcohol hydrochloride
(exemplary compounds 2-185)
Embodiment 25 (a)
4-(5-phenyl penta-1-alkynyl) thiophene-2-formaldehyde
18.1g (126mmol) 5-phenyl penta-1-alkynes is dissolved in the 100ml tetrahydrofuran (THF), close palladium to wherein adding 18.7g (98mmol) 4-bromothiophene-2-formaldehyde, 150ml (1.07mol) triethylamine, 962mg (5.05mmol) cupric iodide (I), 3.54g (5.04mmol) dichloro two (triphenyl phosphines) that are dissolved in the 200ml tetrahydrofuran (THF), nitrogen atmosphere, 50 ℃ of following stirrings 4 hours.Filtering reacting liquid, filtrate is heated up in a steamer in decompression then.Add ether in resistates, water, saturated brine wash.With anhydrous sodium sulfate drying ether layer, decompression is heated up in a steamer and is desolvated then.Resistates is through silica gel column chromatography (eluting solvent; Hexane: ethyl acetate=100: 1-10: 1) purifying obtains 19.4g (78%) title compound.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3) δ ppm:9.88 (1H, s), 7.72 (1H, s), 7.71 (1H, s), 7.35-7.27 (2H, m), 7.24-7.16 (3H, m), 2.78 (2H, t, J=7.2Hz), 2.41 (2H, t, J=7.2Hz), 1.98-1.88 (2H, m)
Infrared absorption spectrum v
MaxCm
-1(liquid film): 2238,1679,1440,1234,1157,858,748,700,665,620
Mass spectrum (FAB) m/z:255 ((M+H)
+).
Embodiment 25 (b)
[4-(5-phenyl penta-1-alkynyl) thiophene-2-yl] methyl alcohol
4-(the 5-phenyl penta-1-alkynyl) thiophene-2-formaldehyde that obtains among 15.0g (59.0mmol) embodiment 25 (a) is dissolved in the 150ml methyl alcohol, under ice-cooled condition, adds 2.29g (60.5mmol) sodium borohydride.Under ice-cooled condition, stirred 25 minutes, decompression is heated up in a steamer and is desolvated then.In resistates, add entry, use ethyl acetate extraction, wash ethyl acetate layer with saturated brine.With the ethyl acetate layer anhydrous sodium sulfate drying, decompression is afterwards heated up in a steamer and is desolvated, and obtains 15.2g (99%) title compound.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3) δ ppm:7.34-7.27 (3H, m), 7.24-7.17 (3H, m), 6.98 (1H, s), 4.78 (2H, d, J=5.6Hz), 2.77 (2H, t, J=7.6Hz), 2.39 (2H, t, J=7.2Hz), 1.96-1.85 (2H, m), 1.77 (1H, t, J=5.6Hz)
Infrared absorption spectrum v
MaxCm
-1(liquid film): 3346,3026,2940,2861,2235,1602,1496,1455,1355,1182,1141,1013,844,748,700,626
Mass spectrum (FAB) m/z:256 (M
+).
Embodiment 25 (c)
[4-(5-phenyl penta-1-alkynyl) thiophene-2-yl] acetonitrile
With synthetic [4-(5-phenyl penta-1-alkynyl) thiophene-2-yl] dissolve with methanol among 4.68g (18.3mmol) embodiment 25 (b) in the 70ml tetrahydrofuran (THF), under ice-cooled condition, drip the tetrahydrofuran (THF) that 20ml has dissolved 0.69ml (7.30mmol) phosphorus tribromide.After drip finishing, under ice-cooled, nitrogen atmosphere, stirred 10 minutes.In reaction solution, add frozen water, use ethyl acetate extraction, with saturated sodium bicarbonate aqueous solution, saturated brine washing ethyl acetate layer.Use the anhydrous sodium sulfate drying ethyl acetate layer, decompression is heated up in a steamer and is desolvated then.Resistates is dissolved in the 120ml acetonitrile, under ice-cooled condition, adds 2.85g (18.3mmol) cyaniding tetraethyl ammonium, under nitrogen atmosphere, room temperature, stirred 1 hour.Reaction solution is poured in 5% sodium bicarbonate aqueous solution, used ethyl acetate extraction, wash ethyl acetate layer with saturated brine.Use the anhydrous sodium sulfate drying ethyl acetate layer, decompression is heated up in a steamer and is desolvated then.With resistates through silica gel column chromatography (eluting solvent; Hexane: ethyl acetate=20: 1-15: 1) purifying obtains 3.21g (66%) title compound.
NMR (Nuclear Magnetic Resonance) spectrum (270MHz, CDCl
3) δ ppm:7.15-7.35 (6H, m), 7.03 (1H, s), 3.86 (2H, s), 2.77 (2H, t, J=7.5Hz), 2.39 (2H, t, J=7.0Hz), 1.83-1.98 (2H, m)
Infrared absorption spectrum v
MaxCm
-1(CHCl
3): 3691,2946,2236,1603,1497,1454,1416,1361.
Embodiment 25 (d)
2-[4-(5-phenyl penta-1-alkynyl) thiophene-2-yl] ethanol
[4-(the 5-phenyl penta-1-alkynyl) thiophene-2-yl] acetonitrile that obtains among 3.21g (12.1mmol) embodiment 25 (c) is dissolved in the 15ml ethanol, under ice-cooled condition, add 1.70g (30.2mmol) potassium hydroxide that is dissolved in the 15ml water, reflux 2 hours.After with 1N hydrochloric acid reaction solution being adjusted to acidity, use ethyl acetate extraction.Through anhydrous sodium sulfate drying, decompression is heated up in a steamer and is desolvated then with ethyl acetate layer.The gained resistates is dissolved in the 15ml tetrahydrofuran (THF), adds 1.69ml (12.1mmol) triethylamine.Afterwards, down in reaction solution, drip the tetrahydrofuran (THF) that 15ml has dissolved 1.21ml (12.7mmol) Vinyl chloroformate, under ice-cooled, nitrogen atmosphere, stirred 30 minutes ice-cooled.Filter this reaction solution, under ice-cooled condition, gained filtrate is slowly added in the aqueous solution (10ml) of 2.29g (60.5mmol) sodium borohydride then, at room temperature stirred 3 days.After the reaction solution cooling, with 1N hydrochloric acid it is adjusted to acidity, use ethyl acetate extraction then, with 1N aqueous sodium hydroxide solution, saturated brine washing ethyl acetate layer.Behind anhydrous sodium sulfate drying, decompression is heated up in a steamer and is desolvated with ethyl acetate layer.With resistates through silica gel column chromatography (eluting solvent; Hexane: ethyl acetate=10: 1-4: 1) purifying obtains 2.74g (84%) title compound.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3) δ ppm:7.15-7.30 (6H, m), 6.86 (1H, s), 3.85 (2H, t, J=6.2Hz), 3.02 (2H, t, J=6.2Hz), 2.77 (2H, t, J=7.6Hz), 2.39 (2H, t, J=7.1Hz), 1.85-1.95 (2H, m)
Infrared absorption spectrum v
MaxCm
-1(CHCl
3): 3620,2947,1732,1603,1497,1454,1359,1250,1046.
Embodiment 25 (e)
2-(2-iodine ethyl)-4-(5-phenyl penta-1-alkynyl) thiophene
Use 2-[4-(the 5-phenyl penta-1-alkynyl) thiophene-2-yl that obtains among 2.69g (9.95mmol) embodiment 25 (d)] ethanol, with the same operation of embodiment 1 (g), make 3.45g (91%) title compound.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3) δ ppm:7.15-7.30 (6H, m), 6.84 (1H, s), 3.30-3.35 (4H, m), 2.77 (2H, t, J=7.6Hz), 2.39 (2H, t, J=7.0Hz), 1.85-1.95 (2H, m)
Infrared absorption spectrum v
MaxCm
-1(CHCl
3): 2946,2863,1603,1497,1454,1429,1360,1172.
Embodiment 25 (f)
2-methyl-2-[4-(5-phenyl penta-1-alkynyl) thiophene-2-yl] ethyl malonic acid one ethyl ester
1.57g (9.02mmol) methyl-malonic ester is dissolved in the 30ml dimethyl formamide, under ice-cooled condition, adds 0.38g (9.47mmol) sodium hydride, under room temperature, nitrogen atmosphere, stirred 1 hour afterwards.Under ice-cooled condition, in reaction solution, drip the dimethyl formamide that 30ml has dissolved gained 2-(2-iodine ethyl) among the embodiment 25 (e)-4-(5-phenyl penta-1-alkynyl) thiophene then, under room temperature, nitrogen atmosphere, stirred 4 hours.After the reaction solution cooling, with 1N hydrochloric acid it is adjusted to acidity, use ethyl acetate extraction then, with 1N aqueous sodium hydroxide solution, saturated brine washing ethyl acetate layer.Behind anhydrous sodium sulfate drying, decompression is heated up in a steamer and is desolvated with ethyl acetate layer.With resistates through silica gel column chromatography (eluting solvent; Hexane: ethyl acetate=50: 1-20: 1) partial purification.The gained mixture is dissolved in 9ml ethanol, the 1ml water, under ice-cooled condition, adds 0.80g (14.3mmol) potassium hydroxide, at room temperature stirred 3 days.With 1N hydrochloric acid reaction solution is adjusted to acidity, uses ethyl acetate extraction then.Behind anhydrous sodium sulfate drying, decompression is heated up in a steamer and is desolvated with ethyl acetate layer.With resistates through silica gel column chromatography (eluting solvent; Methylene dichloride: purifying methyl alcohol=50: 1) obtains 1.02g (28%) title compound.
NMR (Nuclear Magnetic Resonance) spectrum (500MHz, CDCl
3) δ ppm:7.15-7.30 (6H, m), 6.79 (1H, s), 4.23 (2H, q, J=7.1Hz), 2.60-2.85 (4H, m), 2.38 (2H, t, J=7.0Hz) 2.20-2.32 (2H, m), 1.86-1.94 (2H, m), 1.53 (3H, s), 1.29 (3H, t, J=7.1Hz)
Infrared absorption spectrum v
MaxCm
-1(CHCl
3): 3509,2944,1732,1713,1455,1377,1254,1181,1113.
Embodiment 25 (g)
2-methoxycarbonyl amino-2-methyl-4-[4-(5-phenyl penta-1-alkynyl) thiophene-2-yl] ethyl butyrate
Use 2-methyl-2-[4-(the 5-phenyl penta-1-alkynyl) thiophene-2-yl that obtains among 0.99g (2.48mmol) embodiment 25 (f)] ethyl malonic acid one ethyl ester, with the same operation of embodiment 1 (j), make 0.85g (80%) title compound.
NMR (Nuclear Magnetic Resonance) spectrum (500MHz, CDCl
3) δ ppm:7.15-7.30 (5H, m), 7.13 (1H, s), 6.75 (1H, s), 5.69 (1H, brs), 4.15-4.33 (2H, m), 3.66 (3H, s), 2.50-2.80 (5H, m), 2.38 (2H, t, J=7.0Hz), 2.15-2.23 (1H, m), 1.87-1.93 (2H, m), 1.60 (3H, s), 1.25-1.30 (3H, m)
Infrared absorption spectrum v
MaxCm
-1(CHCl
3): 3417,2987,2945,1719,1504,1453,1323,1077.
Embodiment 25 (h)
4-methyl-4-{2-[4-(5-phenyl penta-1-alkynyl) thiophene-2-yl] } Yi Ji oxazolidine-2-ketone
With 2-methoxycarbonyl amino-2-methyl-4-[4-(the 5-phenyl penta-1-alkynyl) thiophene-2-yl that obtains among 0.82g (1.92mmol) embodiment 25 (g)] ethyl butyrate is dissolved in 15ml ethanol, the 10ml tetrahydrofuran (THF), under ice-cooled condition, add 0.24g (5.75mmol) lithium chloride, 0.22g (5.75mmol) sodium borohydride, nitrogen atmosphere, 70 ℃ of following stirrings 2 hours.After the reaction solution cooling, with 1N hydrochloric acid it is adjusted to acidity, use ethyl acetate extraction then, wash ethyl acetate layer with saturated brine.Behind anhydrous sodium sulfate drying, decompression is heated up in a steamer and is desolvated with ethyl acetate layer.With resistates through silica gel column chromatography (eluting solvent; Hexane: ethyl acetate=4: 1-1: 1) purifying obtains 0.65g (96%) title compound.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3) δ ppm:7.15-7.35 (6H, m), 6.79 (1H, s), 5.38 (1H, brs), 4.18 (1H, d, J=8.6Hz), 4.08 (1H, d, J=8.6Hz), 2.80-2.90 (2H, m), 2.77 (2H, t, J=7.6Hz), 2.38 (2H, t, J=7.0Hz), 1.85-2.00 (4H, m), 1.41 (3H, s)
Infrared absorption spectrum v
MaxCm
-1(CHCl
3): 3450,2978,2945,1757,1497,1401,1382,1249,1046.
Embodiment 25 (i)
2-amino-2-methyl-4-[4-(5-phenyl penta-1-alkynyl) thiophene-2-yl] fourth-1-alcohol hydrochloride
With 4-methyl-4-{2-[4-(the 5-phenyl penta-1-alkynyl) thiophene-2-yl that obtains among 200mg (0.57mmol) embodiment 25 (h)] } Yi Ji oxazolidine-2-ketone is dissolved in the 1ml tetrahydrochysene and blows in the 2ml methyl alcohol of muttering, under ice-cooled condition, add 2ml 5N potassium hydroxide aqueous solution, reflux 18 hours.In reaction solution, add entry, use dichloromethane extraction.Behind anhydrous sodium sulfate drying, decompression is heated up in a steamer and is desolvated with dichloromethane layer.Resistates is dissolved in 2ml 1, in the 4-diox, under ice-cooled condition, adds 4N Yan Suan dioxane solution, heat up in a steamer and desolvate, wash the white solid that obtains with ether then, drying obtains 165mg (80%) title compound.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CD
3OD) δ ppm:7.15-7.30 (6H, m), 6.84 (1H, s), 3.61 (1H, d, J=11.5Hz), 3.52 (1H, d, J=11.5Hz), 2.80-2.95 (2H, m), 2.75 (2H, t, J=7.5Hz), 2.35 (2H, t, J=7.0Hz), 1.82-2.10 (4H, m), 1.32 (3H, s)
Infrared absorption spectrum v
MaxCm
-1(KBr): 3351,3027,2928,1594,1509,1455,1389,1062.
Embodiment 26
2-amino-2-methyl-4-[4-(5-phenylpentyl) thiophene-2-yl] fourth-1-alcohol hydrochloride
(exemplary compounds 2-39)
Embodiment 26 (a)
4-methyl-4-{2-[4-(5-phenylpentyl) thiophene-2-yl] } Yi Ji oxazolidine-2-ketone
With 4-methyl-4-{2-[4-(the 5-phenyl penta-1-alkynyl) thiophene-2-yl that obtains among 174mg (0.49mmol) embodiment 25 (h)] } Yi Ji oxazolidine-2-ketone is dissolved in the 9ml ethanol, adds 90mg 5% palladium on carbon, under hydrogen atmosphere, stirred 4 hours.Use the diatomite filtration catalyzer, filtrate is heated up in a steamer in decompression afterwards.Resistates is through silica gel column chromatography (eluting solvent; Hexane: ethyl acetate=1: 1) purifying obtains 164mg (93%) title compound.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3) δ ppm:7.25-7.30 (2H, m), 7.15-7.20 (3H, m), 6.70 (1H, s), 6.63 (1H, s), 5.33 (1H, brs), 4.18 (1H, d, J=8.6Hz), 4.07 (1H, d, J=8.6Hz), 2.80-2.90 (2H, m), 2.61 (2H, t, J=7.8.Hz), 2.53 (2H, t, J=7,7Hz), 1.93-2.02 (2H, m), and 1.55-1.70 (4H, m), 1.35-1.45 (5H, m)
Infrared absorption spectrum v
MaxCm
-1(CHCl
3): 3451,2977,2934,2858,1757,1400,1382,1045.
Embodiment 26 (b)
2-amino-2-methyl-4-[4-(5-phenylpentyl) thiophene-2-yl] fourth-1-alcohol hydrochloride
Use 4-methyl-4-{2-[4-(5-phenylpentyl) thiophene-2-yl that obtains among 136mg (0.38mmol) embodiment 26 (a)] } Yi Ji oxazolidine-2-ketone, with the same operation of embodiment 25 (i), obtain 107mg (76%) title compound.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3) δ ppm:7.10-7.30 (5H, m), 6.63 (1H, s), 6.61 (1H, s), 3.66 (2H, s), 2.80-2.95 (2H, m), 2.58 (2H, t, J=7.7Hz), 2.47 (2H, t, J=7.7Hz), and 2.00-2.18 (2H, m), 1.52-1.67 (4H, m), 1.25-1.45 (5H, m)
Infrared absorption spectrum v
MaxCm
-1(KBr): 3223,2929,2887,1606,1525,1455,1400,1054.
Embodiment 27
2-amino-2-methyl-4-[4-(5-phenyl pentanoyl) thiophene-2-yl] fourth-1-alcohol hydrochloride
(exemplary compounds 2-343)
With 2-amino-2-methyl-4-[4-(the 5-phenyl penta-1-alkynyl) thiophene-2-yl that obtains among 178mg (0.49mmol) embodiment 26 (i)] fourth-1-alcohol hydrochloride is dissolved in the 2ml methyl alcohol, adds 2ml 6N sulfuric acid, reflux 4 hours.After reaction solution is adjusted to alkalescence with the 1N aqueous sodium hydroxide solution, use dichloromethane extraction.Through the anhydrous sodium sulfate drying dichloromethane layer, decompression is afterwards heated up in a steamer and is desolvated.Resistates is dissolved in 2ml 1, in the 4-diox, under ice-cooled condition, adds 4N Yan Suan dioxane solution, heat up in a steamer and desolvate, wash the white solid that obtains with ether then, drying obtains 100mg (53%) title compound.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CD
3OD) δ ppm:8.14 (1H, s), 7.29 (1H, s), 7.10-7.27 (5H, m), 3.63 (1H, d, J=11.6Hz), 3.53 (1H, d, J=11.6Hz), 2.85-3.00 (4H, m), 2.64 (2H, t, J=7.0Hz), 1.92-2.13 (2H, m), 1.67-1.75 (4H, m), 1.33 (3H, s)
Infrared absorption spectrum v
MaxCm
-1(KBr): 3361,3026,2939,1666,1591,1456,1154,1072.
Embodiment 28
2-amino-2-ethyl-4-[5-(5-cyclohexyl penta-1-alkynyl) thiophene-2-yl] fourth-1-alcohol maleate
(exemplary compounds 1-1909)
Using racemic modification 4-[2-(5-bromothiophene-2-yl)] ethyl-4-Yi Ji oxazolidine-2-ketone makes raw material, and operation obtaining title compound similarly to Example 1.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CD
3OD) δ ppm:6.90 (1H, d, J=3.6Hz), 6.72 (1H, d, J=3.6Hz), 6.25 (2H, s), 3.61 (1H, d, J=11.7Hz), 3.57 (1Hd, J=11.7Hz), 2.75-2.90 (2H, m), 2.38 (2H, t, J=7.0Hz), 1.88-2.06 (2H, m), 1.52-1.82 (9H, m), 1.12-1.37 (6H, m), 0.85-1.04 (5H, m)
Infrared absorption spectrum v
MaxCm
-1(KBr): 3191,2922,2851,1576,1521,1386,1362,1193,1068
Embodiment 29
2-amino-2-ethyl-4-[5-(5-cyclohexyl amyl group) thiophene-2-yl] fourth-1-alcohol maleate
(exemplary compounds 1-1764)
Use 2-amino-2-ethyl-4-[5-(the 5-cyclohexyl penta-1-alkynyl) thiophene-2-yl that obtains among the embodiment 28] fourth-1-alcohol, operation obtains title compound similarly to Example 11.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CD
3OD) δ ppm:6.64 (1H, d, J=3.7Hz), 6.57 (1H, d, J=3.7Hz), 6.25 (2H, s), 3.61 (1H, d, J=11.8Hz), 3.57 (1H, d, J=11.8Hz), 2.70-2.87 (4H, m), and 1.88-2.05 (2H, m), 1.56-1.82 (9H, m), and 1.10-1.38 (10H, m), 0.99 (3H, t, J=7.5Hz), 0.81-0.93 (2H, m)
Infrared absorption spectrum v
MaxCm
-1(KBr): 3196,2923,2852,1581,1523,1385,1368,1193,1067,1016
Embodiment 30
2-amino-2-ethyl-4-[5-(5-cyclohexyl pentanoyl) thiophene-2-yl] fourth-1-alcohol maleate
(exemplary compounds 1-2097)
Use 2-amino-2-ethyl-4-[5-(the 5-cyclohexyl penta-1-alkynyl) thiophene-2-yl that obtains among the embodiment 28] fourth-1-alcohol, operation obtains title compound similarly to Example 17.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CD
3OD) δ ppm:7.72 (1H, d, J=3.7Hz), 6.99 (1H, d, J=3.7Hz), 6.25 (2H, s), 3.63 (1H, d, J=11.6Hz), 3.59 (1H, d, J=11.6Hz), 2.85-3.02 (4H, m), and 1.94-2.12 (2H, m), 1.60-1.83 (9H, m), and 1.10-1.42 (8H, m), 1.01 (3H, t, J=7.5Hz), 0.82-0.96 (2H, m)
Infrared absorption spectrum v
MaxCm
-1(KBr): 3395,2922,2851,1654,1582,1520,1458,1385,1370,1203,1067
Embodiment 31
(2R)-and amino-2-methyl-4-[5-(4-cyclohexyloxy fourth-1-alkynyl) thiophene-2-yl] fourth-1-alcohol Malaysia
Hydrochlorate
(exemplary compounds 1-1072)
Using 4-[2-(5-bromothiophene-2-yl)] ethyl-4-Jia Ji oxazolidine-2-ketone makes raw material, and operation obtaining title compound similarly to Example 1.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CD
3OD) δ ppm:6.93 (1H, d, J=3.6Hz), 6.73 (1H, d, J=3.6Hz), 6.25 (2H, s), 3.57-3.67 (3H, m), 3.51 (1H, d, J=11.6Hz), and 3.32-3.42 (1H, m), 2.78-2.95 (2H, m), 2.63 (2H, t, J=6.7Hz), 1.50-2.10 (7H, m), 1.17-1.37 (8H, m)
Infrared absorption spectrum v
MaxCm
-1(KBr): 3394,2932,2858,1583,1506,1386,1367,1194,1104
Embodiment 32
2-amino-2-methyl-4-[5-(4-cyclohexyl p-methoxy-phenyl) thiophene-2-yl] fourth-1-alcohol
(exemplary compounds 1-1729)
Using 4-[2-(5-bromothiophene-2-yl)] ethyl-4-Jia Ji oxazolidine-2-ketone makes raw material, and operation obtaining title compound similarly to Example 1.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CD
3OD) δ ppm:7.45 (2H, d, J=8.7Hz), 7.02 (1H, d, J=3.6Hz), 6.88 (2H, d, J=8.7Hz), 6.76 (1H, d, J=3.6Hz), 3.77 (2H, d, J=6.3Hz), 3.40 (1H, d, J=10.9Hz), 3.36 (1H, d, J=10.9Hz), and 2.91-2.79 (2H, m), 1.90-1.68 (8H, m), 1.41-1.08 (5H, m), 1.11 (3H, s)
Embodiment 33
2-amino-2-methyl-4-[5-(4-benzyloxy phenyl) thiophene-2-yl] fourth-1-alcohol
(exemplary compounds 1-1744)
Using 4-[2-(5-bromothiophene-2-yl)] ethyl-4-Jia Ji oxazolidine-2-ketone makes raw material, and operation obtaining title compound similarly to Example 1.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CD
3OD) δ ppm:7.51-7.27 (7H, m), 7.07 (1H, d, J=3.6Hz), 6.98 (2H, d, J=8.7Hz), 6.76 (1H, d, J=3.6Hz) 5.06 (2H, s), 3.44-3.38 (2H, m), 2.91-2.80 (2H, m), 1.86-1.74 (2H, m), 1.11 (3H, s)
Embodiment 34
(2R)-and amino-2-methyl-4-{5-[3-(4-methylphenoxy) proyl] thiophene-2-yl } fourth-1-alcohol
Maleate
(exemplary compounds 1-1063)
Operation obtains title compound similarly to Example 1.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CD
3OD) δ ppm:1.31 (3Hs), 1.88-2.10 (2H, m), 2.27 (3H, s), 2.80-2.95 (2H, m), 3.51 (1H, d, J=11.6Hz), 3.60 (1H, d, J=11.6Hz), 4.89 (2H, s), 6.25 (2H, s), 6.77 (1H, d, J=3.6Hz), 6.88 (2H, d, J=8.6Hz), 7.05 (1H, d, J=3.6Hz), 7.09 (2H, d, J=8.6Hz)
Infrared absorption spectrum v
MaxCm
-1(KBr:3338,3211,3006,2923,2229,1583,1511,1372,1228,1018
Embodiment 35
(2R)-and amino-2-methyl-4-{5-[3-(4-methylphenoxy) propyl group] thiophene-2-yl } fourth-1-alcohol horse
Come hydrochlorate
(exemplary compounds 1-391)
Use (2R)-amino-2-methyl-4-{5-[3-(4-methylphenoxy) proyl that obtains among the embodiment 34] thiophene-2-yl } fourth-1-alcohol maleate, operation obtains title compound similarly to Example 11.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CD
3OD) δ ppm:1.31 (3H, s), 1.88-2.10 (4H, m), 2.25 (3H, s), 2.77-2.92 (2H, m), 2.94 (2H, t, J=7.5Hz), 3.51 (1H, d, J=11.6Hz), 3.60 (1H, d, J=11.6Hz), 3.93 (2H, t, J=6.2Hz), 6.25 (2H, s), 6.62 (1H, d, J=3.3Hz), 6.65 (1H, d, J=3.3Hz), 6.77 (2H, d, J=8.5Hz) 7.04 (2H, d, J=8.5Hz)
Infrared absorption spectrum v
MaxCm
-1(KBr): 3412,3028,2947,2926,1577,1513,1387,1357,1239,1055
Embodiment 36
(2R)-and amino-2-methyl-4-{5-[3-(3-methylphenoxy) proyl] thiophene-2-yl } fourth-1-alcohol
Oxalate
(exemplary compounds 1-2276)
Operation obtains title compound similarly to Example 1.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CD
3OD) δ ppm:1.31 (3H, s), 1.90-2.10 (2H, m), 2.31 (3H, s), 2.82-2.96 (2H, m), 3.52 (1H, d, J=11.7Hz), 3.60 (1H, d, J=11.7Hz), 4.90 (2H, s), 6.73-6.85 (4H, m), 7.05 (1H, d, J=3.6Hz), 7.16 (1H, m)
Infrared absorption spectrum v
MaxCm
-1(KBr): 2923,2575,2226,1621,1583,1559,1489,1290,1255,1154,1045
Embodiment 37
(2R)-and amino-2-methyl-4-{5-[3-(4-ethylbenzene hydrogen base) proyl] thiophene-2-yl } fourth-1-alcohol
Maleate
(exemplary compounds 1-1064)
Operation obtains title compound similarly to Example 1.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CD
3OD) δ ppm:1.20 (3H, t, J=7.6Hz), 1.31 (3H, s), 1.88-2.10 (2H, m), 2.68 (2H, q, J=7.6Hz), 2.80-2.95 (2H, m), 3.51 (1H, d, J=11.5Hz), 3.60 (1H, d, J=11.5Hz), 4.89 (2H, s), 6.25 (2H, s), 6.77 (1H, d, J=3.6Hz), 6.90 (2H, d, J=8.6Hz), 7.05 (1H, d, J=3.6Hz), 7.12 (2H, d, J=8.6Hz)
Infrared absorption spectrum v
MaxCm
-1(KBr): 3385,2959,2928,2226,1581,1510,1384,1232,1020
Embodiment 38
(2R)-and amino-2-methyl-4-{5-[3-(4-methylthio group phenoxy group) proyl] thiophene-2-yl } fourth-1-alcohol
Maleate
(exemplary compounds 1-1068)
Operation obtains title compound similarly to Example 1.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CD
3OD) δ ppm:1.31 (3H, s), 1.88-2.10 (2H, m), 2.42 (3H, s), and 2.81-2.96 (2H, m), 3.51 (1H, d, J=11.5Hz), 3.60 (1H, d, J=11.5Hz), 4.92 (2H, s), 6.25 (2H, s), 6.78 (1H, d, J=3.6Hz), 6.96 (2H, d, J=8.9Hz), 7.06 (1H, d, J=3.6Hz), 7.27 (2H, d, J=8.9Hz)
Infrared absorption spectrum v
MaxCm
-1(KBr): 3401,2984,2918,2227,1575,1492,1376,1237,1011
Embodiment 39
(2R)-and amino-2-methyl-4-{5-[3-(3,5-dimethoxy phenoxy group) proyl] thiophene-2-yl } fourth-
1-alcohol fumarate
(exemplary compounds 1-2285)
Operation obtains title compound similarly to Example 1.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CD
3OD) δ ppm:1.31 (3H, s), 1.90-2.10 (2H, m), 2.82-2.96 (2H, m), 3.51 (1H, d, J=11.6Hz), 3.61 (1H, d, J=11.6Hz), 3.75 (6H, s), 4.89 (2H, s), 6.13 (1H, dd, J=2.2,2.2Hz), 6.43 (2H, d, J=2.2Hz), 6.69 (2H, s), 6.78 (1H, d, J=3.6Hz), 7.07 (1H, d, J=3.6Hz)
Infrared absorption spectrum v
MaxCm
-1(KBr): 3382,2936,2222,1682,1601,1476,1205,1152,1066
Embodiment 40
(2R)-and amino-2-methyl-4-{5-[3-(3,4-dimethoxy phenoxy group) proyl] thiophene-2-yl } fourth-
1-alcohol maleate
(exemplary compounds 1-2284)
Operation obtains title compound similarly to Example 1.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CD
3OD) δ ppm:1.31 (3H, s), 1.88-2.10 (2H, m), 2.81-2.95 (2H, m), 3.51 (1H, d, J=11.4Hz), 3.61 (1H, d, J=11.4Hz), 3.78 (3H, s), 3.81 (3H, s), 4.88 (2H, s), 6.25 (2H, s), 6.54 (1H, dd, J=8.7,2.7Hz), 6.66 (1H, d, J=2.7Hz), 6.78 (1H, d, J=3.6Hz), 6.87 (1H, d, J=8.7Hz), 7.05 (1H, d, J=3.6Hz)
Infrared absorption spectrum v
MaxCm
-1(KBr): 3361,2934,2221,1581,1512,1385,1369,1228,1196,1023
Embodiment 41
(2R)-and amino-2-methyl-4-{ 5-[3-(4-ethanoyl phenoxy group) proyl] thiophene-2-yl } fourth-1-alcohol
(exemplary compounds 1-2288)
Operation obtains title compound similarly to Example 1.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CD
3OD) δ ppm:1.07 (3H, s), 1.68-1.82 (2H, m), 2.56 (3H, s), and 2.77-2.91 (2H, m), 3.33 (1H, d, J=11.0Hz), 3.36 (1H, d, J=11.0Hz), 5.05 (2H, s), 6.73 (1H, d, J=3.6Hz), 7.04 (1H, d, J=3.6Hz), 7.10 (2H, d, J=9.0Hz), 8.00 (2H, d, J=9.0Hz)
Infrared absorption spectrum v
MaxCm
-1(KBr): 3351,3315,3287,2916,2878,2734,2229,1673,1599,1376,1364,12553,1174
Embodiment 42
(2R)-and amino-2-methyl-4-{5-[3-(4-carboxyl phenoxy group) proyl] thiophene-2-yl } fourth-1-alcohol
Hydrochloride
(exemplary compounds 1-2289)
Operation obtains title compound similarly to Example 1.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CD
3OD) δ ppm:1.31 (3H, s), 1.90-2.10 (2H, m), 2.82-2.96 (2H, m), 3.51 (1H, d, J=11.5Hz), 3.61 (1H, d, J=11.5Hz), 5.04 (2H, s), 6.79 (1H, d, J=3.7Hz), 7.05-7.11 (3H, m), 7.99 (2H, d, J=8.8Hz)
Infrared absorption spectrum v
MaxCm
-1(KBr): 3383,3064,2226,1699,1604,1508,1379,1233,1170,1002
Embodiment 43
(2R)-and amino-2-methyl-4-{5-[3-(3-methoxyl group phenoxy group) proyl] thiophene-2-yl } fourth-1-alcohol
Maleate
(exemplary compounds 1-2283)
Operation obtains title compound similarly to Example 1.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CD
2OD) δ ppm:1.31 (3H, s), 1.88-2.10 (2H, m), 2.80-2.96 (2H, m), 3.51 (1H, d, J=11.6Hz), 3.60 (1H, d, J=11.6Hz), 3.77 (3H, s), 4.91 (2H, s), 6.25 (2H, s), 6.52-6.61 (3H, m), 6.78 (1H, d, J=3.6Hz), 7.06 (1H, d, J=3.6Hz), 7.18 (1H, t, J=8.4Hz)
Infrared absorption spectrum v
MaxCm
-1(KBr): 3005,2940,2223,1583,1493,1387,1362,1284,1191,1153,1080,1045,1020,866,813,758,687,565
Embodiment 44
(2R)-and amino-2-methyl-4-{5-[4-(4-methylphenoxy) fourth-1-alkynyl] thiophene-2-yl } fourth-1-alcohol
Maleate
(exemplary compounds 1-1139)
Operation obtains title compound similarly to Example 1.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CD
3OD) δ ppm:1.31 (3H, s), 1.87-2.10 (2H, m), 2.26 (3H, s), 2.85 (2H, t, J=6.8Hz), 2.78-2.95 (2H, m), 3.51 (1H, d, J=11.6Hz), 3.61 (1H, d, J=11.6Hz), 4.09 (2H, t, J=6.8Hz), 6.25 (2H, s), 6.73 (1H, d, J=3.6Hz), 6.82 (2H, d, J=8.4Hz), 6.96 (1H, d, J=3.6Hz), 7.07 (2H, d, J=8.4Hz)
Infrared absorption spectrum v
MaxCm
-1(KBr): 3032,2925,2596,1578,1513,1388,1359,1293,1244,1205,1176,1079,1039,867,812,509
Embodiment 45
(2R)-and amino-2-methyl-4-{5-[4-(4-fluorophenoxy) fourth-1-alkynyl] thiophene-2-yl } fourth-1-alcohol
(exemplary compounds 1-1135)
Operation obtains title compound similarly to Example 1.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CD
3OD) δ ppm:1.15 (3H, s), 1.72-1.89 (2H, m), 2.22 (3H, brs), 2.88 (2H, t, J=6.8Hz), 2.76-2.93 (2H, m), 3.37 (1H, d, J=10.8Hz), 3.42 (1H, d, J=10.8Hz), 4.11 (2H, t, J=6.8Hz), 6.64 (1H, d, J=3.6Hz), 6.84-6.90 (2H, m), 6.93-7.03 (3H, m)
Infrared absorption spectrum v
MaxCm
-1(KBr): 3356,3296,3090,2971,2950,2916,2896,2877,2812,2735,1589,1506,1465,1389,1289,1245,1219,1203,1154,1065,1039,974,923,831,819,742,568,523,509
Embodiment 46
(2R)-and amino-2-methyl-4-{5-[3-(3, the 4-dimethyl phenoxy) proyl] thiophene-2-yl } fourth-1-
The alcohol maleate
(exemplary compounds 1-2278)
Operation obtains title compound similarly to Example 1.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CD
3OD) δ ppm:1.31 (3H, s), 1.90-2.09 (2H, m), 2.19 (3H, s), 2.23 (3H, s), 2.81-2.94 (2H, m), 3.31 (1H, s), 3.51 (1H, d, J=11.6Hz), 3.61 (1H, d, J=11.6Hz), 4.87 (2H, s), 6.25 (2H, s), 6.70-6.78 (3H, m), 7.01-7.04 (2H, m)
Infrared absorption spectrum v
MaxCm
-1(liquid film): 3353,3022,2971,2923,2226,1579,1500,1385,1368,1287,1249,1205,1165,1120,1077,1039,930,865,806,713,573,446
Embodiment 47
(2R)-and 2-amino-2-methyl-4-[2-(3-phenyl propoxy-) thiophene-5-yl] fourth-1-alcohol winestone hydrochlorate
(exemplary compounds 1-2395)
Embodiment 47 (a)
(2R)-amino-2-methyl-4-thiophene-2-Ji Ding-1-alcohol 1/2D-(-)-tartrate
(4R)-methyl-4-[2-(thiophene-2-yl)] Yi Ji oxazolidine-2-ketone of the 85%ee that obtains among 7.30g (34.6mmol) embodiment 56 is dissolved in 35ml tetrahydrofuran (THF) and the 70ml methyl alcohol, under ice-cooled condition, add 70ml 5N potassium hydroxide aqueous solution, stirred 2 days at 80 ℃.In reaction solution, add methylene dichloride, wash with water.Through anhydrous magnesium sulfate drying, decompression is heated up in a steamer and is desolvated with dichloromethane layer.6.20g gained resistates is dissolved in the 60ml ethanol, adds 5.19g (34.6mmol) D-(-)-tartaric 50ml ethanolic soln, filter the precipitation that obtains separating out, obtain the rough title compound of 7.56g.With 75ml ethanol and 50ml water the rough target compound of 7.54g gained is carried out recrystallization, obtain the title compound of 5.89g (98%ee).With 60ml ethanol and 54ml water 5.88g gained target compound is carried out recrystallization once more, obtain the title compound of 5.11g (57%, 99.7%ee).
Infrared absorption spectrum v
MaxCm
-1(KHr): 3400,3218,3126,2937,2596,1599,1530,1400,1124,1077,715
The ultimate analysis value; (with respect to C
9H
15NOS0.5C
4H
4O
6%)
Calculated value: C, 50.95; H, 6.61; N, 5.40; S, 12.36
Measured value: C, 50.68; H, 6.91; N, 5.38; S, 12.48
[α]
D 24-14(c1.00，H
2O)
Embodiment 47 (b)
(2R)-acetate acetylamino-2-methyl-4-(thiophene-2-yl) butyl ester
Under ice-cooled, add 30ml 1N aqueous sodium hydroxide solution in (2R)-amino-2-methyl-4-thiophene-2-Ji Ding of gained in 5.11g (19.6mmol) embodiment 47 (a)-1-alcohol 1/2D-(-)-tartrate, after making it become free form, use dichloromethane extraction.Dichloromethane layer is behind anhydrous sodium sulfate drying, and decompression is heated up in a steamer and desolvated, obtain 3.55g (98%) (2R)-amino-2-methyl-4-thiophene-2-Ji Ding-1-alcohol.In 1.51g (8.15mmol) gained (2R)-amino-2-methyl-4-(thiophene-2-yl) fourth-1-alcohol, add the 30ml pyridine, under ice-cooled, to wherein adding 1.95ml (20.7mmol) diacetyl oxide, 200mg (1.64mmol) 4-(dimethylamino) pyridine.Under nitrogen atmosphere, room temperature, stirred 2.5 hours.Reaction solution is poured under ice-cooled in the 150ml 1N hydrochloric acid, used ethyl acetate extraction, wash ethyl acetate layer successively with 1N hydrochloric acid, saturated brine.Ethyl acetate layer is behind anhydrous sodium sulfate drying, and decompression is heated up in a steamer and desolvated.With resistates through silica gel column chromatography (eluting solvent; Hexane: ethyl acetate=3: 1-1: 2) purifying obtains 2.15g (98%) title compound.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3): δ 1.37 (3H, s), 1.93 (3H, s), 1.94-2.10 (1H, m), 2.10 (3H, s), 2.24-2.38 (1H, m), 2.85 (2H, t, J=8.0Hz), 4.18 (1H, d, J=11.6Hz), 4.32 (1H, d, J=11.6Hz), 5.39 (1H, brs), 6.81 (1H, dd, J=1.2,3.6Hz), 6.92 (1H, dd, J=3.6,5.2Hz), 7.12 (1H, dd, J=1.2,5.2Hz)
Infrared absorption spectrum v
MaxCm
-1(KBr): 3265,3079,2933,2862,1735,1638,1559,1472,1441,1374,1318,1241,1179,1039,701,616
Embodiment 47 (c)
(2R)-acetate acetylamino-2-methyl-4-(5-bromothiophene-2-yl) butyl ester
(2R)-acetate acetylamino-2-methyl-4-(thiophene-2-yl) butyl ester that obtains among 1.81g (6.70mmol) embodiment 47 (b) is dissolved in the 20ml dimethyl formamide; under ice-cooled condition; add 1.27g (7.11mmol) N-bromine succinimide; nitrogen atmosphere, ice-cooled stirring down 10 minutes, under room temperature, stir diel.Reaction solution is poured in the water, used ethyl acetate extraction, ethyl acetate layer is washed with saturated brine.Ethyl acetate layer is behind anhydrous sodium sulfate drying, and decompression is heated up in a steamer and desolvated.With resistates through silica gel column chromatography (eluting solvent; Hexane: ethyl acetate=3: 1-1: 2) purifying obtains 2.32g (99%) title compound.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3): δ 1.35 (3H, s), 1.95 (3H, s), 1.95-2.08 (1H, m), 2.10 (3H, s), 2.24-2.37 (1H, m), 2.76 (2H, t, J=8.4Hz), 4.15 (1H, d, J=11.2Hz), 4.30 (1H, d, J=11.2Hz), 5.39 (1H, brs), 6.57 (1H, d, J=3.6Hz), 6.84 (1H, d, J=3.6Hz)
Infrared absorption spectrum v
MaxCm
-1(liquid film): 3300,3076,2980,2937,1740,1657,1544,1466,1446,1373,1242,1045,794,604
Embodiment 47 (d)
(2R)-and 2-amino-2-methyl-4-[2-(3-phenyl propoxy-) thiophene-5-yl] fourth-1-alcohol winestone hydrochlorate
(0.06g 2.6mmol), slowly heats up, and stirs 3 hours down at 80 ℃ to 90 ℃ to add sodium in 3-phenyl-1-propyl alcohol (1ml).Put cold; (the 2R)-acetate acetylamino-2-methyl-4-that in wherein adding embodiment 47 (c), obtains (5-bromothiophene-2-yl) butyl ester (0.177g, 0.51mmol), potassiumiodide (0.8mg, 0.005mmol) and cupric oxide (II) (21.0mg; 0.26mmol), stirred 19 hours at 90 ℃.After the cooling, with reaction solution silica gel column chromatography (eluting solvent; Methylene dichloride: methyl alcohol: triethylamine, 10: 1: 0-100: 10: 1, V/V/V) with alkaline silica gel column chromatography (eluting solvent; Methylene dichloride: methyl alcohol, 100: 1, V/V) carry out purifying, obtain (2R)-2-amino-2-methyl-4-[2-(3-phenyl propoxy-) thiophene-5-yl] fourth-1-alcohol (9.1mg, yield 6%).
With gained (2R)-2-amino-2-methyl-4-[2-(3-phenyl propoxy-) thiophene-5-yl] (15.2mg 0.048mmol) is dissolved in the methyl alcohol (1ml) fourth-1-alcohol, and (4.5mg 0.049mmol), at room temperature stirred 1.5 hours to add tartrate.Concentrating under reduced pressure to wherein adding ethyl acetate, filters the crystallization that obtains separating out, and washs after drying with ethyl acetate, obtains target compound (18.5mg, 95%).
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CD
3OD) δ ppm:1.30 (3H, s), 1.86-2.07 (4H, m), 2.68-2.79 (4H, m), 3.51 (1H, d, J=11.6Hz), 3.59 (1H, d, J=11.6Hz), 3.97 (2H, t, J=6.5Hz), 6.00 (1H, d, J=3.7Hz), 6.44 (1H, d, J=3.7Hz), 7.14-7.28 (5H, m)
Mass spectrum (ESI) m/z:342. (M+Na)
+, 320 (M+H)
+
Embodiment 48
(2R)-and amino-2-methyl-4-{5-[3-(3-ethanoyl phenoxy group) proyl] thiophene-2-yl } fourth-1-alcohol
Oxalate
(exemplary compounds 1-2287)
Operation obtains title compound similarly to Example 1.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CD
3OD): δ 1.31 (3H, s), 1.88-2.10 (2H, m), 2.60 (3H, s), and 2.82-2.95 (2H, m), 3.51 (1H, d, J=11.6Hz), 3.60 (1H, d, J=11.6Hz), 5.02 (2H, s), 6.78 (1H, d, J=3.6Hz), 7.06 (1H, d, J=3.6Hz), 7.26 (1H, m), 7.44 (1H, m), 7.61-7.67 (2H, m)
Infrared absorption spectrum v
MaxCm
-1(KBr): 3346,3213,2929,2224,1679,1596,1582,1277,1205,721
Embodiment 49
(2R)-and amino-2-methyl-4-[5-(5-phenyl penta-1-alkynyl) thiophene-2-yl] fourth-1-alcohol oxalate
(exemplary compounds 1-824)
Embodiment 49 (a)
(2R)-and acetate acetylamino-2-methyl-4-[5-(5-phenyl penta-1-alkynyl) thiophene-2-yl] butyl ester
Synthetic (2R) among 1.60g (4.59mmol) embodiment 47 (c)-acetate acetylamino-2-methyl-4-(5-bromothiophene-2-yl) butyl ester is dissolved in the 16ml dimethyl formamide; add 1.99g (13.8mmol) 5-phenyl penta-1-alkynes, 6.40ml (45.9mmol) triethylamine, 175mg (0.92mmol) cupric iodide (I) and 322mg (0.46mmol) dichloro two (triphenyl phosphines) and close palladium, nitrogen atmosphere, 80 ℃ of following stirrings 2 hours.Reaction solution is poured in the water, used ethyl acetate extraction, ethyl acetate layer is behind anhydrous magnesium sulfate drying, and decompression is heated up in a steamer and desolvated.With resistates through silica gel column chromatography (eluting solvent; Hexane: ethyl acetate=2: 1-2: 3) purifying obtains 1.41g (75%) title compound.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3): δ 1.36 (3H, s), 1.85-2.05 (3H, m), 1.94 (3H, s), 2.10 (3H, s), 2.25-2.35 (1H, m), 2.43 (2H, t, J=7.0Hz), 3.70-3.80 (4H, m), 4.17 (1H, d, J=11.2Hz), 4.31 (1H, d, J=11.2Hz), 5.38 (1H, brs), 6.64 (1H, d, J=3.6H2), 6.94 (1H, d, J=3.6Hz), 7.15-7.42 (5H, m)
Infrared absorption spectrum v
MaxCm
-1(CHCl
3): 3443,2946,2862,1737,1681,1511,1374,1251,1042
Embodiment 49 (b)
(2R)-and amino-2-methyl 4-[5-(5-phenyl penta-1-alkynyl) thiophene-2-yl] fourth-1-alcohol oxalate
With (2R)-acetate acetylamino-2-methyl-4-[5-(the 5-phenyl penta-1-alkynyl) thiophene-2-yl that obtains among 1.40g (3.40mmol) embodiment 49 (a)] butyl ester is dissolved in the 14ml tetrahydrofuran (THF): methyl alcohol: in the solution of water=1: 1: 1; add 1.43g (34.0mmol) lithium hydroxide monohydrate, stirred 4 hours at 50 ℃.Reaction solution is poured in the water, used dichloromethane extraction, dichloromethane layer is behind anhydrous sodium sulfate drying, and decompression is heated up in a steamer and desolvated.With resistates through silica gel column chromatography (eluting solvent; Methylene dichloride: methyl alcohol: purifying ammoniacal liquor=20: 1: 0-10: 1: 0.1), obtain 1.11g (100%) (2R)-amino-2-methyl-4-[5-(5-phenyl penta-1-alkynyl) thiophene-2-yl] fourth-1-alcohol.With 360mg (1.10mmol) gained (2R)-amino-2-methyl-4-[5-(5-phenyl penta-1-alkynyl) thiophene-2-yl] fourth-1-alcohol is dissolved in the methyl alcohol, add 99mg (1.10mmol) oxalic acid, with methyl alcohol recrystallization is carried out in the crystallization of separating out, obtain 394mg (86%) and be the title compound of white crystals.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CD
3OD): δ 1.31 (3H, s), 1.82-2.10 (4H, m), 2.40 (2H, t, J=7.0Hz), 2.75 (2H, t, J=7.5Hz), 2.80-2.95 (2H, m), 3.62 (1H, d, J=11.5Hz), 3.61 (1H, d, J=11.5Hz), 6.73 (1H, d, J=3.6Hz), 6.94 (1H, d, J=3.6Hz), 7.13-7.30 (5H, m)
Infrared absorption spectrum v
MaxCm
-1(KBr): 3383,3106,3026,2980,2942,2622,2514,1721,1609,1639,1198,699
Mass spectrum (FAB) m/z:328 (M+H)
+(free form)
The ultimate analysis value; (with respect to C
20H
25NOSC
2H
2O
40.2H
2The % of O)
Calculated value: C, 62.75; H, 6.65; N, 3.32; S, 7.61
Measured value: C, 62.50; H, 6.29; N, 3.39; S, 7.70
[α]
D 25-0.9 (c1.00, methyl alcohol)
Embodiment 50
(2R)-and amino-2-methyl-4-[5-(5-phenyl pentanoyl) thiophene-2-yl] fourth-1-alcohol oxalate
(exemplary compounds 1-1344)
With (2R)-amino-2-methyl-4-[5-(the 5-phenyl penta-1-alkynyl) thiophene-2-yl that obtains among 387mg (1.18mmol) embodiment 49] fourth-1-alcohol is dissolved in the 4ml methyl alcohol, adds 4ml 6N sulfuric acid, reflux 4 hours.After reaction solution is cooled to 0 ℃, it is adjusted to alkalescence (pH14), uses dichloromethane extraction then with the 1N aqueous sodium hydroxide solution.Dichloromethane layer is behind anhydrous sodium sulfate drying, and decompression is heated up in a steamer and desolvated, with resistates through silica gel column chromatography (ChromatorexNH (100-200 order)) (eluting solvent; Methylene dichloride: methyl alcohol=1: 0-50: 1) purifying, obtain 336mg (82%) (2R)-amino-2-methyl-4-[5-(5-phenyl pentanoyl) thiophene-2-yl] fourth-1-alcohol.It is dissolved in the methyl alcohol, adds 88mg (0.97mmol) oxalic acid, recrystallization is carried out in the gained crystallization, obtain 332mg (78%) and be the title compound of white crystals with methyl alcohol.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, DMSO-d
6): δ 1.19 (3H, s), 1.55-1.67 (4H, m), 1.80-1.98 (2H, m), 2.60 (2H, t, J=6.7Hz), 2.83-2.96 (4H, m), 3.40 (1H, d, J=11.3Hz), 3.47 (1H, d, J=11.3Hz), 7.00 (1H, d, J=3.7Hz), and 7.13-7.22 (3H, m), 7.23-7.31 (2H, m), 7.80 (1H, d, J=3.7Hz)
Infrared absorption spectrum v
MaxCm
-1(KBr): 3126,2942,2657,1915,1718,1649,1609,1547,1445,1205,700
Mass spectrum (FAB) m/z:346 (M+H)
+(free form)
The ultimate analysis value; (with respect to C
20H
27NO
2SC
2H
2O
40.5H
2The % of O)
Calculated value: C, 59.44; H, 6.80; N, 3.15; S, 7.21
Measured value: C, 59.62; H, 6.53; N, 3.31; S, 7.43
Embodiment 51
(2R)-and amino-2-methyl-4-[5-(5-phenylpentyl) thiophene-2-yl] fourth-1-alcohol oxalate
(exemplary compounds 1-152)
With (2R)-acetate acetylamino-2-methyl-4-[5-(the 5-phenyl penta-1-alkynyl) thiophene-2-yl that obtains among 337mg (0.82mmol) embodiment 49 (a)] butyl ester is dissolved in the 17ml methyl alcohol; add 170mg 10% palladium on carbon, under hydrogen atmosphere, stirred 16 hours.Behind diatomite elimination catalyzer, the decompression heat up in a steamer filtrate, obtain 318mg (93%) (2R)-acetate acetylamino-2-methyl-4-[5-(5-phenylpentyl) thiophene-2-yl] butyl ester.With 298mg (0.72mmol) gained (2R)-acetate acetylamino-2-methyl-4-[5-(5-phenylpentyl) thiophene-2-yl] butyl ester is dissolved in the 6ml tetrahydrofuran (THF): methyl alcohol: in the solution of water=1: 1: 1; add 301mg (7.17mmol) lithium hydroxide monohydrate, stirred 6 hours at 50 ℃.Reaction solution is poured in the water, used dichloromethane extraction, dichloromethane layer is behind anhydrous sodium sulfate drying, and decompression is heated up in a steamer and desolvated.The 243mg resistates is dissolved in the methyl alcohol, adds 65mg (0.72mmol) oxalic acid, filter the crystallization that obtains separating out, obtain 251mg (83%) and be the title compound of white crystals.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CD
3OD): δ 1.31 (3H, s), 1.32-1.42 (2H, m), 1.58-1.70 (4H, m), 1.88-2.08 (2H, m), 2.59 (2H, t, J=7.6Hz), 2.74 (2H, t, J=7.4Hz), 2.75-2.91 (2H, m), 3.52 (1H, d, J=11.6Hz), 3.61 (1H, d, J=11.6Hz), 6.56 (1H, d, J=3.3Hz), 6.63 (1H, d, J=3.3Hz), and 7.09-7.17 (3H, m), 7.19-7.27 (2H, m)
Infrared absorption spectrum v
MaxCm
-1(KBr): 3458,3134,2929,2855,2595,1724,1642,1543,1219,710cm
-1
Embodiment 52
(2R)-and amino-2-methyl-4-{5-[3-(4-chlorophenoxy) proyl] thiophene-2-yl } fourth-1-alcohol grass Hydrochlorate(exemplary compounds 1-2273)
Embodiment 52 (a)
(2R)-and acetate acetylamino-2-methyl-4-[5-(3-hydroxypropyn base) thiophene-2-yl] butyl ester
Synthetic (2R) among 1.38g (3.95mmol) embodiment 47 (c)-acetate acetylamino-2-methyl-4-(5-bromothiophene-2-yl) butyl ester is dissolved in the 20ml dimethyl formamide; add 0.69ml (11.9mmol) propargyl alcohol, 5.60ml (40.1mmol) triethylamine, 76mg (0.40mmol) cupric iodide (I) and 276mg (0.39mmol) dichloro two (triphenyl phosphines) and close palladium, nitrogen atmosphere, 80 ℃ of following stirrings 1 hour.Reaction solution is poured in the water, used ethyl acetate extraction, wash ethyl acetate layer with saturated brine.Ethyl acetate layer is behind anhydrous sodium sulfate drying, and decompression is heated up in a steamer and desolvated.With resistates through silica gel column chromatography (eluting solvent; Hexane: ethyl acetate=3: 1-1: 3) purifying obtains 685mg (54%) and is the title compound of white crystals.
NMR (Nuclear Magnetic Resonance) spectrum (500MHz, CDCl
3): δ 1.35 (3H, s), 1.91 (1H, brs), 1.94 (3H, s), 1.97-2.05 (1H, m), 2.10 (3H, s), 2.27-2.35 (1H, m), 2.75-2.82 (2H, m), 4.16 (1H, d, J=11.2Hz), 4.31 (1H, d, J=11.2Hz), 4.49 (2H, s), 5.43 (1H, brs), 6.66 (1H, d, J=3.6Hz), 7.02 (1H, d, J=3.6Hz)
Infrared absorption spectrum v
MaxCm
-1(KBr): 3295,3077,2981,2217,1740,1644,1556,1373,1251,1028
Embodiment 52 (b)
(2R)-and amino-2-methyl-4-{5-[3-(4-chlorophenoxy) proyl] thiophene-2-yl } fourth-1-alcohol grass
Hydrochlorate
With synthetic (2R) among 285mg (0.88mmol) embodiment 52 (a)-acetate acetylamino-2-methyl-4-[5-(3-hydroxypropyn base) thiophene-2-yl] butyl ester and 136mg (1.06mmol) 4-chlorophenol be dissolved in the 5ml anhydrous tetrahydro furan; at ice-cooled 230mg (1.32mmol) diethyl azodiformate and 346mg (1.32mmol) triphenyl phosphine of adding down, at room temperature stirred 4 hours.Reaction mixture is injected water, use ethyl acetate extraction.Ethyl acetate layer is behind anhydrous magnesium sulfate drying, and decompression is heated up in a steamer and desolvated, with resistates through silica gel column chromatography (eluting solvent; Hexane: ethyl acetate=2: 1-1: 3) purifying obtains 195mg (51%) and is (2R)-acetate acetylamino-2-methyl-4-{5-[3-(4-chlorophenoxy) proyl of faint yellow oily thing] thiophene-2-yl } butyl ester.It is dissolved in the 6ml tetrahydrofuran (THF): methyl alcohol: in the solution of water=1: 1: 1, add 370mg (8.82mmol) lithium hydroxide monohydrate, stirred 6 hours at 50 ℃.Reaction solution is poured in the water, used dichloromethane extraction, dichloromethane layer is behind anhydrous sodium sulfate drying, and decompression is heated up in a steamer and desolvated.175mg (0.50mmol) resistates is dissolved in the 5ml ethyl acetate, adds 45mg (0.50mmol) oxalic acid, filter the crystallization that obtains separating out, obtain 198mg (86%) and be the title compound of white crystals.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, DMSO-d
6): δ 1.18 (3H, s), 1.7-2.0 (2H, m), 2.84 (2H, t, J=8.7Hz), 3.43 (2H, m), 5.07 (2H, s), 6.83 (1H, d, J=3.6Hz), 7.05 (2H, d, J=9.0Hz), 7.19 (1H, d, J=3.6Hz), 7.37 (2H, d, J=9.0Hz)
Infrared absorption spectrum v
MaxCm
-1(KBr): 3416,1719,1597,1490,1375,1241,1201,1092,1006,830
Mass spectrum (FAB) m/z:350 (M+H)
+(free form)
The ultimate analysis value; (with respect to C
20H
27NO
2SC
2H
2O
4%)
Calculated value: C, 54.61; H, 5.04; N, 3.18; S, 7.29; Cl, 8.06
Measured value: C, 54.61; H, 5.04; N, 3.01; S, 7.16; Cl, 7.77
Embodiment 53
(2R)-and amino-2-methyl-4-[5-(1-hydroxyl-5-phenylpentyl) thiophene-2-yl] fourth-1-alcohol oxalate
(exemplary compounds 1-1686)
With (2R)-amino-2-methyl-4-[5-(the 5-phenyl pentanoyl) thiophene-2-yl that obtains among 130mg (0.38mmol) embodiment 50] fourth-1-alcohol is dissolved in the 3ml methyl alcohol; at ice-cooled 17mg (0.45mmol) sodium borohydride that adds down, at room temperature stirred 1 hour.In reaction solution, add entry down ice-cooled, use ethyl acetate extraction.Ethyl acetate layer is washed with saturated brine, and behind anhydrous magnesium sulfate drying, decompression is heated up in a steamer and is desolvated.The gained resistates is dissolved in the methyl alcohol, adds 34mg (0.38mmol) oxalic acid, decompression is heated up in a steamer and is desolvated.To wherein adding 3ml ethanol, filter and obtain precipitation, obtain 95mg (58%) and be the title compound of white crystals.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CD
3OD): δ 1.25-1.50 (2H, m), 1.30 (3H, s), 1.58-1.68 (2H, m), and 1.70-2.08 (4H, m), 2.52-2.64 (2H, m), 2.80-2.94 (2H, m), 3.53 (1H, d, J=11.7Hz), 3.59 (1H, d, J=11.7Hz), 4.74 (1H, t, J=6.8Hz), 6.69 (1H, d, J=3.6Hz), 6.74 (1H, d, J=3.6Hz), 7.08-7.27 (5H, m)
Infrared absorption spectrum v
MaxCm
-1(KBr): 3357,2933,2857,1579,1496,1454,1310,1070,699
Embodiment 54
(2R)-and amino-2-methyl-4-[5-(4-phenyl fourth-1-alkynyl) thiophene-2-yl] fourth-1-alcohol oxalate
(exemplary compounds 1-756)
The same with embodiment 49, use (2R)-acetate acetylamino-2-methyl-4-(5-bromothiophene-2-yl) butyl ester and 4-phenyl fourth-1-alkynes, make title compound.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CD
3OD): δ 1.31 (3H, s), 1.88-2.09 (2H, m), 2.68 (2H, t, J=7.3Hz), 2.78-2.93 (4H, m), 3.52 (1H, d, J=11.6Hz), 3.61 (1H, d, H=11.6Hz), 6.72 (1H, d, J=3.6Hz), 6.88 (1H, d, J=3.6Hz), 7.16-7.31 (5H, m)
Infrared absorption spectrum v
MaxCm
-1(KBr): 3204,3110,3026,2981,2929,2887,1719,1608,1541,1202,699
Embodiment 55
(2R)-and amino-2-methyl-4-[5-(4-phenyl butyryl radicals) thiophene-2-yl] fourth-1-alcohol oxalate
(exemplary compounds 1-1330)
The same with embodiment 50, use (2R)-amino-2-methyl-4-[5-(the 4-phenyl fourth-1-alkynyl) thiophene-2-yl that obtains among the embodiment 54] fourth-1-alcohol, make title compound.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, DMSO-d
3): δ 1.19 (3H, s), 1.82-1.98 (4H, m), 2.62 (2H, t, J=7.7Hz), 2.85-2.97 (4H, m), 3.39 (1H, d, J=11.7Hz), 3.45 (1H, d, J=11.7Hz), 7.00 (1H, d, J=3.8Hz), 7.15-7.33 (5H, m), 7.76 (1H, d, J=3.8Hz)
Infrared absorption spectrum v
MaxCm
-1(KBr): 3410,3210,2941,2653,2576,1665,1641,1530,1452,1325
Embodiment 56
(2R)-and amino-2-methyl-4-[5-(4-cyclohexyl fourth-1-alkynyl) thiophene-2-yl] fourth-1-alcohol
(exemplary compounds 1-743)
Operation obtains title compound similarly to Example 1.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CD
3OD): δ 0.87-0.99 (2H, m), 1.08 (3H, s), 1.11-1.50 (6H, m), and 1.62-1.81 (7H, m), 2.41 (2H, t, J=7.2Hz), 2.74-2.88 (2H, m), 3.34 (1H, d, J=11.0Hz), 3.37 (1H, d, J=11.0Hz), 6.66 (1H, d, J=3.6Hz), 6.87 (1H, d, J=3.6Hz)
Infrared absorption spectrum v
MaxCm
-1(KBr): 3334,3269,3153,2922,2851,1618,1449,1060,804
Embodiment 57
(2R)-and amino-2-methyl-4-[5-(4 cyclohexyl butyl) thiophene-2-yl] fourth-1-alcohol
(exemplary compounds 1-71)
Use (2R)-amino-2-methyl-4-[5-(the 4-cyclohexyl fourth-1-alkynyl) thiophene-2-yl that obtains among the embodiment 56] fourth-1-alcohol, operation obtains title compound similarly to Example 11.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CD
3OD): δ 0.80-0.95 (2H, m), 1.08 (3H, s), 1.10-1.40 (8H, m), 1.54-1.81 (9H, m), 2.68-2.87 (4H, m), 3.34 (1H, d, J=10.9Hz), 3.37 (1H, d, J=10.9Hz), 6.53 (1H, d, J=3.2Hz), 6.58 (1H, d, J=3.2Hz)
Infrared absorption spectrum v
MaxCm
-1(KBr): 3333,3269,3170,2923,2850,1619,1461,1447,1059,801
Embodiment 58
(2R)-and amino-2-methyl-4-[5-(4-cyclohexyl butyryl radicals) thiophene-2-yl] fourth-1-alcohol
(exemplary compounds 1-1329)
Use (2R)-amino-2-methyl-4-[5-(the 4-cyclohexyl fourth-1-alkynyl) thiophene-2-yl that obtains among the embodiment 56] fourth-1-alcohol, operation obtains title compound similarly to Example 17.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CD
3OD): δ 0.83-0.97 (2H, m), 1.09 (3H, s), 1.10-1.33 (6H, m), 1.61-1.86 (9H, m), 2.82-3.00 (4H, m), 3.35 (1H, d, J=10.9Hz), 3.39 (1H, d, J=0.9Hz), 6.94 (1H, d, J=3.7Hz), 7.69 (1H, d, J=3.7Hz)
Infrared absorption spectrum v
MaxCm
-1(KBr): 3333,3268,3142,2921,2849,1648,1457,1208,1057,923,816
Embodiment 59
2-amino-2-methyl-4-[5-(3-cyclohexyl methoxy propyl alkynyl) thiophene-2-yl] fourth-1-alcohol Malaysia
Hydrochlorate
(exemplary compounds 1-1185)
Operation obtains title compound similarly to Example 1.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CD
3OD): δ 0.92-1.04 (2H, m), 1.13-1.37 (3H, m), 1.31 (3H, s), 1.53-1.82 (6H, m), 1.89-2.11 (2H, m), 2.82-2.96 (2H, m), 3.35 (2H, d, J=6.4Hz), 3.51 (1H, d, J=11.5Hz), 3.61 (1H, d, J=11.5Hz), 4.87 (2H, s), 6.25 (2H, s), 6.78 (1H, d, J=3.6Hz), 7.05 (1H, d, J=3.6Hz)
Infrared absorption spectrum v
MaxCm
-1(KBr): 2924,2852,2218,1577,1496,1386,1366,1195,1089,866
Embodiment 60
(2R)-and amino-2-methyl-4-[5-(4-cyclohexyloxy butyl) thiophene-2-yl] fourth-1-alcohol maleate
(exemplary compounds 1-400)
Use (2R)-amino-2-methyl-4-[5-(the 4-cyclohexyloxy fourth-1-yl) thiophene-2-yl that obtains among the embodiment 31] fourth-1-alcohol, operation obtains title compound similarly to Example 11.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CD
3OD): δ 1.15-1.35 (5H, m), 1.31 (3H, s), 1.50-1.80 (7H, m), and 1.85-2.08 (4H, m), 2.73-2.92 (4H, m), and 3.20-3.30 (1H, m), 3.45-3.55 (3H, m), 3.60 (1H, d, J=11.6Hz), 6.25 (2H, s), 6.59 (1H, d, J=3.3Hz), 6.64 (1H, d, J=3.3Hz)
Infrared absorption spectrum v
MaxCm
-1(KBr): 2931,2856,1577,1490,1471,1459,1388,1357,1108,1081,868
Embodiment 61
(2R)-and amino-2-methyl-4-{5-[4-(4-fluorophenoxy) butyl] thiophene-2-yl } fourth-1-alcohol
(exemplary compounds 1-463)
Use (2R)-amino-2-methyl-4-{5-[4-(4-fluorophenoxy) fourth-1-alkynyl that obtains among the embodiment 45] thiophene-2-yl } fourth-1-alcohol, operation obtains title compound similarly to Example 11.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CD
3OD): δ 1.08 (3H, s), 1.70-1.85 (6H, m), 2.73-2.88 (4H, m), 3.34 (1H, d, J=10.9Hz), 3.38 (1H, d, J=10.9Hz), 3.94 (2H, t, J=5.9Hz), 6.58 (1H, d, J=3.7Hz), 6.60 (1H, d, J=3.7Hz), 6.83-6.90 (2H, m), 6.93-7.00 (2H, m)
Infrared absorption spectrum v
MaxCm
-1(KBr): 3333,3268,3162,2940,2865,1509,1474,1244,1220,1060,830,763
Embodiment 62
(2R)-and amino-2-methyl-4-{5-[4-(4-methoxyl group phenoxy group) butyl] thiophene-2-yl } fourth-1-alcohol
(exemplary compounds 1-479)
Use (4R)-methyl-4-{2-[4-(the 4-methoxyl group phenoxy group) fourth-1-alkynyl that makes with the same operation of embodiment 1h] } second base oxazolidine, make title compound according to embodiment 26.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CD
3OD): δ 1.08 (3H, s), 1.68-1.84 (6H, m), 2.73-2.87 (4H, m), 3.34 (1H, d, J=10.8Hz), 3.38 (1H, d, J=10.8Hz), 3.72 (3H, s), 3.91 (2H, t, J=6.0Hz), 6.58 (1H, d, J=3.1Hz), 6.60 (1H, d, J=3.1Hz), 6.81 (4H, s)
Infrared absorption spectrum v
MaxCm
-1(KBr): 3335,3273,3183,2945,2868,1514,1473,1233,1045,825,735
Embodiment 63
(2R)-and amino-2-methyl-4-[5-(4-benzyloxy fourth-1-alkynyl) thiophene-2-yl] fourth-1-alcohol oxalate
(exemplary compounds 1-1266)
Operation obtains title compound similarly to Example 1.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CD
3OD): δ 1.31 (3H, s), 1.89-2.10 (2H, m), 2.70 (2H, t, J=6.8Hz), 2.80-2.94 (2H, m), 3.52 (1H, d, J=11.6Hz), 3.61 (1H, d, J=11.6Hz), 3.64 (2H, t, J=6.8Hz), 4.57 (2H, s), 6.74 (1H, d, J=3.6Hz), 6.94 (1H, d, J=3.6Hz), 7.23-7.39 (5H, m)
Infrared absorption spectrum v
MaxCm
-1(KBr): 3358,3028,2926,2544,1719,1702,1605,1496,1468,1454,1402,1279,1204,1105,806,739,720,699,500
Mass spectrum (FAB) m/z:344 (M+H)
+(free form)
Embodiment 64
(2R)-and amino-2-methyl-4-[5-(4-benzyloxy butyl) thiophene-2-yl] fourth-1-alcohol maleate
(exemplary compounds 1-594)
With (2R)-amino-2-methyl-4-[5-that obtains among the embodiment 63 (4-benzyloxy fourth-1-alkynyl) thiophene-2-yl] fourth-1-alcohol, operation makes title compound similarly to Example 11.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CD
3OD): δ 1.31 (3H, s), 1.59-1.76 (4H, m), 1.88-2.08 (2H, m), 2.76 (2H, t, J=7.2Hz), 2.79-2.91 (2H, m), 3.49 (2H, t, J=6.4Hz), 3.51 (1H, d, J=11.6Hz), 3.60 (1H, d, J=11.6Hz), 4.48 (2H, s), 6.25 (2H, s), 6.58 (1H, d, J=3.6Hz), 6.64 (1H, d, J=3.6Hz), 7.23-7.38 (5H, m)
Infrared absorption spectrum v
MaxCm
-1(KBr): 2935,2862,1579,1496,1386,1363,1195,1104,1077,1012,875,866,804,737,698,569
Mass spectrum (FAB) m/z:348 (M+H)
+(free form)
Embodiment 65
(2R)-and amino-2-methyl-4-{5-[3-(4-methyl cyclohexane chloro) proyl] thiophene-2-yl } fourth-1-alcohol
Maleate
(exemplary compounds 1-1050)
Operation obtains title compound similarly to Example 1.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CD
3OD): δ 0.89,0.90 (3H, d, J=6.4Hz), 1.31 (3H, s), 0.92-1.56,1.70-2.12 (11H, m), 2.81-2.96 (2H, m), 3.40-3.49,3.73-3.79 (1H, m), 3.52 (1H, d, J=11.2Hz), 3.61 (1H, d, J=11.2Hz), 4.36,4.39 (2H, s), 6.25 (2H, s), 6.78 (1H, d, J=3.6Hz), 7.04 (1H, d, J=3.6Hz)
Infrared absorption spectrum v
MaxCm
-1(KBr): 2927,2864,2219,1579,1508,1386,1366,1193,1093,1077,876,865,807,717,568
Mass spectrum (FAB) m/z:336 (M+H)
+(free form)
Embodiment 66
(4R)-methyl-4-[2-(thiophene-2-yl) ethyl] oxazolidine-2-ketone (exemplary compounds 4-4
Embodiment 66 (a)
(2R)-the positive hexylyloxy of t-butoxycarbonyl amino-3--2-methyl isophthalic acid-propyl alcohol
With 20.0g (97.4mmol) 2-t-butoxycarbonyl amino-2-methyl isophthalic acid, ammediol is suspended in the 200ml diisopropyl ether, adds 16.3ml (0.10mol) n-caproic acid vinyl acetate and 0.8g lipase [from the fixedly lipase (TOYOBO of Rhodopseudomonas; 0.67U/mg)], at room temperature vigorous stirring is 2 hours.Filtering reacting liquid, filtrate is heated up in a steamer in decompression then.The gained resistates is passed through silica gel column chromatography (eluting solvent; Hexane: ethyl acetate=10: 1-2: 1) purifying obtains 25.0g (85%) and is the title compound of colorless oil.
By analyzing with optically-active HPLC post (ChiralCel OF (Daicel), (0.46cm * 25cm), eluting solvent; Normal hexane: 2-propyl alcohol=70: 30, flow velocity: 0.5ml/ minute) determines the optical purity of the positive hexylyloxy of gained (2R)-t-butoxycarbonyl amino-3--2-methyl isophthalic acid-propyl alcohol.
(8.2 minutes) of elder generation's wash-out are the 2S bodies, and (10.5 minutes) of back wash-out are the 2R bodies, confirm that the optical purity in this reaction is 85%ee.
[α]
D 25-8.5(c1.86，CHCl
3)
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3) δ ppm:4.86 (s, 1H), 4.25 (d, 1H, J=11.2Hz), 4.19 (d, 1H, J=11.2Hz), 3.86 (brs, 1H), 3.70-3.55 (m, 2H), 2.36 (t, 2H, J=7.4Hz), and 1.68-1.58 (m, 2H), 1.44 (s, 9H), and 1.40-1.30 (m, 4H), 1.25 (s, 3H), 0.90 (t, 3H, J=7.0Hz)
Infrared absorption spectrum vmax cm
-1(liquid film): 3415,3380,2961,2935,2874,1721,1505,1458,1392,1368,1293,1248,1168,1076
Mass spectrum (FAB) m/z:304 ((M+H)
+)
Embodiment 66 (b)
(2S)-the positive hexylyloxy of t-butoxycarbonyl amino-3--2-methyl isophthalic acid-propionic aldehyde
The positive hexylyloxy of (2R)-t-butoxycarbonyl amino-3--2-methyl isophthalic acid-propyl alcohol of gained among 30.7g (0.10mol) embodiment 66 (a) is dissolved in the 600ml methylene dichloride, at the ice-cooled 220g4 that adds down
Molecular sieve and 43.6g (0.20mol) pyridinium chlorochromate at room temperature stirred 2 hours afterwards.Reaction solution is diluted with ether, filter then.Filtrate is heated up in a steamer in decompression, and resistates is passed through silica gel column chromatography (eluting solvent; Normal hexane: ethyl acetate=10: 1-5: 1) purifying obtains 28.8g (95%) and is the title compound of colorless oil.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3) δ ppm:9.45 (s, 1H), 5.26 (brs, 1H), 4.44 (d, 1H, J=11.2Hz), 4.32 (d, 1H, J=11.2Hz), 2.32 (t, 2H, J=7.6Hz), 1.70-1.55 (m, 2H), 1.45 (s, 9H), 1.38 (s, 3H), 1.40-1.25 (m, 4H), 0.90 (t, 3H, J=7.0Hz)
Infrared absorption spectrum vmax cm
-1(liquid film): 3367,2961,2935,2874,1742,1707,1509,1458,1392,1369,1290,1274,1254,1166,11100,1078
Mass spectrum (FAB) m/z:302 ((M+H)
+)
Embodiment 66 (c)
(2R)-the positive hexylyloxy of t-butoxycarbonyl amino-1--2-methyl-4-(thiophene-2-yl)-3-butylene
67.1g (0.15mol) bromination 2-thienyl methyl San Ben Phosphonium is suspended in the 750ml tetrahydrofuran (THF),, under room temperature, nitrogen atmosphere, stirred 20 minutes to wherein adding 17.2g (0.15mol) potassium tert.-butoxide.Under ice-cooled condition, the positive hexylyloxy of (2S)-t-butoxycarbonyl amino-3--2-methyl isophthalic acid-propionic aldehyde that is dissolved in 23.0g (76.4mmol) embodiment 66 (b) gained in the 250ml tetrahydrofuran (THF) is added drop-wise in this reaction solution, after dripping end, stirred 30 minutes down ice-cooled.In reaction solution, add entry afterwards, use ethyl acetate extraction, wash ethyl acetate layer with saturated brine.Through anhydrous sodium sulfate drying, decompression is afterwards heated up in a steamer and is desolvated, and resistates is passed through silica gel column chromatography (eluting solvent with ethyl acetate layer; Normal hexane: ethyl acetate=20: 1) purifying obtains 27.8g (96%) and is the title compound of colorless oil.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3) δ ppm:7.32-7.26, and 7.16-7.14 (m, 1H), 7.04-7.01,7.01-6.93 (m, 2H), 6.63 (d, 0.5H, J=16.0Hz), 6.60 (d, 0.5H, J=13.6Hz), 6.10 (d, 0.5H, J=16.0Hz), 5.58 (d, 0.5H, J=13.6Hz), 4.94,4.93 (brs, 1H), 4.40-4.10 (m, 2H), 2.34 (t, 2H, J=7.4Hz), and 1.70-1.55 (m, 2H), 1.57,1.50,1.44 (s, 9H), 1.40-1.25 (m, 7H), 0.88 (t, 3H, J=7.0Hz)
Infrared absorption spectrum v max cm
-1(liquid film): 3370,2961,2933,1725,1495,1456,1391,1367,1247,1167,1109,1100,1072,697
Mass spectrum (FAB) m/z:381 (M
+)
Embodiment 66 (d)
(4R)-methyl-4-[2-(thiophene-2-yl) vinyl] oxazolidine-2-ketone
The positive hexylyloxy of (2R)-t-butoxycarbonyl amino-1--2-methyl-4-(thiophene-2-the yl)-3-butylene of gained among 40.5g (0.11mol) embodiment 66 (c) is dissolved in 150ml tetrahydrofuran (THF), the 150ml methyl alcohol, under ice-cooled, to wherein adding 530ml 1N aqueous sodium hydroxide solution, stirred 30 minutes down ice-cooled, at room temperature stirred 1 hour.Behind the reaction solution concentrating under reduced pressure, add entry, use dichloromethane extraction, wash dichloromethane layer with saturated brine.Through anhydrous sodium sulfate drying, decompression is heated up in a steamer and is desolvated then, obtains the 35.0g crude product with dichloromethane layer.This crude product is dissolved in the 300ml tetrahydrofuran (THF),, stirred 10 minutes down, at room temperature stirred 40 minutes ice-cooled at ice-cooled 17.8g (0.16mol) potassium tert.-butoxide that adds down.In reaction solution, add entry, use ethyl acetate extraction, wash ethyl acetate layer with saturated brine.Behind anhydrous sodium sulfate drying, decompression is heated up in a steamer and is desolvated with ethyl acetate layer.Resistates is passed through silica gel column chromatography (eluting solvent; Hexane: ethyl acetate=3: 1-1: 1) purifying obtains 18.0g (81%) and is the title compound of white solid.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3) δ ppm:7.34 (d, 0.5H, J=5.1Hz), 7.19 (d, 0.5H, J=5.0Hz), 7.07-6.91 (m, 2H), 6.74 (d, 0.5H, J=16.0Hz), 6.59 (d, 0.5H, J=12.5), 6.17 (brs, 1H), 6.06 (d, 0.5H, J=16.0Hz), 5.65 (d, 0.5H, J=12.5Hz), 4.41 (d, 0.5H, J=8.6Hz), 4.31-4.16 (m, 1.5H), 1.60 (s, 1.5H), 1.55 (s, 1.5H)
Infrared absorption spectrum vmax cm
-1(KBr): 3275,3110,2974,1752,1391,1376,1281,1169,1039,960,704
Mass spectrum (FAB) m/z:209 (M
+)
Embodiment 66 (e)
(4R)-methyl-4-[2-(thiophene-2-yl) ethyl] oxazolidine-2-ketone
(4R)-methyl-4-[2-(thiophene-2-yl) vinyl] oxazolidine-2-ketone of gained among 18.0g (86.0mmol) embodiment 66 (d) is dissolved in the 150ml methyl alcohol, adds 4.5g 10% palladium on carbon, under hydrogen atmosphere, room temperature, stirred 10 hours.Palladium on carbon in the reaction solution is filtered with the paulownia mountain funnel that has applied one deck thin silicon glue, and filtrate is heated up in a steamer in decompression.The gained solid is washed after drying with diethyl ether, obtain 16.5g (91%) and be the title compound of white solid.
By analyzing with optically-active HPLC post (ChiralCel OD-H (Daicel), (0.46cm * 25cm), eluting solvent; Normal hexane: 2-propyl alcohol=60: 40, flow velocity: 0.5ml/ minute) determines the optical purity of gained (4R)-methyl-4-[2-(thiophene-2-yl) ethyl] oxazolidine-2-ketone.
(16.8 minutes) of elder generation's wash-out are the 2S bodies, and (17.6 minutes) of back wash-out are the 2R bodies, confirm that the optical purity in this reaction is 85%ee.
[α]
D 25+5.1(c2.4，CHCl
3)
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3) δ ppm:7.15 (d, 1H, J=5.2Hz), 6.93 (dd, 1H, J=5.2,3.6Hz), 6.81 (d, 1H, J=3.6Hz), 5.39 (brs, 1H), 4.19 (d, 1H, J=8.4Hz), 4.08 (d, 1H, J=8.4Hz), 3.00-2.84 (m, 2H), 2.08-1.92 (m, 2H), 1.42 (s, 3H)
Infrared absorption spectrum vmax cm
-1(KBr): 3283,1770,1399,1244,1043,941,846,775,706,691
Mass spectrum (EI) m/z:211 (M
+)
To this optical purity of 11g is to add 25ml ethyl acetate and 5.0ml normal hexane in (4R)-methyl-4-[2-(thiophene-2-yl) ethyl] oxazolidine-2-ketone of 85%ee, and heating for dissolving was at room temperature placed 2 hours afterwards.The white crystals that filtration obtains separating out, drying obtains the title compound that the 4.0g optical purity is 99%ee.
[α]
D 25+7.8(c2.0，CHCl
3)
Embodiment 67
(4R)-methyl-4-[2-(thiophene-2-yl) ethyl] oxazolidine-2-ketone (exemplary compounds 4-4)
Embodiment 67 (a)
(2R)-the positive hexylyloxy of t-butoxycarbonyl amino-1--2-methyl-4-(thiophene-2-yl) butane
The positive hexylyloxy of (2R)-t-butoxycarbonyl amino-1--2-methyl-4-(thiophene-2-the yl)-3-butylene of gained among 27.6g (72.4mmol) embodiment 66 (c) is dissolved in the 450ml ethanol, add 14.0g 10% palladium on carbon, under hydrogen atmosphere, room temperature, stirred 4.Through diatomite filtration, filtrate is heated up in a steamer in decompression then with the palladium on carbon in the reaction solution.Resistates is passed through silica gel column chromatography (eluting solvent; Hexane: ethyl acetate=20: 1-10: 1) purifying obtains 22.1g (80%) and is the title compound of colorless oil.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3) δ ppm:7.02 (d, 1H, J=5.2Hz), 6.91 (dd, 1H, J=5.2,3.6Hz), 6.80 (d, 1H, J=3.6Hz), 4.53 (brs, 1H), 4.26-4.12 (m, 2H), 2.85 (t, 2H, J=8.4Hz), 2.34 (t, 2H, J=7.6Hz), 2.26-2.16 (m, 1H), 2.01-1.90 (m, 1H), 1.68-1.56 (m, 2H), 1.44 (s, 9H), 1.31 (s, 3H), 1.40-1.26 (m, 4H), 0.89 (t, 3H, J=7.6Hz)
Infrared absorption spectrum vmax cm
-1(liquid film): 3371,2961,2933,2872,2864,1721,1502,1466,1455,1392,1367,1246,1168,1074,694,
Mass spectrum (FAB) m/z:384 ((M+H)
+)
Embodiment 67 (b)
(2R)-t-butoxycarbonyl amino-2-methyl-4-(thiophene-2-yl)-1-butanols
The positive hexylyloxy of (2R)-t-butoxycarbonyl amino-1--2-methyl-4-(thiophene-2-yl) butane of gained among 22.0g (57.4mmol) embodiment 67 (a) is dissolved in the mixed solution of 140ml tetrahydrofuran (THF) and 280ml methyl alcohol, ice-cooled following to wherein adding 280ml 1N aqueous sodium hydroxide solution, stirred 30 minutes down ice-cooled, at room temperature stirred 1 hour.With the reaction solution concentrating under reduced pressure, add entry then, use dichloromethane extraction, wash dichloromethane layer with saturated brine.Behind anhydrous sodium sulfate drying, decompression is heated up in a steamer and is desolvated, and obtains 15.5g (95%) and is the title compound of white solid with dichloromethane layer.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3) δ ppm:7.11 (d, 1H, J=5.2Hz), 6.92 (dd, 1H, J=5.2,3.6Hz), 6.81 (d, 1H, J=3.6Hz), 4.64 (brs, 1H), 4.08 (brs, 1H), 3.74-3.60 (m, 2H), 2.98-2.76 (m, 2H), 2.20-2.10 (m, 1H), 2.03-1.90 (m, 1H), 1.44 (s, 9H), 1.22 (s, 3H)
Infrared absorption spectrum vmax cm
-1(KBr): 3279,3250,3067,2973,2929,2908,2857,1679,1552,1367,1291,1245,1167,1076,1064,1009,861,851,701
Mass spectrum (FAB) m/z:286 ((M+H)
+)
Embodiment 67 (c)
(4R)-methyl-4-[2-(thiophene-2-yl) ethyl] oxazolidine-2-ketone
(2R)-t-butoxycarbonyl amino-2-methyl-4-(thiophene-2-the yl)-1-butanols of gained among 15.4g (53.9mmol) embodiment 67 (b) is dissolved in 200ml N, in the dinethylformamide, at ice-cooled 9.07g (80.8mmol) potassium tert.-butoxide that adds down, stirred 10 minutes down ice-cooled, at room temperature stirred 40 minutes.In reaction solution, add entry, use ethyl acetate extraction, ethyl acetate layer is washed with saturated brine.Through anhydrous sodium sulfate drying, decompression is heated up in a steamer and is desolvated then with ethyl acetate layer.Resistates is passed through silica gel column chromatography (eluting solvent; Isohexane ethyl acetate=3: 1-1: 1) purifying obtains 11.5g (100%) and is the title compound of white solid.Various instrument datas are all consistent with embodiment 66 gained materials.
Embodiment 68
(4R)-[2-(benzo [b] thiophene-6-yl) ethyl]-4-Jia Ji oxazolidine-2-ketone
(exemplary compounds 4-17)
Embodiment 68 (a)
(2R)-the positive hexylyloxy of t-butoxycarbonyl amino-1--2-methyl-4-(benzo [b] thiophene-6-yl)-3-fourth
Alkene
Synthetic (2R) among 28.2g (93.6mmol) embodiment 66 (the b)-positive hexylyloxy of t-butoxycarbonyl amino-3--2-methyl isophthalic acid-propionic aldehyde and 45.8g (93.6mmol) 6-bromination San Ben Phosphonium benzo [b] thiophene are suspended in the 700ml tetrahydrofuran (THF), to wherein adding 11.6g (0.10mol) potassium tert.-butoxide, at room temperature stirred 30 minutes.In reaction solution, add entry afterwards, use ethyl acetate extraction, ethyl acetate layer is washed with saturated brine.Through anhydrous sodium sulfate drying, decompression is heated up in a steamer and is desolvated then with ethyl acetate layer.Resistates is passed through silica gel column chromatography (eluting solvent; Hexane: ethyl acetate=10: 1) purifying obtains 28.0g (69%) and is the title compound of colorless oil.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3) δ ppm:7.82 (d, 1H, J=9.7Hz), 7.75 (d, 1H, J=8.2Hz), and 7.44-7.39 (m, 1H), 7.32-7.26 (m, 2H), 6.74,5.73 (d, 1H, J=12.6Hz), 6.61,6.34 (d, 1H, J=16.2Hz), 4.87,4.69 (br s, 1H), 4.34-4.16, (m, 2H), 2.37-2.32 (m, 2H), and 1.67-1.15 (m, 20H), 0.91-0.84 (m, 3H).
Infrared absorption spectrum v
MaxCm
-1(liquid film): 3440,3373,2961,2932,2872,1724,1597,1498,1457,1390,1367,1247,1167,1099,1073.
Mass spectrum (FAB) m/z:431 (M
+)
Embodiment 68 (b)
(2R)-the positive hexylyloxy of t-butoxycarbonyl amino-1--2-methyl-4-(benzo [b] thiophene-6-yl) butane
The positive hexylyloxy of (2R)-t-butoxycarbonyl amino-1--2-methyl-4-(benzo [b] thiophene-6-yl) butylene of gained among 28.0g (64.9mmol) embodiment 68 (a) is dissolved in the 700ml methyl alcohol, add 14.0g 10% palladium on carbon, under hydrogen atmosphere, room temperature, stirred 6.Through diatomite filtration, filtrate is heated up in a steamer in decompression then with the palladium on carbon in the reaction solution.Resistates is passed through silica gel column chromatography (eluting solvent; Hexane: ethyl acetate=15: 1-10: 1) purifying obtains 24.30g (87%) and is the title compound of colorless oil.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3) δ ppm:7.73 (d, 1H, J=8.2Hz), 7.69 (s, 1H), 7.36 (d, 1H, J=5.2Hz), 7.28 (d, 1H, J=5.6Hz), 7.19 (d, 1H, J=8.1Hz), 4.56 (br s, 1H), 4.28 (d, 1H, J=11.0Hz), 4.14 (d, 1H, J=11.0Hz), 2.73 (t, 2H, J=8.7Hz), 2.34 (t, 2H, J=7.5Hz), 1.68-1.61 (m, 2H), 1.45 (s, 9H), 1.41-1.38 (m, 8H), 0.89 (t, 3H, J=6.7Hz).
Infrared absorption spectrum vmax cm
-1(liquid film): 3371,2960,2933,2870,1720,1604,1501,1466,1392,1367,1248,1167,1074.
Mass spectrum (FAB) m/z:456 ((M+Na)
+)
Embodiment 68 (c)
(4R)-[2-(benzo [b] thiophene-6-yl) ethyl]-4-Jia Ji oxazolidine-2-ketone
The positive hexylyloxy of (2R)-t-butoxycarbonyl amino-1--2-methyl-4-(benzo [b] thiophene-6-yl) butane of gained among 24.3g (56.0mmol) embodiment 68 (b) is dissolved in 220ml tetrahydrofuran (THF) and the 110ml methyl alcohol, ice-cooled following to wherein adding 110ml 1N aqueous sodium hydroxide solution, stirred 15 minutes down ice-cooled, under room temperature, stirred 2 hours again.Behind the reaction solution concentrating under reduced pressure, add entry, use dichloromethane extraction, wash dichloromethane layer with saturated brine.Through anhydrous sodium sulfate drying, decompression is heated up in a steamer and is desolvated then, obtains the crude product of 18.8g (100%) with dichloromethane layer.The gained crude product is dissolved in the 380ml dimethyl formamide,, stirred 5 minutes down, at room temperature stirred 1 hour ice-cooled at ice-cooled 9.43g (84.1mmol) potassium tert.-butoxide that adds down.In reaction solution, add entry, use ethyl acetate extraction, ethyl acetate layer is washed with saturated brine.Through anhydrous sodium sulfate drying, decompression is heated up in a steamer and is desolvated then with ethyl acetate layer.Resistates is passed through silica gel column chromatography (eluting solvent; Hexane: ethyl acetate=3: 2-2: 1) purifying obtains 13.8g (94%) and is the title compound of white solid.
By analyzing with optically-active HPLC post (ChiralCel AD (Daicel), (0.46cm * 25cm), eluting solvent; Normal hexane: 2-propyl alcohol=70: 30, flow velocity: 0.5ml/ minute) determines the optical purity of gained (4R)-[2-(benzo [b] thiophene-6-yl) ethyl]-4-Jia Ji oxazolidine-2-ketone.
(15.9 minutes) of elder generation's wash-out are the 4S bodies, and (17.6 minutes) of back wash-out are the 4R bodies, confirm that the optical purity in this reaction is 80%ee.
[α]
D 24+2.3(c0.6，CHCl
3)
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3) δ ppm:7.73 (d, 1H, J=8.2Hz), 7.68 (s, 1H), 7.38 (d, 1H, J=5.7Hz), 7.29 (d, 1H, J=13.0Hz), 7.18 (d, 1H, J=13.6Hz), 5.91 (br s, 1H), 4.21 (d, 1H, J=8.7Hz), 4.09 (d, 1H, J=8.7Hz), 2.84-2.76 (m, 2H), 1.97 (t, J=8.5Hz, 3H).
Infrared absorption spectrum vmax cm
-1(KBr): 3292,2970,2930,1749,1722,1601,1479,1461,1397,1277,1045.
Mass spectrum (EI) m/z:261 (M
+)
Embodiment 69
(2R)-the positive hexylyloxy of t-butoxycarbonyl amino-3--2-methyl isophthalic acid-propyl alcohol
With 200mg (0.97mmol) 2-t-butoxycarbonyl amino-2-methyl isophthalic acid, ammediol is dissolved in the 2ml diisopropyl ether, add 0.16ml (1.02mmol) n-caproic acid vinyl acetate and 20mg lipase [from the fixedly lipase of Rhodopseudomonas (TOYOBO, 0.67U/mg)], at room temperature stirred 4 hours.
Behind the insolubles in the elimination reaction mixture, with the resistates concentrating under reduced pressure, with the quick silica gel column chromatography (eluting solvent of resistates warp; Normal hexane: ethyl acetate=10: 1-7: 3) carry out purifying, obtain 258mg (87%) and be the title compound of colorless oil.
By analyzing with optically-active HPLC post (ChiralCel OF, Daicel, 0.46cm φ * 25cm, eluting solvent; Hexane: 2-propyl alcohol=70: 30, flow velocity: 0.5ml/ minute) determines the optical purity of the positive hexylyloxy of gained (2R)-t-butoxycarbonyl amino-3--2-methyl isophthalic acid-propyl alcohol.
(8.2 minutes) of elder generation's wash-out are the 2S bodies, and (10.5 minutes) of back wash-out are the 2R bodies, confirm that the optical purity in this reaction is 89%ee.
In addition, can be by comparative studies easily by the middle compound known of the synthetic document (TetrahedronAsymmetry 10 (1999) 4653-4661) of this compound, be the specific rotatory power of (2R)-t-butoxycarbonyl amino-2-methyl-3-butene-1-alcohol prepared in the reference example 1 (a), determine its absolute configuration.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CD
3CL
3) δ ppm:4.89 (1H, br.s), 4.24 (1H, d, J=11.2H), 4.19 (1H, d, J=11.2Hz), 3.66-3.54 (2H, m), 2.36 (2H, t, J=7.4Hz), and 1.69-1.57 (2H, m), 1.44 (9H, s), and 1.39-1.22 (4H, m), 1.25 (3H, s), 0.90 (3H, t, J=6.6Hz)
Infrared absorption spectrum v
MaxCm
-1(CHCL
3): 3411,3380,2961,2934,1722,1504,1459,1392,1368,1292,1248,1168,1077,1015
Specific rotation [α]
24 D:-1.1 ° (c=0.81, methyl alcohol)
Embodiment 70
(2R)-the positive hexylyloxy of t-butoxycarbonyl amino-3--2-ethyl-1-propyl alcohol
Use 200mg (0.91mmol) 2-t-butoxycarbonyl amino-2-ethyl-1, ammediol is operated equally with embodiment 69, obtains 252mg (87%) and is the title compound of colorless oil.
By analyzing with optically-active HPLC post (ChiralCel OF, Daicel, 0.46cm φ * 25cm, eluting solvent; Hexane: 2-propyl alcohol=70: 30, flow velocity: 0.5ml/ minute) determines the optical purity of the positive hexylyloxy of gained (2R)-t-butoxycarbonyl amino-3--2-ethyl-1-propyl alcohol.
(8.5 minutes) of elder generation's wash-out are the 2S bodies, and (10.7 minutes) of back wash-out are the 2R bodies, confirm that the optical purity in this reaction is 95%ee.
In addition, can be by comparative studies easily by the middle compound known of the synthetic document (HelveticaChimica Acta 69 (1986) 1365-1377) of this compound, be the specific rotatory power of (+)-(R)-α-ethyl-α-vinyl glycine prepared in the reference example 5 (f), determine its absolute configuration.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3) δ ppm:4.78 (1H, br.s), 4.28 (1H, d, J=11.1Hz), 4.13 (1H, d, J=11.1Hz), 3.72-3.57 (2H, m), 2.35 (2H, t, J=7.6Hz), 1.83-1.54 (4H, m), 1.44 (9H, s), 1.38-1.24 (4H, m), 0.95-0.86 (6H, m)
Infrared absorption spectrum v
Max(CHCl
3) cm
-1: 3371,2966,2935,1722,1503,1450,1368,1249,1168,1086,1028,866,781
Specific rotation [α]
24 D:-2.4 ° (c=0.72, methyl alcohol)
Use synthetic compound among embodiment 69 or the embodiment 70, prepare known useful compound (-)-(R)-Alpha-Methyl-α-vinyl glycine (reference example 1), (+)-(S)-Alpha-Methyl-α-ethynyl glycine (reference example 2) and (+)-(R)-α-ethyl-α-vinyl glycine (reference example 3).
Reference example 1
(-)-(R)-Alpha-Methyl-α-vinyl glycine
Reference example 1 (a)
(2R)-t-butoxycarbonyl amino-2-methyl-3-butene-1-alcohol
In 1.5g (4.9mmol) embodiment 69, add 4A molecular sieve (10.5g) in the dichloromethane solution (18ml) of the prepared positive hexylyloxy of (2R)-t-butoxycarbonyl amino-3--2-methyl isophthalic acid-propyl alcohol, at room temperature stirred 10 minutes, add 2.1g (9.8mmol) pyridinium chlorochromate then, stirred 1 hour.
In this reaction solution, add diethyl ether, use silica gel short column (elutriant: elimination insolubles diethyl ether) then.Organic solvent is heated up in a steamer in decompression, obtains the 1.5g resistates, uses it for subsequent reaction.
At 0 ℃, in the tetrahydrofuran (THF) suspension (10ml) of 4.5g (12.5mmol) Diethylaminoethyl San Ben Phosphonium, add 1.3g (11.5mmol) potassium tert.-butoxide, stirred 1 hour.
In this reaction solution, drip the tetrahydrofuran solution (10ml) of gained resistates in the reaction of front.
This reaction solution was stirred 30 minutes at 0 ℃, behind the adding distilled water, use ethyl acetate extraction.It is washed successively with distilled water, saturated brine, through dried over mgso.Heat up in a steamer and desolvate, then by silica gel short column (elutriant; Hexane: ethyl acetate=10: 1) remove insolubles.
Concentrated solvent is made methanol solution (20ml) with 1.2g gained resistates then, to wherein adding 1N aqueous sodium hydroxide solution (20ml), at room temperature stirs 30 minutes.In this reaction solution, add diethyl ether, wash successively with distilled water, saturated brine then, through dried over mgso.
Heat up in a steamer and desolvate, then by preparation thin-layer chromatography (elutriant; Hexane: ethyl acetate=1: 1) carry out purifying, obtain 180mg (0.894mmol, yield 18%) title compound.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3) δ ppm:5.89 (1H, ddd, J=11.0,6.6,1.5Hz), 5.21 (1H, d, J=1.5Hz), 5.17 (1H, d, J=6.6Hz), 4.84 (1H, br.s), 3.76 (1H, br.s), 3.62 (2H, m), 1.44 (9H, s), 1.32 (3H, s)
Infrared absorption spectrum v
Max(CHCl
3) cm
-1: 3418,3348,2979,1692,1499,1455,1393,1368,1283,1253,1170,1074,918
Specific rotation [α]
24 D:+10.4 ° (c=0.51, methyl alcohol)
Reference example 1 (b)
(2R)-t-butoxycarbonyl amino-2-methyl-3-crotonaldehyde
(2R)-t-butoxycarbonyl amino-2-methyl-3-butene-1-alcohol of gained among 180mg (0.894mmol) reference example 1 (a) is dissolved in the 5.0ml methylene dichloride, under ice-cooled, add 2.0g 4A molecular sieve, 386mg (1.79mmol) pyridinium chlorochromate, at room temperature stirred 1 hour.In reaction solution, add ether, behind the insolubles in the elimination reaction mixture, with the resistates concentrating under reduced pressure.
Resistates is passed through quick silica gel column chromatography (eluting solvent; Normal hexane: ethyl acetate=10: 1) carry out purifying, obtain 160mg (90%) and be the title compound of colorless oil.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3) δ ppm:9.26 (1H, s), 5.83 (1H, dd, J=17.5,10.6Hz), 5.35 (1H, d, J=10.6Hz), 5.32 (1H, d, J=17.5Hz), 5.22 (1H, br.s), 1.48 (3H, s), 1.45 (9H, s)
Infrared absorption spectrum v
Max(CHCl
3) cm
-1: 3350,2980,1737,1707,1505,1455,1369,1279,1256,1168,1069,925,867
Reference example 1 (c)
(2R)-t-butoxycarbonyl amino-2-methyl-3-butenoic acid
(2R)-t-butoxycarbonyl amino-2-methyl-3-crotonaldehyde of gained among 160mg (0.803mmol) reference example 1 (b) is dissolved in the 8.0ml trimethyl carbinol and the 2.0ml water, add 0.38ml (3.61mmol) 2-methyl-2-butene, 96mg (0.803mmol) SODIUM PHOSPHATE, MONOBASIC dihydrate, 254mg (2.81mmol) Textone, at room temperature stirred 1 hour.
In reaction solution, add ethyl acetate, ethyl acetate layer is washed with saturated brine.Through anhydrous magnesium sulfate drying, decompression is heated up in a steamer and is desolvated then with ethyl acetate layer.
Resistates is passed through quick silica gel column chromatography (eluting solvent; Normal hexane: ethyl acetate=20: 1-1: 1) carry out purifying, obtain 130mg (75%) and be the title compound of colorless oil.
NMR (Nuclear Magnetic Resonance) spectrum (400MHa, CDCl
3) δ ppm:5.07 (1H, br.s), 5.68 (1H, br.s), 5.12 (1H, d, J=17.4Hz), 5.05 (1H, d, J=10.6Hz), 1.48 (3H, s), 1.40 (9H, s)
Infrared absorption spectrum v
Max(CHCl
3) cm
-1: 3394,2980,1691,1602,1483,1455,1368,1253,1172,1066,756
Reference example 1 (d)
(-)-(R)-Alpha-Methyl-α-vinyl glycine hydrochloride
(2R)-t-butoxycarbonyl amino-2-methyl-3-butenoic acid of gained among 120mg (0.557mmol) reference example 1 (c) is dissolved in the 1.5ml ethanol, adds 1.5ml 4N Yan Suan dioxane solution, at room temperature stirred 18 hours.
With the reaction solution concentrating under reduced pressure, with the ether washing, drying obtains 72mg (85%) white solid.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3) δ ppm:6.07 (1H, dd, J=17.6,11.0Hz), 5.48 (1H, d, J=11.1Hz), 5.47 (1H, d, J=17.6Hz), 1.66 (3H, s)
Infrared absorption spectrum v
Max(KBr) cm
-1: 3349,3029,1751,1524,1200,954
Specific rotation [α]
36 D:-18.7 ° of (c=0.70, H
2O)
Reference example 1 (e)
(-)-(R)-Alpha-Methyl-α-vinyl glycine
(-)-(R)-Alpha-Methyl-α-vinyl glycine hydrochloride of gained among 60mg (0.40mmol) reference example 1 (d) is dissolved in the 1.5ml ethanol, adds the 1.5ml 1,2 epoxy prapane, reflux 2 hours.By the white solid in the filtering reacting liquid, obtain 32mg (70%) and be the title compound of white solid.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3) δ ppm:6.17 (1H, dd, J=17.2,10.6Hz), 5.56 (1H, d, J=10.6Hz), 5.54 (1H, d, J=17.2Hz), 1.43 (3H, s)
Infrared absorption spectrum v
Max(KBr) cm
-1: 3600-2500,1605,1535,1455,1415,1385,1360,1280,1235,1150,1000,940
Specific rotation [α]
26 D:-27.6 ° of (c=0.62, H
2O)
Reference example 2
(+)-(S)-Alpha-Methyl-α-ethynyl glycine
Reference example 2 (a)
3-tertbutyloxycarbonyl-2, the 2-dimethyl-(4R)-positive hexylyloxy methyl-4-Jia Ji oxazolidine
The positive hexylyloxy of (2R)-t-butoxycarbonyl amino-3--2-methyl isophthalic acid-propyl alcohol of gained among 10.1g (33.3mmol) embodiment 69 is dissolved in the 152ml methylene dichloride, add 16.4ml (133mmol) acetone dimethyl-acetal and 172mg (1.00mmol) tosic acid, at room temperature stirred 12 hours.
Concentration of reaction solution passes through quick silica gel column chromatography (eluting solvent with resistates; Normal hexane: ethyl acetate=10: 1) carry out purifying, obtain 5.72g (50%) and be the title compound of colorless oil.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3) δ ppm:4.29 (1H, s), 4.18 (1H, s), 3.99 (1H, m), 3.64 (1H, m), 2.28-2.34 (2H, m), 1.26-1.25 (24H, m), 0.89 (3H, t)
Specific rotation [α]
25 D:+17.2 ° of (c=1.50, CHCl
3)
Reference example 2 (b)
3-tertbutyloxycarbonyl-2, the 2-dimethyl-(4S)-hydroxymethyl-4-Jia Ji oxazolidine
3-tertbutyloxycarbonyl-2 with gained among 13.7g (39.9mmol) reference example 2 (a), the 2-dimethyl-(4R)-just hexylyloxy methyl-4-Jia Ji oxazolidine is dissolved in the 200ml methylene dichloride, at-78 ℃, drip 99ml (99.7mmol) diisobutylaluminium hydride (1.0M hexane solution).
After 30 minutes, return back to room temperature-78 ℃ of stirrings, add the sodium tartrate-aqueous solutions of potassium of 200ml 10% weight, vigorous stirring 30 minutes.
Reaction solution is extracted with diethyl ether, the ether layer through anhydrous sodium sulfate drying, then with the resistates concentrating under reduced pressure, is passed through quick silica gel column chromatography (eluting solvent with resistates; Normal hexane: ethyl acetate=5: 2) carry out purifying, obtain 10.5g (100%) and be the title compound of white crystals.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3) δ ppm:4.49 (1H, br.s), 3.55-3.71 (4H, m), 1.56 (3H, s), 1.49 (12H, s), 1.42 (3H, s)
Specific rotation [α]
25 D:-1.67 ° of (c=1.45, CHCl
3).
Reference example 2 (c)
3-tertbutyloxycarbonyl-2, the 2-dimethyl-(4R)-formyl radical-4-Jia Ji oxazolidine
3-tertbutyloxycarbonyl-2 with gained among 9.79g (39.9mmol) reference example 2 (b), 2-dimethyl-(4S)-hydroxymethyl-4-Jia Ji oxazolidine is dissolved in the 150ml methylene dichloride, at ice-cooled 13.0g (59.8mmol) pyridinium chlorochromate and the 65.0g 4A molecular sieve of adding down, at room temperature stirred 1 hour.
Add diethyl ether in reaction solution, use the silicagel column filtering reacting liquid then, concentrating under reduced pressure filtrate afterwards is by quick silica gel column chromatography (eluting solvent; Normal hexane: ethyl acetate=8: 1) carry out purifying, obtain 8.07g (88%) and be the title compound of white crystals.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3) δ ppm:9.40-9.48 (1H, s), 3.91 (1H, d, J=9.2Hz), 3.67 (1H, d, J=9.2Hz), 1.14-1.66 (18H, m)
Specific rotation [α]
25 D+ 20.6 ° of (c=1.25, CHCl
3)
Reference example 2 (d)
3-tertbutyloxycarbonyl-2, the vinyl-4-Jia Ji oxazolidine of 2-dimethyl-(4S)-(2, the 2-dibromo)
17.3g (65.8mmol) triphenyl phosphine is dissolved in the 25ml methylene dichloride, drips 10.9g (32.9mmol) carbon tetrabromide is dissolved in formed solution in the 15ml methylene dichloride down, stirred 5 minutes down ice-cooled ice-cooled.In described reaction solution, add resulting 4.00g (16.4mmol) 3-tertiary butyloxycarbonyl carbonyl-2 in the reference example 2 (c); 2-dimethyl-(4S)-formyl radical-4-Jia Ji oxazolidine is dissolved in the 40ml methylene dichloride and the solution that forms; at room temperature stirred 14 hours; behind the insolubles in the elimination reaction mixture; the concentrating under reduced pressure resistates obtains 4.70g (71.2%) and is the not purifying title compound of colorless oil.
Reference example 2 (e)
3-tertbutyloxycarbonyl-2, the 2-dimethyl-(4S)-ethynyl-4-Jia Ji oxazolidine
3-tertbutyloxycarbonyl-2 with gained among 4.70g (11.8mmol) reference example 2 (d), the 2-dimethyl-(4S)-(2, the 2-dibromo) vinyl-4-Jia Ji oxazolidine is dissolved in the 94ml tetrahydrofuran (THF),-78 ℃, stir under, drip n-Butyl Lithium (1.6N hexane solution), stirred 3.5 hours at-78 ℃.
In reaction solution, add the 100ml saturated aqueous ammonium chloride, use ethyl acetate extraction.With the ethyl acetate layer anhydrous sodium sulfate drying, the concentrating under reduced pressure resistates passes through quick silica gel column chromatography (eluting solvent with resistates then; Normal hexane: ethyl acetate=15: 1) carry out purifying, obtain 2.21g (78%) and be the title compound of white crystals.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3) δ ppm:4.13 (1H, d, J=8.4Hz), 3.84 (1H, d, J=8.4Hz), 2.32 (1H, s), 1.49-1.69 (18H, m)
Specific rotation [α]
25 D:+65.6 ° of (c=1.10, CHCl
3)
Reference example 2 (f)
(2S)-amino-2-methyl-3-butine-1-alcohol
The 3-tertbutyloxycarbonyl-2 of gained in 350mg (1.46mmol) reference example 2 (e), add 10ml hydrochloric acid in 2-dimethyl-(4S)-ethynyl-4-Jia Ji oxazolidine, at room temperature stirred 2 hours, with the reaction solution concentrating under reduced pressure, obtaining 127mg is the not purifying title compound of yellow oil.
Reference example 2 (g)
(2S)-t-butoxycarbonyl amino-2-methyl-3-butine-1-alcohol
(2S)-amino-2-methyl-3-butine-1-alcohol of gained among 127mg (1.28ml) reference example 2 (f) is dissolved in 1ml water and the 5ml tetrahydrofuran (THF), add 380mg (1.74mmol) dimethyl dicarbonate butyl ester and 385mg (3.63mmol) anhydrous sodium carbonate, at room temperature stirred 14 hours.
In reaction solution, add the 6ml saturated aqueous ammonium chloride, use ethyl acetate extraction, with ethyl acetate layer through anhydrous sodium sulfate drying, concentrating under reduced pressure resistates afterwards.
Resistates is passed through quick silica gel column chromatography (eluting solvent; Normal hexane: ethyl acetate=1: 1) carry out purifying, obtain 154mg (53%) and be the title compound of white crystals.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3) δ ppm:5.00 (1H, br.s), 3.78 (1H, dd, J=6.0 and 11.2Hz), 3.67 (1H, dd, J=7.9 and 11.2Hz), 3.20 (1H, br.s), 2.40 (1H, s), 1.55 (3H, s), 1.46 (9H, s)
Specific rotation [α]
25 D:+1.89 ° of (c=0.70, CHCl
3)
Reference example 2 (h)
(2S)-t-butoxycarbonyl amino-2-methyl-3-butynoic acid
(2S)-t-butoxycarbonyl amino-2-methyl-3-butine-1-alcohol of gained among 1.20g (6.02mmol) reference example 2 (g) is dissolved in the 30ml acetone, adds 3.48ml (9.03mmol) Jones reagent down, stirred 2 hours down ice-cooled ice-cooled.Add 3.48ml (9.03mmol) Jones reagent again, at room temperature stirred 14 hours.
In reaction solution, add 5ml 2-propyl alcohol and 30ml water, use ethyl acetate extraction.With ethyl acetate layer through anhydrous sodium sulfate drying, concentrating under reduced pressure resistates then, obtaining 1.38g is the not purifying title compound of yellow oil.
Reference example 2 (i)
(+)-(S)-Alpha-Methyl-α-ethynyl glycine hydrochloride
(2S)-t-butoxycarbonyl amino-2-methyl-3-butynoic acid of gained among 1.38g (6.02mmol) reference example 2 (h) is dissolved in the 20ml tetrahydrofuran (THF), adds 10ml hydrochloric acid, at room temperature stirred 5 hours.With the reaction solution concentrating under reduced pressure, add 20ml water and 10ml ethyl acetate, the concentrating under reduced pressure water layer obtains 0.24g (27%) and is the not purifying title compound of yellow crystal.
Reference example 2 (j)
(+)-(S)-Alpha-Methyl-α-ethynyl glycine
In 0.24g (6.02mmol) reference example 2 (i), add 9ml ethanol and 3ml 1,2 epoxy prapane, reflux 2 hours in (+)-(S)-Alpha-Methyl-α-ethynyl glycine hydrochloride of gained.Filtering reacting liquid washs solids with ether, obtain 108mg (60%) and be the title compound of white crystals.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3) δ ppm:3.06 (1H, s), 1.77 (3H, s)
Specific rotation [α]
25 D:+41.7 ° of (c=0.96, H
2O)
Reference example 3
(+)-(R)-α-ethyl-α-vinyl glycine
Reference example 3 (a)
(2S)-the positive hexylyloxy of t-butoxycarbonyl amino-2-ethyl-3--1-propionic aldehyde
The positive hexylyloxy of (2R)-t-butoxycarbonyl amino-3--2-ethyl-1-propyl alcohol of gained among 3g (9.45mmol) embodiment 70 is dissolved in the 60ml methylene dichloride, in ice-cooled 20g 4A molecular sieve, 4.07g (18.9mmol) pyridinium chlorochromate of adding down, at room temperature stirred 1 hour.Add ether in reaction solution, the insolubles in the elimination reaction mixture is then with the resistates concentrating under reduced pressure.
Resistates is passed through quick silica gel column chromatography (eluting solvent; Normal hexane: ethyl acetate=10: 1) carry out purifying, obtain 2.79g (94%) and be the title compound of colorless oil.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3) δ ppm:9.34 (1H, s), 5.29 (1H, br.s), 4.60 (1H, d, J=11.5Hz), 4.40 (1H, d, J=11.5Hz), 2.28 (2H, t, J=7.5Hz), 2.05-2.20 (1H, m), 1.70-1.80 (1H, m), 1.55-1.65 (2H, m), 1.45 (9H, s), and 1.25-1.40 (4H, m), 0.90 (3H, t, J=7.0Hz), 0.81 (3H, t, J=7.5Hz)
Infrared absorption spectrum v
Max(CHCl
3) cm
-1: 3418,2979,2934,2873,1737,1710,1496,1369,1251,1160
Mass spectrum (FAB) m/z:316 ((M+H)
+)
Reference example 3 (b)
(2R)-t-butoxycarbonyl amino-2-ethyl-3-butene-1-alcohol-n-hexoate
7.90g (22.0mmol) Diethylaminoethyl San Ben Phosphonium is suspended in the 25ml tetrahydrofuran (THF),, under nitrogen atmosphere, stirred 1 hour at ice-cooled 2.28g (20.3mmol) potassium tert.-butoxide that adds down.
The positive hexylyloxy of (2S)-t-butoxycarbonyl amino-2-ethyl-3--1-propionic aldehyde with gained among 2.79g (8.85mmol) reference example 3 (a) is dissolved in the 25ml tetrahydrofuran (THF) afterwards, is added drop-wise under ice-cooled in the previous reaction liquid, stirs 15 minutes.
In reaction solution, add entry, use ethyl acetate extraction, ethyl acetate layer is washed with saturated brine, then with ethyl acetate layer through anhydrous magnesium sulfate drying, decompression is afterwards heated up in a steamer and is desolvated.
Resistates is passed through quick silica gel column chromatography (eluting solvent; Normal hexane: ethyl acetate=40: 1-20: 1) carry out purifying, obtain 1.30g (47%) and be the title compound of colorless oil.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3) δ ppm:5.78 (1H, dd, J=17.6,11.0Hz), 5.22 (1H, d, J=11.0Hz), 5.12 (1H, d, J=17.6Hz), 4.62 (1H, br.s), 4.29 (2H, s), 2.31 (2H, t, J=7.5Hz), 1.83-1.95 (1H, m), 1.55-1.75 (3H, m), 1.44 (9H, s), 1.25-1.35 (4H, m), 0.83-0.93 (6H, m)
Infrared absorption spectrum v
Max(CHCl
3) cm
-1: 3448,2972,2934,2873,1721,1494,1368,1249,1163
Mass spectrum (FAB) m/z:314 ((M+H)
+)
Reference example 3 (c)
(2R)-t-butoxycarbonyl amino-2-ethyl-3-butene-1-alcohol
(2R)-t-butoxycarbonyl amino-2-ethyl-3-butene-1-alcohol-n-hexoate of gained among 1.30g (4.15mmol) reference example 3 (b) is dissolved in the 20ml methyl alcohol,, at room temperature stirred 2 hours at the ice-cooled 40ml 1N sodium hydroxide that adds down.
In reaction solution, add entry,, the ether layer washed with saturated brine with diethyl ether extraction, then with the ether layer through anhydrous magnesium sulfate drying, decompression is afterwards heated up in a steamer and is desolvated.
Resistates is passed through quick silica gel column chromatography (eluting solvent; Normal hexane: ethyl acetate=9: 1-4: 1) carry out purifying, obtain 0.85g (95%) and be the title compound of white solid.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3) δ ppm:5.77 (1H, dd, J=17.0,10.7Hz), 5.25 (1H, d, J=10.7Hz), 5.16 (1H, d, J=17.0Hz), 4.77 (1H, br.s), 4.10 (1H, br.s), 3.65-3.75 (2H, m), 1.58-1.83 (2H, m), 1.45 (9H, s), 0.87 (3H, t, J=7.5Hz)
Infrared absorption spectrum v
Max(CHCl
3) cm
-1: 3348,3275,2987,2969,2935,1685,1541,1277,1170,1053
Mass spectrum (FAB) m/z:216 ((M+H)
+)
Specific rotation [α]
24 D:+2.8 ° (c=1.03, methyl alcohol)
Reference example 3 (d)
(2R)-t-butoxycarbonyl amino-2-ethyl-3-crotonaldehyde
Use (2R)-t-butoxycarbonyl amino-2-ethyl-3-butene-1-alcohol of gained among 0.79g (3.67mmol) reference example 3 (c),, obtain 0.63g (80%) and be the title compound of white solid with the same operation of reference example 3 (a).
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3) δ ppm:9.24 (1H, s), 5.83 (1H, dd, J=17.5,10.7Hz), 5.39 (1H, d, J=10.7Hz), 5.31 (1H, d, J=17.5Hz), 5.29 (1H, br.s), 1.85-2.15 (2H, m), 1.57 (9H, s), 0.85 (3H, t, J=7.5Hz)
Infrared absorption spectrum v
Max(CHCl
3) cm
-1: 3443,3416,2980,1712,1489,1369,1249,1162
Mass spectrum (FAB) m/z:214 ((M+H)
+)
Specific rotation [α]
25 D:+69 ° (c=1.00, methyl alcohol)
Reference example 3 (e)
(2R)-t-butoxycarbonyl amino-2-ethyl-3-butenoic acid
(2R)-t-butoxycarbonyl amino-2-ethyl-3-crotonaldehyde of gained among 0.60g (2.81mmol) reference example 3 (d) is dissolved in the 8ml trimethyl carbinol and the 2ml water, add 1.34ml (12.7mmol) 2-methyl-2-butene, 0.44g (2.81mmol) SODIUM PHOSPHATE, MONOBASIC dihydrate and 0.89g (9.85mmol) Textone, at room temperature stirred 1 hour.
In reaction solution, add ethyl acetate, ethyl acetate layer is washed with saturated brine.Behind anhydrous magnesium sulfate drying, decompression is heated up in a steamer and is desolvated with ethyl acetate layer.
Resistates is passed through quick silica gel column chromatography (eluting solvent; Normal hexane: ethyl acetate=20: 1-1: 1) carry out purifying, obtain 0.42g (65%) and be the title compound of white solid.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3) δ ppm:6.05 (1H, dd, J=17.3,10.7Hz), 5.25-5.35 (3H, m), 1.95-2.20 (2H, m), 1.44 (9H, s), 0.90 (3H, t, J=7.4Hz)
Infrared absorption spectrum v
Max(CHCl
3) cm
-1: 3430,2981,1713,1493,1369,1252,1166
Mass spectrum (FAB) m/z:230 ((M+H)
+)
Specific rotation [α]
25 D:+19.4 ° (c=1.00, methyl alcohol)
Reference example 3 (f)
(+)-(R)-α-ethyl-α-vinyl glycine
(2R)-t-butoxycarbonyl amino-2-ethyl-3-butenoic acid of gained among 379mg (1.65mmol) reference example 3 (e) is dissolved in the 2ml ethanol, adds 2ml 4N Yan Suan dioxane solution, at room temperature stirred 18 hours.
With the reaction solution concentrating under reduced pressure, with ether washing, drying.The gained white solid is dissolved in the 6ml ethanol, adds the 2ml 1,2 epoxy prapane, reflux 2 hours by the white solid in the filtering reacting liquid, obtains the title compound that 83mg is a white solid.After filtrate decompression concentrated, resistates is dissolved in the water, with Bond Elut HF (C
18) filter, concentrating under reduced pressure obtains 61mg title compound (adding up to 144mg, yield 75%) then.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3) δ ppm:6.08 (1H, dd, J=17.7,11.1Hz), 5.41 (1H, d, J=11.1Hz), 5.34 (1H, d, J=17.7Hz), 1.82-2.12 (2H, m), 0.95 (3H, t, J=7.6Hz)
Infrared absorption spectrum v
Max(KBr) cm
-1: 3200-2400,1623,1605,1511,1369
Mass spectrum (FAB) m/z:130 ((M+H)
+)
Specific rotation [α]
28 D:+20.6 ° of (c=1.00, H
2O)
Reference example 4
5-(4-fluorophenyl) penta-1-alkynes
2.11g (48.4mmol) sodium hydride is suspended in the 60ml anhydrous tetrahydro furan, drips 10.84g (48.4mmol) diethyl phosphonyl ethyl acetate down, stirred 10 minutes ice-cooled.Dropwise 5 .00g (40.3mmol) 4-fluorobenzaldehyde is dissolved in formed solution in the 60ml anhydrous tetrahydro furan under same temperature subsequently.Reaction solution was stirred 3 hours, inject the 150ml frozen water afterwards, use ethyl acetate extraction.With the organic layer dried over mgso, decompression is heated up in a steamer and is desolvated then, and resistates is passed through quick silica gel column chromatography (eluting solvent; Hexane: ethyl acetate=10: 1-3: 1) carry out purifying, obtain 6.69g (86%) and be the 4-fluoro cinnamic acid ethyl ester of colorless oil.
This ester of 6.52g (33.6mmol) is dissolved in the 100ml ethyl acetate, adds 1.30g5% rhodium/aluminum oxide, under hydrogen atmosphere, room temperature, stirred 8 hours.By diatomite filtration, concentrating under reduced pressure filtrate is dissolved in resistates in the 30ml anhydrous tetrahydro furan with reaction mixture.Under ice-cooled, this drips of solution is added in the suspension that makes 1.26g (33.2mmol) lithium aluminum hydride be suspended in the 60ml anhydrous tetrahydro furan and form.Reaction mixture was stirred 30 minutes under same temperature, add saturated aqueous sodium sulfate then, under room temperature, stirred 10 minutes again.Mixture by diatomite filtration, is used ethyl acetate extraction with filtrate.Organic layer is washed with saturated brine, use dried over mgso then.Decompression is heated up in a steamer and is desolvated, and resistates is passed through quick silica gel column chromatography (eluting solvent; Hexane: ethyl acetate=5: 1-1: 1) carry out purifying, obtain 4.86g (95%) and be 4-fluorophenyl third-1-alcohol of colorless oil.
4.83g (31.3mmol) gained 4-fluorophenyl third-1-alcohol is dissolved in the 50ml methylene dichloride, adds 6.55ml (47.0mmol) triethylamine and 2.91ml (37.6mmol) methylsulfonyl chloride down, under nitrogen atmosphere, stirred 30 minutes ice-cooled.Reaction mixture with the dilution of 50ml methylene dichloride, with 10% ice-cooled hydrochloric acid, saturated brine washing, is used dried over mgso successively then.Decompression is heated up in a steamer and is desolvated, and resistates is dissolved in the 100ml acetone.Then add 9.39g (62.6mmol) sodium iodide, nitrogen atmosphere, 50 ℃ of following stirrings 2 hours.Reaction mixture with the dilution of 250ml ethyl acetate, successively with 10% sodium thiosulfate solution, saturated brine washing, is used dried over mgso then.Decompression is heated up in a steamer and is desolvated, and resistates is passed through quick silica gel column chromatography (eluting solvent; Hexane: ethyl acetate=5: 1-2: 1) carry out purifying, obtain 7.12g (86%) and be the 4-fluorophenyl-propyl iodide of faint yellow oily thing.
Add 50ml sodium carbide (18% dimethylbenzene suspension) in the 20ml hexamethylphosphoramide, under ice-cooled, the 4-fluorophenyl-propyl iodide that adds the previous gained of 7.00g (26.5mmol) is dissolved in formed solution in the 20ml anhydrous dimethyl formamide.Reaction mixture was at room temperature stirred 2 hours.Under ice-cooled, very carefully to wherein injecting frozen water, with the mixture ethyl acetate extraction.Organic layer is washed with saturated brine, use dried over mgso then.Decompression is heated up in a steamer and is desolvated, and resistates is passed through quick silica gel column chromatography (eluting solvent; Hexane) carries out purifying, obtain 2.67g (62%) and be the title compound of colorless oil.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3): δ 1.82 (2H, m), 1.99 (1H, t, J=2.6Hz), 2.19 (2H, m), 2.71 (2H, t, J=7.5Hz), 6.97 (2H, m), 7.14 (2H, m)
Mass spectrum (EI) m/z:162 (M
+)
Reference example 5
5-(4-p-methoxy-phenyl) penta-1-alkynes
The same with reference example 4, make title compound with 3-(4-p-methoxy-phenyl)-propyl iodide and sodium carbide.
NMR (Nuclear Magnetic Resonance) spectrum (500MHz, CDCl
3): δ 1.78-1.88 (2H, m), 1.98 (1H, t, J=2.6Hz), 2.15-2.22 (2H, m), 2.67 (2H, t, J=7.5 Hz), 3.79 (3H, s), 6.83 (2H, d, J=8.6Hz), 7.11 (2H, d, J=8.6Hz)
Mass spectrum (EI) m/z:174 (M
+)
Reference example 6
5-phenyl penta-1-alkynes
The same with reference example 4, make title compound with 3-phenyl-propyl iodide and sodium carbide.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3): δ 1.81-1.89 (2H, m), 1.99 (1H, t, J=2.8Hz), 2.21 (2H, dt, J=2.8,7.6Hz), 2.74 (2H, t, J=7.6 Hz), 7.16-7.23 (3H, m), 7.26-7.32 (2H, m)
Mass spectrum (EI) m/z:144 (M
+)
Reference example 7
5-cyclohexyl penta-1-alkynes
The same with reference example 4, make title compound with 3-cyclohexyl-1-sulphur propane and sodium carbide.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3): δ 0.75-1.38 (13H, m), 1.48-1.59 (2H, m), 1.94 (1H, t, J=2.8Hz), 2.16 (2H, dt, J=2.8,7.2Hz)
Mass spectrum (EI) m/z:150 (M
+)
Reference example 8
4-(4-fluorophenoxy) fourth-1-alkynes
5.00g (44.6mmol) 4-fluorophenol, 3.38ml (44.6mmol) 3-butine-1-alcohol, 17.5g (66.9mmol) triphenyl phosphine are dissolved in the 100ml tetrahydrofuran (THF), at ice-cooled 11.7g (66.9mmol) diethyl azodiformate that adds down, at room temperature stirred 18 hours.The concentrating under reduced pressure solvent adds 200ml hexane and 20ml ethyl acetate then, removes by filter the precipitation of separating out, concentrating under reduced pressure filtrate.The gained resistates is passed through quick silica gel column chromatography (eluting solvent; Hexane: ethyl acetate=1: 0) carry out purifying, obtain title compound.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3): δ 2.05 (1H, t, J=2.7Hz), 2.63-2.70 (2H, m), 4.07 (2H, t, J=7.0Hz), 6.82-6.90 (2H, m), 6.94-7.02 (2H, m)
Mass spectrum (EI) m/z:164 (M
+)
Reference example 9
3-(4-methylphenoxy)-1-propine
The same with reference example 8, make title compound with 4-methylphenol and propargyl alcohol.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3): δ 2.29 (3H, s), 2.50 (1H, t, J=2.4Hz), 4.67 (2H, d, J=2.4Hz), 6.88 (2H, d, J=8.4Hz), 7.10 (2H, d, J=8.4Hz)
Mass spectrum (EI) m/z:146 (M
+)
Reference example 10
The 3-[(4-methylthio group) phenoxy group]-the 1-propine
The same with reference example 8, make title compound with 4-(methylthio group) phenol and propargyl alcohol.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3): δ 2.45 (3H, s), 2.52 (1H, t, J=2.4Hz), 4.68 (2H, d, J=2.4Hz), 6.93 (2H, d, J=8.9Hz), 7.27 (2H, d, J=8.9Hz)
Mass spectrum (EI) m/z:178 (M
+)
Reference example 11
3-(3-methoxyl group phenoxy group)-1-propine
The same with reference example 8, make title compound with 3-methoxyphenol and propargyl alcohol.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3): δ 2.52 (1H, t, J=2.4Hz), 3.79 (3H, s), 4.67 (2H, d, J=2.4Hz), 6.53-6.60 (3H, m), 7.16-7.23 (1H, m)
Mass spectrum (EI) m/z:162 (M
+)
Reference example 12
3-(3, the 4-dimethyl phenoxy)-1-propine
The same with reference example 8, with 3,4-xylenol and propargyl alcohol make title compound.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3): δ 2.20 (3H, s), 2.24 (3H, s), 2.49 (1H, t, J=2.4Hz), 4.65 (2H, d, J=2.4Hz), 6.72 (1H, dd, J=2.4,8.0Hz), 6.78 (1H, d, J=2.4Hz), 7.04 (1H, d, J=8.0Hz)
Mass spectrum (EI) m/z:160 (M
+)
Reference example 13
4-(4-methylphenoxy) fourth-1-alkynes
The same with reference example 8, make title compound with 4-methylphenol and 3-butine-1-alcohol.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3): δ 2.03 (1H, t, J=2.8Hz), 2.28 (3H, s), 2.66 (2H, dt, J=2.8,7.2Hz), 4.07 (2H, t, J=7.2Hz), 6.81 (2H, d, J=8.8Hz), 7.08 (2H, d, J=8.8Hz)
Mass spectrum (EI) m/z:160 (M
+)
Reference example 14
4-cyclohexyloxy fourth-1-alkynes
Add 32ml (0.31mol) pimelinketone, 33.5ml (0.46mol) 1 in the 950ml anhydrous methylene chloride, ammediol, 51.5ml (0.31mol) triethyl orthoformate, 1.44g (6.18mmol) zirconium chloride stirred 1 hour under nitrogen atmosphere, room temperature.Add the ice-cooled 1N aqueous sodium hydroxide solution of 1.5L, use dichloromethane extraction, wash dichloromethane layer with water.Use the anhydrous sodium sulfate drying dichloromethane layer, decompression is heated up in a steamer and is desolvated then.By underpressure distillation purifying resistates, obtain 26.8g (55%) pimelinketone trimethylammonium ketal.
Under nitrogen atmosphere, slowly add 20.5g (0.54mmol) sodium borohydride in the suspension that forms to making 24.9g (0.11mol) zirconium chloride be suspended in the 500ml tetrahydrofuran (THF), at room temperature stirred 20 minutes.Nitrogen atmosphere, ice-cooled down, to wherein drip the 170ml tetrahydrofuran solution that contains the previous gained pimelinketone trimethylammonium ketal of 16.9g (0.11mol), drip finish after, at room temperature stir diel.Add the ice-cooled 2N hydrochloric acid of 600ml down ice-cooled, make reaction terminating, tetrahydrofuran (THF) is heated up in a steamer in decompression.Water ethyl acetate extraction with residual washs ethyl acetate layer with saturated brine.With ethyl acetate layer with anhydrous sodium sulfate drying after, decompression is heated up in a steamer and is desolvated.Resistates is passed through silica gel column chromatography (eluting solvent; Hexane: ethyl acetate=10: 1-5: 2) purifying obtains 13.4g (78%) 3-cyclohexyloxy third-1-alcohol.
11.5g (72.9mmol) gained 3-cyclohexyloxy third-1-alcohol is dissolved in the 240ml methylene dichloride,, under nitrogen atmosphere, stirred 1 hour 40 minutes in ice-cooled 58g 4A molecular sieve, 23.8g (0.11mol) pyridinium chlorochromate of adding down.In reaction solution, add diethyl ether, through diatomite filtration.Diatomite is washed with diethyl ether, and merging filtrate reduces pressure to heat up in a steamer and desolvates afterwards.Resistates is passed through silica gel column chromatography (eluting solvent; Hexane: ethyl acetate=20: 1-10: 1) thick purifying obtains the thick 3-cyclohexyloxy of 8.60g propionic aldehyde.
At nitrogen atmosphere, ice-cooled following, in the 120ml methylene dichloride that contains 36.5g (0.11mol) carbon tetrabromide, drip the 120ml methylene dichloride that contains 57.7g (0.22mol) triphenyl phosphine, after dropping finishes, restir 5 minutes.At nitrogen atmosphere, ice-cooled following, after wherein dripping the 90ml methylene dichloride that contains the thick 3-cyclohexyloxy of 8.60g gained propionic aldehyde, dripping end, stirred 25 minutes.Reaction solution is diluted with methylene dichloride, with saturated sodium bicarbonate aqueous solution, saturated brine washing reaction liquid.With the dichloromethane layer anhydrous sodium sulfate drying, decompression is heated up in a steamer and is desolvated then.Resistates is passed through silica gel column chromatography (eluting solvent; Hexane: ethyl acetate=100: 1-33: 1) purifying obtains 12.6g (55%, 2 step) 4-cyclohexyloxy-1,1-dibromo but-1-ene.
Nitrogen atmosphere ,-78 ℃, to containing 12.6g (40.4mmol) gained 4-cyclohexyloxy-1, Dropwise 5 4ml (81.0mmol) 1.5N n-Butyl Lithium hexane solution in the 130ml tetrahydrofuran (THF) of 1-dibromo but-1-ene.After dripping end, stirred 1 hour, slowly be warming up to room temperature afterwards.After at room temperature stirring 50 minutes, under ice-cooled, add entry, make reaction terminating.With the diethyl ether extraction, the diethyl ether layer is washed with saturated brine.Through anhydrous sodium sulfate drying, decompression is heated up in a steamer and is desolvated then with the diethyl ether layer.Resistates is passed through silica gel column chromatography (eluting solvent; Hexane: ethyl acetate=100: 1-50: 1) purifying obtains 4.35g (71%) title compound.
NMR (Nuclear Magnetic Resonance) spectrum (400MHz, CDCl
3): δ 1.13-1.36 (5H, m), 1.48-1.58 (1H, m), 1.67-1.81 (2H, m), 1.85-1.95 (2H, m), 1.97 (1H, t, J=2.8Hz), 2.45 (2H, dt, J=2.8,7.2Hz), 3.23-3.32 (1H, m), 3.59 (2H, t, J=7.2Hz)
Mass spectrum (EI) m/z:153 (M+H)
+
Test case 1
Mensuration is to the inhibition activity of rat HvGR (graft-vs-host reaction)
(1) adopts the rat [Lewis (male, 6 ages in week, Japanese Charles River Co., Ltd.) and the Japanese SLC of WKAH/Hkm (male, 7 all ages) Co., Ltd.] of 2 strains.5 every group rats (host) have been used.
(2) HvGR's induces
From the spleen separating spleen cell of WKAH/Hkm rat or Lewis rat, with 1 * 10
8The concentration of individual/ml is suspended in the RPMI1640 substratum (LIFE TECHNOLOGIES, Rockville MD U.S.A.).(the spleen cell number is 1 * 10 with 100 μ l
7) the spleen cell suspension subcutaneous injection of WKAH/Hkm rat or Lewis rat goes into the two hind legs foot pads (foot pad) of Lewis rat.
(3) compound gives
Compound is suspended in the 0.5% tragacanth gum solution.With the ratio of the compound after suspending, 1 time on the 1st, give compound from continuous 4 days per os of spleen cell injection day beginning and organize (injected WKAH/Hkm Rats Spleen cell and given the Lewis rat of test compounds) with 5ml/kg.To giving 0.5% tragacanth gum solution but not test compounds with the strain group Lewis rat of Lewis Rats Spleen cell (injected group) and control group (injected WKAH/Hkm Rats Spleen cell but do not give the Lewis rat of test compounds) per os.
(4) to the active measuring method of the inhibition of HvGR
Deduct average rouge lymphoglandula weight with the strain group (" the rouge lymphoglandula weight that causes by HvGR ") from the rouge lymphoglandula weight of each rat, with respect to average " the rouge lymphoglandula weight that is caused by HvGR " of control group, " the rouge lymphoglandula weight that is caused by HvGR " of each rat is calculated inhibiting rate in being organized by compound.The inhibition activity of representing compound with the ID50 value of calculating by compound administered dose and inhibiting rate with method of least squares (mg/kg).
[table 5]
In the last table, the compound that comparative compound 1 is put down in writing for embodiment 29 in WO 94/08943 communique.
Test case 2
Mensuration is to the inhibition activity of adjuvant arthritis morbidity
1. the preparation of adjuvant
Following preparation: the dead bacterium of butyric acid mycobacterium (Mycobacterium butyricum) is suspended in the whiteruss, makes its ratio reach 2mg/ml, ultrasonication.
2. the preparation of test compounds
Test compounds is suspended or be dissolved in the 0.5% tragacanth gum solution.
3. adjuvant arthritis induces
The adjuvant intradermal injection of preparation among the 0.05ml 1 is gone into the right hind foot sole of the foot of rat (being generally Lewis system).Common 1 group is 5.Set 1 group and be the group of injection adjuvant (normal group) not.
4. compound gives
Ratio with 1kg rat body weight 5ml is injected day from adjuvant, and 1 time on the 1st, continuous 21 days per os give the compound of preparation in 2.To 1 group (control group) having given adjuvant and not the group of injection adjuvant give 0.5% tragacanth gum solution.
5. compound is to the active computing method of inhibition of morbidity
After finally giving 1, measure the volume of right hind with sufficient sole of the foot determinator, deduct the mean value of normal group from the value of each rat, should be worth as the swelling volume.With respect to the average swelling volume of control group, calculate inhibiting rate by the swelling volume of each rat that has given compound.Calculate the ID50 value by the administered dose of compound and (group is average) inhibiting rate separately.
This test-results shows that The compounds of this invention has excellent inhibition activity.
[table 6]
In the last table, the compound that comparative compound 1 is put down in writing for embodiment 29 in WO 94/08943 communique.
Claims (9)
- By general formula (La) or (Lb) expression compound:In the formula,R 1And R 2Identical or different, the expression hydrogen atom or as the protecting group of the amino of giving a definition;R 3aThe expression hydrogen atom or as the protecting group of the hydroxyl of giving a definition, perhaps work as R 1During for hydrogen atom, R 2And R 3aTogether expression-(C=O)-group;R 4aExpression C 1-C 6Alkyl;M represents the integer of 0-4;The benzothienyl that Ar represents thienyl, is selected from thienyl that the substituting group as the substituting group group a that gives a definition replaces, benzothienyl or replaced by 1-4 substituting group that is selected from as the substituting group group a that gives a definition by 1-4;Substituting group group a by halogen atom, as the low alkyl group of giving a definition, as the lower alkoxy of giving a definition, as giving a definition lower alkylthio, carboxyl and as the rudimentary aliphatic acidyl of giving a definition form;The protecting group of described amino is selected from as the lower alkoxycarbonyl of giving a definition or can chooses wantonly by the lower alkoxycarbonyl as giving a definition of halogen atom or the replacement of three low alkyl group silyls, and wherein each low alkyl group is as giving a definition;The protecting group of described hydroxyl is selected from as rudimentary aliphatic acidyl of giving a definition and the aromatic acyl group as giving a definition;Described low alkyl group is that carbonatoms is the straight or branched alkyl of 1-6;Described lower alkoxy is that carbonatoms is the straight or branched alkoxyl group of 1-6;Described lower alkylthio is that carbonatoms is the alkylthio of 1-6;Described rudimentary aliphatic acidyl is the carbonyl that links to each other with hydrogen atom or above-mentioned low alkyl group;Described lower alkoxycarbonyl is the carbonyl that links to each other with lower alkoxy as defined above;Described aromatic acyl group for comprise that carbonatoms is the carbonyl that the aryl of the aromatic hydrocarbon of 6-10 links to each other.
- 2. the compound of claim 1, it has general formula (La).
- 3. claim 1 or 2 compound, wherein R 1Be hydrogen atom.
- 4. claim 1 or 2 compound, wherein R 2And R 3aBe together formula-(C=O)-group.
- 5. claim 1 or 2 compound, wherein R 3aBe hydrogen atom.
- 6. claim 1 or 2 compound, wherein R 4aBe methyl or ethyl.
- 7. claim 1 or 2 compound, wherein Ar is thienyl or the thienyl that replaced by 1-4 substituting group that is selected from as the substituting group group a of claim 1 definition.
- 8. claim 1 or 2 compound, wherein Ar is benzothienyl or the benzothienyl that replaced by 1-4 substituting group that is selected from as the substituting group group a of claim 1 definition.
- 9. claim 1 or 2 compound, wherein m is 0.
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| Application Number | Priority Date | Filing Date | Title |
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| JP2000212246 | 2000-07-13 | ||
| JP212246/2000 | 2000-07-13 | ||
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| JP283218/2000 | 2000-09-19 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102260177A (en) * | 2010-05-25 | 2011-11-30 | 中国医学科学院药物研究所 | Propylene glycol derivative, preparation method thereof, pharmaceutical composition thereof and application thereof |
| CN102260178A (en) * | 2010-05-25 | 2011-11-30 | 中国医学科学院药物研究所 | Hydroxyl propanediol derivative, its preparation method, its pharmaceutical composition and its purpose |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1030584A (en) * | 1987-06-30 | 1989-01-25 | 田边制药株式会社 | Novel thiophene derivant and preparation method thereof |
| EP0492497A2 (en) * | 1990-12-24 | 1992-07-01 | Hoechst Aktiengesellschaft | Process for acylating alcohols with immobilized pseudomonaslipase |
| WO1994008943A1 (en) * | 1992-10-21 | 1994-04-28 | Yoshitomi Pharmaceutical Industries, Ltd. | 2-amino-1,3-propanediol compound and immunosuppressant |
| WO1996006068A1 (en) * | 1994-08-22 | 1996-02-29 | Yoshitomi Pharmaceutical Industries, Ltd. | Benzene compound and medicinal use thereof |
| JPH09124564A (en) * | 1995-11-06 | 1997-05-13 | Nikko Rika Kk | Optically active compound mixture and its production |
-
2001
- 2001-07-10 CN CNB2006100025042A patent/CN100415735C/en not_active Expired - Fee Related
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2003
- 2003-01-03 ZA ZA200300086A patent/ZA200300086B/en unknown
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1030584A (en) * | 1987-06-30 | 1989-01-25 | 田边制药株式会社 | Novel thiophene derivant and preparation method thereof |
| EP0492497A2 (en) * | 1990-12-24 | 1992-07-01 | Hoechst Aktiengesellschaft | Process for acylating alcohols with immobilized pseudomonaslipase |
| WO1994008943A1 (en) * | 1992-10-21 | 1994-04-28 | Yoshitomi Pharmaceutical Industries, Ltd. | 2-amino-1,3-propanediol compound and immunosuppressant |
| WO1996006068A1 (en) * | 1994-08-22 | 1996-02-29 | Yoshitomi Pharmaceutical Industries, Ltd. | Benzene compound and medicinal use thereof |
| JPH09124564A (en) * | 1995-11-06 | 1997-05-13 | Nikko Rika Kk | Optically active compound mixture and its production |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102260177A (en) * | 2010-05-25 | 2011-11-30 | 中国医学科学院药物研究所 | Propylene glycol derivative, preparation method thereof, pharmaceutical composition thereof and application thereof |
| CN102260178A (en) * | 2010-05-25 | 2011-11-30 | 中国医学科学院药物研究所 | Hydroxyl propanediol derivative, its preparation method, its pharmaceutical composition and its purpose |
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| CN1800175A (en) | 2006-07-12 |
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