CN102477032B - 2-cyclopropyl-4-substituted-phenoxy-quinoline derivatives, and its preparation method, intermediate and application - Google Patents
2-cyclopropyl-4-substituted-phenoxy-quinoline derivatives, and its preparation method, intermediate and application Download PDFInfo
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Abstract
The invention discloses 2-cyclopropyl-4-substituted-phenoxy-quinoline derivatives as represented by formula A, and its preparation method, intermediate and application. The 2-cyclopropyl-4-substituted phenoxy-quinoline derivatives provided in the invention have good activity in inhibiting HMG-CoA reductase and can be used for preparing medicines which can inhibit HMG-CoA reductase or treat diseases related to hyperlipidemia. In formula A, R1 is H or halogen, R2 is H, halogen, C1-C4 alkoxy groups or a group as represented by formula Q, R3 is H, halogen, or a group as represented by formula Q, and R4 is a group as represented by formula Q, wherein, in formula Q, R is H, halogen, C1-C4 alkyl groups or C1-C4 alkoxy groups.
Description
Technical field
The present invention relates to a class 2-cyclopropyl-4-substituted phenoxyl quinoline derivative, its preparation method, intermediate and the application in field of medicaments thereof.
Background technology
Since the important paathogenic factor that hypercholesterolemia is confirmed to be atherosclerosis and cardiovascular disorder, the researchdevelopment about blood lipid-lowering medicine is rapid.3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (also known as " statin " class) is the main product (Cai Zhengyan of hypolipidemic, Zhou Weicheng, the progress of HMG-CoA reductase inhibitor, Chinese Journal of New Drugs, 2006,15 (22): 1907-1911).The complete synthesis statins gone on the market at present has fluvastatin, atorvastatin, Rosuvastatin and pitavastatin.The value volume and range of product of these medicines also far can not meet the demand of people, and scientific research personnel also must make great efforts to explore, and finds the newtype drug more efficient, cheap, side effect is little.
In prior art, the structure of complete synthesis statins is made up of female ring (indole ring, pyrrole ring, quinoline ring, pyrimidine ring etc.) and side chain two portions.Show the research of the quinoline structure of modification taking pitavastatin as representative: the hydrogen atom cyclopropyl on 2, quinoline ring replaced, and introduce side chain on 3, the quinoline obtained has the activity suppressing HMG-CoA reductase preferably; Quinoline ring introduces the groups such as methyl, chlorine atom or methoxyl group for 6,7 and 8, the derivative obtained also has good Inhibiting enzyme activity (Cai Zhengyan, the progress of Zhou Weicheng .HMG CoA reductase inhibitor, Chinese Journal of New Drugs, 2006,15 (22): 1907-1911).In prior art, 4, quinoline ring is general to be directly connected with to fluorophenyl, Chinese patent CN101210011 with CN101220021 individually discloses two compounds be connected with phenyl ring by sulphur atom and Sauerstoffatom on 4, quinoline ring, and these compounds all have the activity of good suppression HMG-CoA reductase.And introduce while cyclopropyl on 2, quinoline ring, 4 by Sauerstoffatom be connected with aromatic ring compound be not reported so far.
Summary of the invention
Technical problem to be solved by this invention is to provide a class 2-cyclopropyl-4-substituted phenoxyl quinoline derivative, its preparation method, intermediate and suppresses HMG-CoA reductase in preparation or treat the application in the diseases related medicine of hyperlipidemia.Compared with prior art, 2-cyclopropyl-4-substituted phenoxyl quinoline derivative of the present invention has the activity preferably suppressing HMG-CoA reductase.
Therefore, the present invention relates to a class such as formula the 2-cyclopropyl-4-substituted phenoxyl quinoline derivative shown in A;
Wherein, R
1for H or halogen; R
2for H, halogen, C
1~ C
4alkoxyl group or such as formula the group shown in Q; R
3for H, halogen or such as formula the group shown in Q; R
4for such as formula the group shown in Q;
In formula Q, R is H, halogen, C
1~ C
4alkyl or C
1~ C
4alkoxyl group.
Wherein, R is worked as
1during for halogen, described halogen is preferably F, Cl, Br or I, and that better is F.
Wherein, R is worked as
2during for halogen, described halogen is preferably F, Cl, Br or I, and that better is F; Work as R
2for C
1~ C
4alkoxyl group time, described C
1~ C
4alkoxyl group be preferably methoxyl group.
Wherein, R is worked as
3during for halogen, described halogen is preferably F, C1, Br or I, and that better is F.
In formula Q, when R is halogen, described halogen is preferably F, Cl, Br or I, and that better is F; When R is C
1~ C
4alkyl time, described C
1~ C
4alkyl be preferably sec.-propyl; When R is C
1~ C
4alkyl time, described C
1~ C
4alkyl be preferably methoxyl group.
In the present invention, described such as formula the 2-cyclopropyl-4-substituted phenoxyl quinoline derivative shown in A preferably for comprising following compounds:
A1:(4R, 6S)-6-{ (E)-2-[2-cyclopropyl-4-(phenoxy group) quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
A2:(4R, 6S)-6-{ (E)-2-[2-cyclopropyl-4-(3-fluorophenoxy) quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
A3:(4R, 6S)-6-{ (E)-2-[2-cyclopropyl-4-(4-fluorophenoxy) quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
A4:(4R, 6S)-6-{ (E)-2-[2-cyclopropyl-4-(3-methoxyphenoxy) quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
A5:(4R, 6S)-6-{ (E)-2-[2-cyclopropyl-4-(4-methoxyphenoxy) quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
A6:(4R, 6S)-6-{ (E)-2-[2-cyclopropyl-4-(2-sec.-propyl phenoxy group) quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
A7:(4R, 6S)-6-{ (E)-2-[2-cyclopropyl-4-(4-sec.-propyl phenoxy group) quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
A8:(4R, 6S)-6-{ (E)-2-[the fluoro-4-of 2-cyclopropyl-6-(phenoxy group)-quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
A9:(4R, 6S)-6-{ (E)-2-[the fluoro-4-of 2-cyclopropyl-6-(3-fluorophenoxy) quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
A10:(4R, 6S)-6-{ (E)-2-[the fluoro-4-of 2-cyclopropyl-6-(4-fluorophenoxy) quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
A11:(4R, 6S)-6-{ (E)-2-[the fluoro-4-of 2-cyclopropyl-6-(3-methoxyphenoxy) quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
A12:(4R, 6S)-6-{ (E)-2-[the fluoro-4-of 2-cyclopropyl-6-(4-methoxyphenoxy) quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
A13:(4R, 6S)-6-{ (E)-2-[the fluoro-4-of 2-cyclopropyl-6-(2-sec.-propyl phenoxy group) quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
A14:(4R, 6S)-6-{ (E)-2-[the fluoro-4-of 2-cyclopropyl-6-(4-sec.-propyl phenoxy group) quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
A15:(4R, 6S)-6-{ (E)-2-[2-cyclopropyl-6-methoxyl group-4-(4-methoxyphenoxy)-quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
A16:(4R, 6S)-6-{ (E)-2-[2-cyclopropyl-6-methoxyl group-4-(2-sec.-propyl phenoxy group)-quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
A17:(4R, 6S)-6-{ (E)-2-[the fluoro-4-of 2-cyclopropyl-5,6-bis-(phenoxy group)-quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
A18:(4R, 6S)-6-{ (E)-2-[the fluoro-4-of 2-cyclopropyl-5,6-bis-(4-methoxyphenoxy)-quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
A19:(4R, 6S)-6-{ (E)-2-[the fluoro-4-of 2-cyclopropyl-6,7-bis-(phenoxy group)-quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
A20:(4R, 6S)-6-{ (E)-2-[the fluoro-4-of 2-cyclopropyl-6,7-bis-(3-fluorophenoxy) quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
A21:(4R, 6S)-6-{ (E)-2-[the fluoro-4-of 2-cyclopropyl-6,7-bis-(4-fluorophenoxy) quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
A22:(4R, 6S)-6-{ (E)-2-[the fluoro-4-of 2-cyclopropyl-6,7-bis-(3-methoxyphenoxy) quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
A23:(4R, 6S)-6-{ (E)-2-[the fluoro-4-of 2-cyclopropyl-6,7-bis-(4-methoxyphenoxy) quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
A24:(4R, 6S)-6-{ (E)-2-[the fluoro-4-of 2-cyclopropyl-6,7-bis-(4-sec.-propyl phenoxy group) quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
A25:(4R, 6S)-6-{ (E)-2-[fluoro-4,7-bis-(phenoxy group)-quinoline-3-bases of 2-cyclopropyl-6-] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
A26:(4R, 6S)-6-{ (E)-2-[2-cyclopropyl-6-fluoro-4,7-bis-(3-fluorophenoxy) quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
A27:(4R, 6S)-6-{ (E)-2-[2-cyclopropyl-6-fluoro-4,7-bis-(4-fluorophenoxy) quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
A28:(4R, 6S)-6-{ (E)-2-[2-cyclopropyl-6-fluoro-4,7-bis-(3-methoxyphenoxy) quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
A29:(4R, 6S)-6-{ (E)-2-[2-cyclopropyl-6-fluoro-4,7-bis-(4-methoxyphenoxy) quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
A30:(4R, 6S)-6-{ (E)-2-[2-cyclopropyl-6-fluoro-4,7-bis-(4-sec.-propyl phenoxy group) quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
A31:(4R, 6S)-6-{ (E)-2-[2-cyclopropyl-4,6-bis-(phenoxy group) quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
A32:(4R, 6S)-6-{ (E)-2-[2-cyclopropyl-4,6,7-tri-(phenoxy group)-quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
Or A33:(4R, 6S)-6-{ (E)-2-[2-cyclopropyl-4,6,7-tri-(4-fluorophenoxy)-6-methoxy-auinolin-3-base] vinyl-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones.
In the present invention, described such as formula the 2-cyclopropyl-4-substituted phenoxyl quinoline derivative shown in A better for comprising following compounds:
A1:(4R, 6S)-6-{ (E)-2-[2-cyclopropyl-4-(phenoxy group) quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
A3:(4R, 6S)-6-{ (E)-2-[2-cyclopropyl-4-(4-fluorophenoxy) quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
A6:(4R, 6S)-6-{ (E)-2-[2-cyclopropyl-4-(2-sec.-propyl phenoxy group) quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
A7:(4R, 6S)-6-{ (E)-2-[2-cyclopropyl-4-(4-sec.-propyl phenoxy group) quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
A8:(4R, 6S)-6-{ (E)-2-[the fluoro-4-of 2-cyclopropyl-6-(phenoxy group)-quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
A12:(4R, 6S)-6-{ (E)-2-[the fluoro-4-of 2-cyclopropyl-6-(4-methoxyphenoxy) quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
A13:(4R, 6S)-6-{ (E)-2-[the fluoro-4-of 2-cyclopropyl-6-(2-sec.-propyl phenoxy group) quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
A15:(4R, 6S)-6-{ (E)-2-[2-cyclopropyl-6-methoxyl group-4-(4-methoxyphenoxy)-quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
A16:(4R, 6S)-6-{ (E)-2-[2-cyclopropyl-6-methoxyl group-4-(2-sec.-propyl phenoxy group)-quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
A17:(4R, 6S)-6-{ (E)-2-[the fluoro-4-of 2-cyclopropyl-5,6-bis-(phenoxy group)-quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
A18:(4R, 6S)-6-{ (E)-2-[the fluoro-4-of 2-cyclopropyl-5,6-bis-(4-methoxyphenoxy)-quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
A20:(4R, 6S)-6-{ (E)-2-[the fluoro-4-of 2-cyclopropyl-6,7-bis-(3-fluorophenoxy) quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
Or A22:(4R, 6S)-6-{ (E)-2-[the fluoro-4-of 2-cyclopropyl-6,7-bis-(3-methoxyphenoxy) quinoline-3-base] vinyl-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones.
The invention further relates to the preparation method such as formula the 2-cyclopropyl-4-substituted phenoxyl quinoline derivative shown in A, it comprises the following step: lactonize such as formula after the compound deprotection shown in I;
Wherein, radicals R
1, R
2, R
3and R
4definition ditto described in.
Wherein, described deprotection and the method for lactonization reaction and condition all can be ordinary method and condition of this type of reaction of this area; the present invention is following method and condition particularly preferably: in organic solvent, reacts under the action of an acid such as formula the compound shown in I.
Wherein, described organic solvent can be the Conventional solvents of this type of reaction of this area, is preferably one or more in tetrahydrofuran (THF), methyl tertiary butyl ether, toluene, methylene dichloride and chloroform; The volume mass of described organic solvent and chemical compounds I is 5 ~ 50ml/g than preferably, and that better is 10ml/g; Described acid can be the conventional acid of this type of reaction of this area, is preferably one or more in acetic acid, trifluoroacetic acid and hydrochloric acid; Described acid concentration is in organic solvent preferably volume percent 5 ~ 66%, and better is 20%; The temperature of described reaction is preferably 0 ~ 80 DEG C, and better is 20 ~ 30 DEG C; Till time of described reaction preferably completes with detection reaction.
Chemical compounds I described in the present invention can be obtained by following method: carry out Wittig-Hornor reaction by such as formula the compound shown in II with such as formula the compound shown in B;
Wherein, radicals R
1, R
2, R
3and R
4definition ditto described in.
Wherein, the method of described Wittig-Hornor reaction and condition all can be ordinary method and the condition of this type of reaction of this area, the present invention is following method and condition particularly preferably: in organic solvent, in the presence of base, react such as formula the compound shown in II with such as formula the compound shown in B.
Wherein, described organic solvent can be the Conventional solvents of this type of reaction of this area, and be preferably one or more in tetrahydrofuran (THF), ether and methyl tertiary butyl ether, better is tetrahydrofuran (THF); The volume mass of described organic solvent and compound ii is 10 ~ 50ml/g than preferably, and that better is 10ml/g; Described alkali can be the conventional alkali of this type of reaction of this area, and be preferably one or more in 2,2,6,6-tetramethyl piperidine lithium, diisopropylamine lithium, two-(trimethyl silicon based) amine lithium, n-Butyl Lithium and sodium hydride, better is n-Butyl Lithium; Described alkali and the mol ratio of compound ii are preferably 1: 1 ~ 4: 1, and better is 1.2: 1; Described compd B and the mol ratio of compound ii are preferably 1: 1 ~ 2: 1, and better is 1.2: 1; The temperature of described reaction is preferably-100 ~ 50 DEG C, and better is-78 ~ 25 DEG C; Till time of described reaction preferably completes with detection reaction, be generally 10 ~ 48 hours.
Compound ii described in the present invention can be obtained by following method: in organic solvent, compound VIII and phenylbenzene oxyethyl group phosphine is reacted;
Wherein, radicals R
1, R
2, R
3and R
4definition ditto described in.
Wherein, described organic solvent can be the Conventional solvents of this type of reaction of this area, and be preferably one or more in tetrahydrofuran (THF), methyl tertiary butyl ether, methylene dichloride, chloroform and toluene, better is toluene; The temperature of described reaction is preferably 20 ~ 150 DEG C, and better is 100 ~ 120 DEG C.
Compound VIII described in the present invention can be obtained by following method: in organic solvent, by compound VII and PBr
3carry out bromination reaction;
Wherein, radicals R
1, R
2, R
3and R
4definition ditto described in.
Wherein, described organic solvent can be the Conventional solvents of this type of reaction of this area, and be preferably one or more in tetrahydrofuran (THF), methyl tertiary butyl ether, methylene dichloride, chloroform and toluene, better is methylene dichloride; The temperature of described reaction is preferably 0 ~ 100 DEG C, and better is 0 ~ 30 DEG C.
Compound VII described in the present invention can be obtained by following method: in organic solvent, and compound VI and diisobutyl aluminium hydride (DIBAL-H) are carried out reduction reaction;
Wherein, radicals R
1, R
2, R
3and R
4definition ditto described in.
Wherein, described organic solvent can be the Conventional solvents of this type of reaction of this area, is preferably one or more in benzene, toluene and tetrahydrofuran (THF); The temperature of described reaction is preferably 0 ~ 30 DEG C.
Compound VI described in the present invention can be obtained by following method: in organic solvent, under the effect of alkali, by compound V and compound Ⅺ (R
4h) substitution reaction is carried out;
Wherein, radicals R
1, R
2, R
3and R
4definition ditto described in; R
5for H, halogen or C
1~ C
4alkoxyl group; R
6for H or halogen.
Wherein, R is worked as
5during for halogen, described halogen is preferably F, Cl, Br or I, and that better is F; Work as R
5for C
1~ C
4alkoxyl group time, described C
1~ C
4alkoxyl group be preferably methoxyl group.
Wherein, R is worked as
6during for halogen, described halogen is preferably F, Cl, Br or I, and that better is F.
Wherein, described organic solvent can be the Conventional solvents of this type of reaction of this area, is preferably one or more in tetrahydrofuran (THF), dimethyl formamide (DMF) and dimethyl sulfoxide (DMSO) (DMSO); Described alkali is preferably sodium carbonate, salt of wormwood, sodium hydride or butyllithium; The temperature of described reaction is preferably 0 ~ 60 DEG C.Select different reaction conditionss, as different substrates, different feed ratio, different alkali, different solvents and different temperature of reaction etc., the polysubstituted or mono-substituted product in 4-position can be obtained respectively.
Compound V described in the present invention can be obtained by following method: in organic solvent, and compounds Ⅳ and phosphorus oxychloride are carried out chlorination;
Wherein, radicals R
1, R
5and R
6definition ditto described in.
Wherein, described organic solvent can be the Conventional solvents of this type of reaction of this area, is preferably one or more in methylene dichloride, toluene and phosphorus oxychloride; The temperature of described reaction is preferably 20 ~ 120 DEG C; Described compounds Ⅳ and the mol ratio of phosphorus oxychloride are preferably 1: 1.4 ~ 1: 5.
Compounds Ⅳ described in the present invention can be obtained by following method: in organic solvent, and compound III is carried out ring-closure reaction;
Wherein, radicals R
1, R
5and R
6definition ditto described in.
Wherein, described organic solvent is preferably one or more in whiteruss, biphenyl and thermal oil; The temperature of described reaction is preferably 150 ~ 180 DEG C.
Compound III described in the present invention can be obtained by following method: in organic solvent, under the effect of alkali, compound Ⅸ and compound Ⅹ is carried out condensation reaction; (preparation method can reference: JOrg Chem, 2004,69:6920-6922; J Org Chem, 1985,50:2622-2624. and SynthComm, 1986,16 (9): 997-1002)
Wherein, radicals R
1, R
5and R
6definition ditto described in.
Wherein, described organic solvent is preferably one or more in triethylamine, pyridine, toluene and dimethyl formamide (DMF); Described alkali is preferably triethylamine, pyridine or salt of wormwood; The temperature of described reaction is preferably 55 ~ 110 DEG C.
On the basis meeting this area general knowledge, in the present invention, above-mentioned each preferred feature can arbitrary combination, obtains the preferred embodiments of the invention.
The present invention also relates to such as formula the midbody compound of the preparation shown in I, II, IV, V, VI, VII or VIII such as formula the 2-cyclopropyl-4-substituted phenoxyl quinoline derivative shown in A further;
Wherein, radicals R
1, R
2, R
3, R
4, R
5and R
6definition all the same described in.
The invention still further relates to and suppress HMG-CoA reductase such as formula the 2-cyclopropyl-4-substituted phenoxyl quinoline derivative shown in A in preparation or treat the application in the diseases related medicine of hyperlipidemia.
2-cyclopropyl-4-substituted phenoxyl quinoline derivative of the present invention can make pharmaceutical composition with any pharmaceutically acceptable carrier.Described carrier is as the pharmaceutical carrier of pharmaceutical field routine: thinner or vehicle, as water etc.; Tackiness agent, as derivatived cellulose, gelatin or polyvinylpyrrolidone etc.; Weighting agent, as starch etc.; To burst apart agent, as calcium carbonate or sodium bicarbonate.In addition, other auxiliarys can also be added as flavouring agent and/or sweeting agent in pharmaceutical composition.
The method of medical field routine can be adopted to make various formulation with the pharmaceutical composition that 2-cyclopropyl-4-substituted phenoxyl quinoline derivative of the present invention is activeconstituents.For time oral, conventional solid preparation can be made into as tablet, pulvis or capsule etc.; During for injecting, injection liquid can be made into.In various preparation, the content of the compounds of this invention is mass percent 0.1 ~ 99.9%, and preferred content is mass percent 0.5 ~ 90%.
With the pharmaceutical preparation that 2-cyclopropyl-4-substituted phenoxyl quinoline derivative of the present invention is activeconstituents, the patient needing this treatment is put on by intravenous injection, subcutaneous injection or oral form, general dosage is 1 ~ 100mg/ kg body weight/sky, specifically can select according to the age of patient, the state of an illness etc.
Raw material described in the present invention or reagent except special instruction, all commercially.
Positive progressive effect of the present invention is: compared with HMG-CoA reductase inhibitor Rosuvastatin in prior art, 2-cyclopropyl-4-substituted phenoxyl quinoline derivative of the present invention has the activity preferably suppressing HMG-CoA reductase, for the diseases related medicine of preparation treatment hyperlipidemia provides a new approach.
Embodiment
Further illustrate the present invention by embodiment below, but the present invention is not limited.
Raw material used in embodiment or reagent except special instruction, all commercially.
Room temperature described in following embodiment all refers to temperature 20 ~ 30 DEG C.
Embodiment 1 prepares 2-cyclopropyl-4-phenoxy group-6-fluorine quinoline-3-carboxylic acid ethyl ester (VI 8)
N
2under protection; 1.13g (12mmol) phenol is dissolved in the DMSO of 30ml drying; at 0 DEG C; add 0.48g (60%; 12mmol) sodium hydride, stirs 0.5h, then adds 2.94g (10mmol) 2-cyclopropyl-4-chloro-6-fluorine quinoline-3-carboxylic acid ethyl ester; be warming up to 80 DEG C, reaction 2h.Cooling, pours in 50ml frozen water, extraction into ethyl acetate, organic phase washed with water, saturated common salt water washing, anhydrous sodium sulfate drying by reaction solution.Filter, concentrated, column chromatography purification, obtains white solid sterling compound VI 83.28g, yield 93.4%.
With 2-cyclopropyl-4-chlorine-quinoline-3-carboxylic acid, ethyl ester for raw material, adopt aforesaid method can obtain compound VI 1 ~ 7; With 2-cyclopropyl-4-chloro-6-fluorine quinoline-3-carboxylic acid ethyl ester for raw material, aforesaid method is adopted to obtain VI 9 ~ 14; With the chloro-6-methoxy quinoline of 2-cyclopropyl-4--3-carboxylic acid, ethyl ester for raw material, adopt aforesaid method can obtain VI 15 and VI 16.
The Structural Identification data of compound VI 1 ~ 7 are in table 1; The Structural Identification data of compound VI 8 ~ 14 are in table 2; The Structural Identification data of compound VI 15 ~ 16 are in table 3.
Embodiment 2 prepares 2-cyclopropyl-4-phenoxy group-6,7-difluoro-quinoline-3-carboxylic acid, ethyl ester (VI 19)
N
2under protection; 0.50g (5.29mmol) phenol is dissolved in the anhydrous THF of 15ml; under ice bath; add 0.212g (60%, 5.29mmol) sodium hydride, stir 0.5h; add 1.5g (4.81mmol) 2-cyclopropyl-4-chloro-6 again; 7-difluoro-quinoline-3-carboxylic acid, ethyl ester (Rf=0.30, sherwood oil: ethyl acetate=20: 1 (v/v)), back flow reaction 9h.Cooling, pours in 50ml frozen water, extraction into ethyl acetate, organic phase washed with water, saturated common salt water washing, anhydrous sodium sulfate drying by reaction solution.Filter, concentrated, sherwood oil recrystallization, obtains colorless crystalline compound VI191.45g, yield 81.4% (Rf=0.25, sherwood oil: ethyl acetate=20: 1 (v/v)).
The synthetic method of compound VI 20 ~ 24 is the same.
With the chloro-6-methoxy quinoline of 2-cyclopropyl-4--3-carboxylic acid, ethyl ester for raw material, adopt aforesaid method can obtain compound VI 17 ~ 18.
The Structural Identification data of compound VI 19 ~ 24 are in table 4; The Structural Identification data of compound VI 17 ~ 18 are in table 3.
Embodiment 3 prepares 2-cyclopropyl-4,7-bis-phenoxy group-6-fluorine quinoline-3-carboxylic acid ethyl ester (VI 25)
1.5g (4.81mmol) 2-cyclopropyl-4-chloro-6,7-difluoro-quinoline-3-carboxylic acid, ethyl ester, 0.95g (10.1mmol) phenol, 1.39g (10.1mmol) salt of wormwood join in 20ml DMF successively, are warming up to 100 DEG C of reaction 4h.Cooling, pours in 50ml frozen water, extraction into ethyl acetate, organic phase washed with water, saturated common salt water washing, anhydrous sodium sulfate drying by reaction solution.Filter, concentrated, sherwood oil recrystallization, obtains colorless crystalline compound VI 251.79g, yield 83.8%, mp:102-4 DEG C.
The synthetic method of compound VI 26 ~ 30 is the same.
The Structural Identification data of compound VI 25 ~ 30 are in table 5.
Embodiment 4 prepares 2-cyclopropyl-4,6-bis-phenoxy-quinolin-3-carboxylic acid, ethyl ester (VI 31)
2.82g (30mmol) phenol is dissolved in the DMSO of 30ml drying, at 0 DEG C, add 1.16g (60%, 29mmol) sodium hydride, stir 1h, add 2.94g (10mmol) 2-cyclopropyl-4-chloro-6-fluorine quinoline-3-carboxylic acid ethyl ester again, be warming up to 140 DEG C, reaction 6h.Cooling, pours in 50ml frozen water, extraction into ethyl acetate, organic phase washed with water, saturated common salt water washing, anhydrous sodium sulfate drying by reaction solution.Filter, concentrated, column chromatography purification (sherwood oil: ethyl acetate=100: 1 (v/v)), obtains compound as white solid VI 8 1.48g (yield 42.2%) and colourless liquid compound VI 31 2.02g (yield 47.5%).
The Structural Identification data of compound VI 31 are in table 5.
Embodiment 5 prepares 2-cyclopropyl-4,6,7-triple phenoxyl-quinoline-3-carboxylic acid ethyl ester (VI 32)
2.94g (31.2mmol) phenol is dissolved in the DMSO of 30ml drying, at 0 DEG C, add 1.25g (60%, 31.2mmol) sodium hydride, stir 1h, then add chloro-6, the 7-difluoro-quinoline-3-carboxylic acid, ethyl esters of 2.78g (8.92mmol) 2-cyclopropyl-4-, be warming up to 100 DEG C, reaction 18h.Cooling, pours in 50ml frozen water, extraction into ethyl acetate, organic phase washed with water, saturated common salt water washing, anhydrous sodium sulfate drying by reaction solution.Filter, concentrated, through column chromatography purification (sherwood oil: ethyl acetate=100: 1 (v/v)), obtain colourless liquid compound VI 322.53g (yield 54.8%, Rf=0.33, sherwood oil: ethyl acetate=10: 1 (v/v)) and compound VI 250.455g (yield 11.5%, Rf=0.39, sherwood oil: ethyl acetate=10: 1 (v/v)).
The synthetic method of compound VI 33 is the same.
The Structural Identification data of compound VI 32 ~ 33 are in table 6.
Embodiment 6 prepares 2-cyclopropyl-4-phenoxy group-6-fluorine quinoline-3-methyl alcohol (VII 8)
N
2under protection, compound VI 8 (2.57g, 7.32mmol) is dissolved in the anhydrous THF of 30ml, is chilled to-70 DEG C, adds LiAlH
4(0.278g, 7.32mmol), changes cryosel bath immediately into, about-15 DEG C reaction 4h, and hydrochloric acid to the system dripping 6mol/L is acid.Ethyl acetate (100ml) extracts, organic phase washed with water, saturated sodium bicarbonate solution, saturated common salt water washing, anhydrous sodium sulfate drying.Filter, concentrated, with ethyl acetate and sherwood oil mixed solvent crystallization, obtain colorless crystalline compound VII 81.58g, yield 69.9%.
The synthetic method of compound VII 1 ~ 7 and compound VII 9 ~ 14 is the same.
The Structural Identification data of compound VII 1 ~ 7 are in table 7; The Structural Identification data of compound VII 8 ~ 14 are in table 8.
Embodiment 7 prepares 2-cyclopropyl-4-(4-methoxyl group-) phenyl-6-methoxy quinoline-3-methyl alcohol (VII 15)
Compound VI 15 (3.46g, 8.72mmol) is dissolved in 35ml dry toluene, at-10 DEG C, drips the toluene solution (8.72ml, 21.8mmol) of diisobutyl aluminium hydride, stirring reaction 4h at 0 DEG C.The hydrochloric acid of instillation 6mol/L, is neutralized to acidity, extraction into ethyl acetate, organic phase washed with water, saturated sodium bicarbonate solution, saturated common salt water washing, anhydrous sodium sulfate drying.Filter, concentrated, with the mixed solvent recrystallization of ethyl acetate and sherwood oil, obtain white crystalline Compound VII 152.028g, yield 65.7%.
The synthetic method of compound VII 16 ~ 33 is the same.
The Structural Identification data of compound VII 15 ~ 18 are in table 9; The Structural Identification data of compound VII 19 ~ 24 are in table 10; The Structural Identification data of compound VII 25 ~ 31 are in table 11; The Structural Identification data of compound VII 32 ~ 33 are in table 12.
Embodiment 8 prepares 2-cyclopropyl-4-phenoxy group-6-fluorine quinoline-3-methyl bromide (VIII 8)
Compound VII 8 (1.58g, 5.11mmol) is dissolved in 10ml CH
2cl
2, at 0 DEG C, dropwise add 0.96ml (2.77g, 10.2mmol) PBr
35ml CH
2cl
2solution, reacts 2h under room temperature, is poured into by reaction solution in 30ml saturated sodium bicarbonate solution, stirs 0.5h.Extraction into ethyl acetate, organic phase saturated common salt water washing, concentrated, obtain compound as white solid VIII 81.81g, yield 95.2%.
The synthetic method of compound VIII 1 ~ 7 and compound VIII 9 ~ 33 is the same.
The Structural Identification data of compound VIII 1 ~ 7 are in table 13; The Structural Identification data of compound VIII 8 ~ 14 are in table 14; The Structural Identification data of compound VIII 15 ~ 18 are in table 15; The Structural Identification data of compound VIII 19 ~ 24 are in table 16; The Structural Identification data of compound VIII 25 ~ 31 are in table 17; The Structural Identification data of compound VIII 32 ~ 33 are in table 18.
Embodiment 9 prepares 2-cyclopropyl-4-phenoxy group-6-fluoro-3-(diphenyl phosphate oxygen methyl) quinoline (II 8)
Compound VIII 8 (1.81g, 4.87mmol) is dissolved in 10ml toluene, dropwise adds 2.1ml (2.24g, 9.7mmol) ethoxy diphenyl base phosphine, is warming up to backflow, reaction 2h, crystallisation by cooling.Filter, obtain compound as white solid II 8 2.2g, yield 91.7%.
The synthetic method of compound ii 1 ~ 7 and compound ii 9 ~ 33 is the same.
The Structural Identification data of compound ii 1 ~ 7 are in table 13; The Structural Identification data of compound ii 8 ~ 14 are in table 14; The Structural Identification data of compound ii 15 ~ 18 are in table 15; The Structural Identification data of compound ii 19 ~ 24 are in table 16; The Structural Identification data of compound ii 25 ~ 31 are in table 17; The Structural Identification data of compound ii 32 ~ 33 are in table 18.
Embodiment 10 prepares (3R, 5S, 6E)-7-[2-cyclopropyl-4-phenoxy group-6-fluorine quinoline-3-]-3,5-dihydroxyl-3, the 5-O-isopropylidenes-6-heptenoic acid tert-butyl ester (I 8)
N
2under protection; compound ii 8 (2.2g, 4.46mmol) is dissolved in the anhydrous THF of 20ml, at 0 DEG C; drip 1.87ml n-BuLi solution (2.86mol/L; 5.35mmol), stir 1h, instillation 1.38g (5.35mmol) (3R; 5S)-6-oxo-3; the 7mlTHF solution of 5-O-isopropylidene-3,5-dihydroxyl hecanoic acid t-butyl ester, room temperature for overnight.System is placed in ice-water bath, drips the hydrochloric acid of 6mol/L, be neutralized to solution in acid, use water, saturated sodium bicarbonate solution, saturated common salt water washing successively, anhydrous sodium sulfate drying.Filter, concentrated, column chromatography purification (sherwood oil: ethyl acetate=20: 1 ~ 10: 1 (v/v)), obtains compound as white solid I 81.044g, yield 43.9%.
The synthetic method of chemical compounds I 1 ~ 7 and chemical compounds I 9 ~ 33 is the same.
The Structural Identification data of chemical compounds I 1 ~ 7 are in table 19; The Structural Identification data of chemical compounds I 8 ~ 14 are in table 20; The Structural Identification data of chemical compounds I 15 ~ 18 are in table 21; The Structural Identification data of chemical compounds I 19 ~ 24 are in table 22; The Structural Identification data of chemical compounds I 25 ~ 31 are in table 23; The Structural Identification data of chemical compounds I 32 ~ 33 are in table 24.
Embodiment 11 prepares (4R, 6S)-6-{ (E)-2-[the fluoro-4-of 2-cyclopropyl-6-(phenoxy group)-quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyls-2H-pyran-2-one (A8)
Chemical compounds I 8 (0.5g, 0.94mmol) is dissolved in 10.5ml CH
2cl
2, at 0 DEG C, instillation 1.4ml (18.7mmol) trifluoroacetic acid, stirring at room temperature 24h.Reaction solution is poured in 20ml saturated sodium bicarbonate solution, extraction into ethyl acetate, organic phase saturated common salt water washing, anhydrous sodium sulfate drying.Filter, concentrated, column chromatography purification (sherwood oil: ethyl acetate=2: 1 (v/v)), obtains compound as white solid A80.256g, yield 65.2%.
The synthetic method of compd A 1 ~ 7 and compd A 9 ~ 33 is the same.
The Structural Identification data of compd A 1 ~ 7 are in table 25; The Structural Identification data of compound A-28 ~ 14 are in table 26; The Structural Identification data of compd A 15 ~ 18 are in table 27; The Structural Identification data of compd A 19 ~ 24 are in table 28; The Structural Identification data of compd A 25 ~ 31 are in table 29; The Structural Identification data of compound A-13 2 ~ 33 are in table 30.
Embodiment 12 prepares (4R, 6S)-6-{ (E)-2-[the fluoro-4-of 2-cyclopropyl-6-(4-fluorophenoxy) quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyls-2H-pyran-2-one (A10)
At 0 ~ 5 DEG C, chemical compounds I 10 (1.20g, 2.1mmol) is dissolved in 24ml CH
2cl
2in, drip 4.8ml (63mmol) CF
3cOOH, reacts 4h under room temperature, reaction solution is poured into the saturated NaHCO of 50ml
3in solution, extraction into ethyl acetate, the saturated NaCl solution of organic phase is washed, anhydrous Na
2sO
4drying, filters, and concentrated, column chromatography purification (ethyl acetate: sherwood oil=1: 2 (v/v)), obtains faint yellow solid 0.652g, yield 68.0%.
Embodiment 13 prepares (4R, 6S)-6-{ (E)-2-[the fluoro-4-of 2-cyclopropyl-6-(4-fluorophenoxy) quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyls-2H-pyran-2-one (A10)
At 0 ~ 5 DEG C, chemical compounds I 10 (1.20g, 2.1mmol) is dissolved in 15ml toluene, adds 10ml acetic acid, reacts 8h under room temperature, reaction solution is poured into the saturated NaHCO of 50ml
3in solution, extraction into ethyl acetate, the saturated NaCl solution of organic phase is washed, anhydrous Na
2sO
4drying, filters, and concentrated, column chromatography purification (ethyl acetate: sherwood oil=1: 2 (v/v)), obtains faint yellow solid 0.461g, yield 48.0%.
Embodiment 14 prepares (4R, 6S)-6-{ (E)-2-[the fluoro-4-of 2-cyclopropyl-6-(4-fluorophenoxy) quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyls-2H-pyran-2-one (A10)
At 0 ~ 5 DEG C, chemical compounds I 10 (0.65g, 1.2mmol) is dissolved in 20ml tetrahydrofuran (THF), adds the hydrochloric acid of 1ml 36%, at 80 DEG C, react 8h.Reaction solution is poured into the saturated NaHCO of 20ml
3in solution, extraction into ethyl acetate, the saturated NaCl solution of organic phase is washed, anhydrous Na
2sO
4drying, filters, and concentrated, column chromatography purification (ethyl acetate: sherwood oil=1: 2 (v/v)), obtains faint yellow solid 0.215g, yield 41.7%.
Embodiment 15 prepares (4R, 6S)-6-{ (E)-2-[2-cyclopropyl-4-(phenoxy group) quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyls-2H-pyran-2-one (A1)
At 0 ~ 5 DEG C, chemical compounds I 1 (0.76g, 1.32mmol) is dissolved in 15ml chloroform, adds 5ml trifluoroacetic acid, at 0 ~ 5 DEG C, react 8h.Reaction solution is poured into the saturated NaHCO of 50ml
3in solution, extraction into ethyl acetate, the saturated NaCl solution of organic phase is washed, anhydrous Na
2sO
4drying, filters, and concentrated, column chromatography purification (ethyl acetate: sherwood oil=1: 2 (v/v)), obtains faint yellow solid 0.321g, yield 52.7%.
The vitro inhibition HMG-CoA reductase activity test of effect example part quinoline A
In the present invention, the test method of quinoline A vitro inhibition HMG-CoA reductase activity can reference Kim HJ et al:Characterization of β-hydroxy-β-methylglutarylcoenzyme A reductase inhibitor from Pueraria thunbergiana.J Agric Food Chem2005,53:5882-5888.
HMG-CoA reductase is extracted and is obtained from male Sprague-Dawley rat liver.
Take Rosuvastatin as positive control, not adding any inhibitor is negative control, simultaneously with without HMG-CoA and unrestraint agent for blank.
3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) is under HMG-CoA reductase catalysis, consume two molecule reduced form NADPs (NADPH), generate 3-methyl-3,5-dihydroxy valeric acid and Reduced nicotinamide-adenine dinucleotide (NADP).NADPH has maximum absorption at ultraviolet 340nm place, and NADP at this wavelength place without absorption, mensuration system can know in the lowering speed of 340nm place ultraviolet absorption value the speed that this reduction reaction is carried out.After adding inhibitor, the inhibit activities of this inhibitor to HMG-CoA reductase can be calculated by system in the change of 340nm ultraviolet absorption value.
Part of compounds A is measured in the present invention to the inhibit activities of HMG-CoA reductase with aforesaid method.Quinoline A to be measured is respectively chosen eight suitable concns, measures its restraining effect to HMG-CoA reductase, matching suppresses curve, obtains half-inhibition concentration (IC
50).The IC of the Rosuvastatin recorded and part quinoline A
50value is in table 31.
Data in table 31 show: compared with Rosuvastatin of the prior art, and part quinoline of the present invention has the activity better suppressing HMG-CoA reductase.
Claims (17)
1. a class is such as formula the 2-cyclopropyl-4-substituted phenoxyl quinoline derivative shown in A;
Wherein, R
1for H or halogen; R
2for H, halogen, C
1~ C
4alkoxyl group or such as formula the group shown in Q; R
3for H or halogen; R
4for such as formula the group shown in Q;
In formula Q, R is H, halogen, C
1~ C
4alkyl or C
1~ C
4alkoxyl group.
2. quinoline as claimed in claim 1, is characterized in that, work as R
1during for halogen, described halogen is F.
3. quinoline as claimed in claim 1, is characterized in that, work as R
2during for halogen, described halogen is F; Work as R
2for C
1~ C
4alkoxyl group time, described alkoxyl group is methoxyl group.
4. quinoline as claimed in claim 1, is characterized in that, work as R
3during for halogen, described halogen is F.
5. quinoline as claimed in claim 1, it is characterized in that, in described formula Q, when R is halogen, described halogen is F; When R is C
1~ C
4alkyl time, described alkyl is sec.-propyl; When R is C
1~ C
4alkoxyl group time, described alkoxyl group is methoxyl group.
6. quinoline as claimed in claim 1, it is characterized in that, described quinoline is selected from following compounds:
(4R, 6S)-6-{ (E)-2-[2-cyclopropyl-4-(phenoxy group) quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
(4R, 6S)-6-{ (E)-2-[2-cyclopropyl-4-(4-fluorophenoxy) quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
(4R, 6S)-6-{ (E)-2-[2-cyclopropyl-4-(2-sec.-propyl phenoxy group) quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
(4R, 6S)-6-{ (E)-2-[2-cyclopropyl-4-(4-sec.-propyl phenoxy group) quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
(4R, 6S)-6-{ (E)-2-[the fluoro-4-of 2-cyclopropyl-6-(phenoxy group)-quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
(4R, 6S)-6-{ (E)-2-[the fluoro-4-of 2-cyclopropyl-6-(4-methoxyphenoxy) quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
(4R, 6S)-6-{ (E)-2-[the fluoro-4-of 2-cyclopropyl-6-(2-sec.-propyl phenoxy group) quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
(4R, 6S)-6-{ (E)-2-[2-cyclopropyl-6-methoxyl group-4-(4-methoxyphenoxy)-quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
(4R, 6S)-6-{ (E)-2-[2-cyclopropyl-6-methoxyl group-4-(2-sec.-propyl phenoxy group)-quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
(4R, 6S)-6-{ (E)-2-[the fluoro-4-of 2-cyclopropyl-5,6-bis-(phenoxy group)-quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
(4R, 6S)-6-{ (E)-2-[the fluoro-4-of 2-cyclopropyl-5,6-bis-(4-methoxyphenoxy)-quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
(4R, 6S)-6-{ (E)-2-[the fluoro-4-of 2-cyclopropyl-6,7-bis-(3-fluorophenoxy) quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones;
(4R, 6S)-6-{ (E)-2-[the fluoro-4-of 2-cyclopropyl-6,7-bis-(3-methoxyphenoxy) quinoline-3-base] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-ones.
7. the preparation method of the formula A compound as described in any one of claim 1 ~ 6, is characterized in that comprising the following step: lactonize such as formula after the compound deprotection shown in I;
Wherein, radicals R
1, R
2, R
3and R
4definition as described in any one of Claims 1 to 5.
8. the preparation method of formula A compound as claimed in claim 7, is characterized in that: described preparation method comprises the following step: in organic solvent, reacts such as formula the compound shown in I under the action of an acid.
9. the preparation method of formula A compound as claimed in claim 8, is characterized in that: described organic solvent is one or more in tetrahydrofuran (THF), methyl tertiary butyl ether, toluene, methylene dichloride and chloroform.
10. the preparation method of formula A compound as claimed in claim 8, is characterized in that: described acid is one or more in acetic acid, trifluoroacetic acid and hydrochloric acid.
The preparation method of 11. formula A compounds as claimed in claim 8, is characterized in that: described acid concentration is in organic solvent volume percent 5 ~ 66%.
The preparation method of 12. formula A compounds as claimed in claim 11, is characterized in that: described acid concentration is in organic solvent volume percent 20%.
The preparation method of 13. formula A compounds as claimed in claim 8, is characterized in that: the temperature of described reaction is 0 ~ 80 DEG C.
The preparation method of 14. formula A compounds as claimed in claim 13, is characterized in that: the temperature of described reaction is 20 ~ 30 DEG C.
The preparation method of 15. formula A compounds as claimed in claim 7, is characterized in that: described chemical compounds I is obtained by following method: compound ii and compd B are carried out Wittig-Hornor reaction;
Wherein, radicals R
1, R
2, R
3and R
4definition as described in any one of Claims 1 to 5.
16. such as formula the midbody compound of the formula A compound of the preparation shown in I as described in any one of claim 1 ~ 6;
Wherein, radicals R
1, R
2, R
3and R
4definition as described in any one of Claims 1 to 5.
17. quinolines as described in any one of claim 1 ~ 6 suppress the application in HMG-CoA reductase or the diseases related medicine for the treatment of hyperlipidemia in preparation.
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