CN102477032A - 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 one type of 2-cyclopropyl-4-substituted phenoxyl quinoline verivate, its preparation method, midbody and the application in field of medicaments thereof.
Background technology
Be confirmed to be since hypercholesterolemia since the important paathogenic factor of atherosclerosis and cardiovascular disorder, rapid about the researchdevelopment of blood lipid-lowering medicine.3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (claiming " his spit of fland " class again) 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).Complete synthesis his the spit of fland medicine that has 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 satisfy people's demand, and the scientific research personnel also must make great efforts to explore, and seeks efficient more, cheap, the little newtype drug of spinoff.
In the prior art, the structure of complete synthesis his spit of fland medicine is made up of mother's ring (indole ring, pyrrole ring, quinoline ring, pyrimidine ring etc.) and side chain two portions.To being that the research of the quinoline structure of modification of representative shows with the pitavastatin: the Wasserstoffatoms on 2 on the quinoline ring is replaced with cyclopropyl, and on 3, introduce side chain, the quinoline that obtains has the activity of better inhibited HMG-CoA reductase enzyme; On the quinoline ring, introduce groups such as methyl, chlorine atom or methoxyl group for 6,7 and 8; But the verivate that obtains also has preferably enzymic activity (Cai Zhengyan, the progress of Zhou Weicheng .HMG CoA reductase inhibitor, Chinese Journal of New Drugs; 2006,15 (22): 1907-1911).In the prior art; 4 on quinoline ring general direct with fluorophenyl is connected; Chinese patent CN101210011 discloses respectively at 4 two compounds that link to each other with phenyl ring through sulphur atom and Sauerstoffatom of quinoline ring with CN101220021, and these compounds all have the activity of good inhibition HMG-CoA reductase enzyme.And when 2 on quinoline ring is introduced cyclopropyl, 4 through Sauerstoffatom be connected with aromatic ring compound do not appear in the newspapers so far.
Summary of the invention
Technical problem to be solved by this invention provides one type of 2-cyclopropyl-4-substituted phenoxyl quinoline verivate, its preparation method, midbody and the application in preparing the diseases related medicine of inhibition HMG-CoA reductase enzyme or treatment hyperlipidemia thereof.Compared with prior art, 2-cyclopropyl of the present invention-4-substituted phenoxyl quinoline verivate has the activity of preferable inhibition HMG-CoA reductase enzyme.
Therefore, the present invention relates to one type suc as formula the cyclopropyl of the 2-shown in the A-4-substituted phenoxyl quinoline verivate;
Wherein, R
1Be H or halogen; R
2Be H, halogen, C
1～C
4Alkoxyl group or suc as formula the group shown in the Q; R
3For H, halogen or suc as formula the group shown in the Q; R
4For suc as formula the group shown in the Q;
Among the formula Q, R is H, halogen, C
1～C
4Alkyl or C
1～C
4Alkoxyl group.
Wherein, work as R
1During for halogen, that described halogen is preferable is F, Cl, Br or I, and that better is F.
Wherein, work as R
2During for halogen, that described halogen is preferable is F, Cl, Br or I, and that better is F; Work as R
2Be C
1～C
4Alkoxyl group the time, described C
1～C
4Alkoxyl group preferable be methoxyl group.
Wherein, work as R
3During for halogen, that described halogen is preferable is F, C1, Br or I, and that better is F.
Among the formula Q, when R was halogen, that described halogen is preferable was F, Cl, Br or I, and that better is F; When R is C
1～C
4Alkyl the time, described C
1～C
4Alkyl preferable be sec.-propyl; When R is C
1～C
4Alkyl the time, described C
1～C
4Alkyl preferable be methoxyl group.
Among the present invention, described suc as formula the cyclopropyl of the 2-shown in the A-4-substituted phenoxyl quinoline verivate preferable for comprising following compounds:
A1: (4R, 6S)-6-{ (E)-2-[2-cyclopropyl-4-(phenoxy) quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
A2: (4R, 6S)-6-{ (E)-2-[2-cyclopropyl-4-(3-fluorophenoxy) quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
A3: (4R, 6S)-6-{ (E)-2-[2-cyclopropyl-4-(4-fluorophenoxy) quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
A4: (4R, 6S)-6-{ (E)-2-[2-cyclopropyl-4-(3-methoxyl group phenoxy) quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
A5: (4R, 6S)-6-{ (E)-2-[2-cyclopropyl-4-(4-methoxyl group phenoxy) quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
A6: (4R, 6S)-6-{ (E)-2-[2-cyclopropyl-4-(2-sec.-propyl phenoxy) quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
A7: (4R, 6S)-6-{ (E)-2-[2-cyclopropyl-4-(4-sec.-propyl phenoxy) quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
A8: (4R, 6S)-6-{ (E)-2-[2-cyclopropyl-6-fluoro-4-(phenoxy)-quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
A9: (4R, 6S)-6-{ (E)-2-[2-cyclopropyl-6-fluoro-4-(3-fluorophenoxy) quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
A10: (4R, 6S)-6-{ (E)-2-[2-cyclopropyl-6-fluoro-4-(4-fluorophenoxy) quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
A11: (4R, 6S)-6-{ (E)-2-[2-cyclopropyl-6-fluoro-4-(3-methoxyl group phenoxy) quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
A12: (4R, 6S)-6-{ (E)-2-[2-cyclopropyl-6-fluoro-4-(4-methoxyl group phenoxy) quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
A13: (4R, 6S)-6-{ (E)-2-[2-cyclopropyl-6-fluoro-4-(2-sec.-propyl phenoxy) quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
A14: (4R, 6S)-6-{ (E)-2-[2-cyclopropyl-6-fluoro-4-(4-sec.-propyl phenoxy) quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
A15: (4R, 6S)-6-{ (E)-2-[2-cyclopropyl-6-methoxyl group-4-(4-methoxyl group phenoxy)-quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
A16: (4R, 6S)-6-{ (E)-2-[2-cyclopropyl-6-methoxyl group-4-(2-sec.-propyl phenoxy)-quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
A17: (4R, 6S)-6-{ (E)-2-[2-cyclopropyl-5,6-two fluoro-4-(phenoxy)-quinoline-3-yls] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
A18: (4R, 6S)-6-{ (E)-2-[2-cyclopropyl-5,6-two fluoro-4-(4-methoxyl group phenoxy)-quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
A19: (4R, 6S)-6-{ (E)-2-[2-cyclopropyl-6,7-two fluoro-4-(phenoxy)-quinoline-3-yls] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
A20: (4R, 6S)-6-{ (E)-2-[2-cyclopropyl-6,7-two fluoro-4-(3-fluorophenoxy) quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
A21: (4R, 6S)-6-{ (E)-2-[2-cyclopropyl-6,7-two fluoro-4-(4-fluorophenoxy) quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
A22: (4R, 6S)-6-{ (E)-2-[2-cyclopropyl-6,7-two fluoro-4-(3-methoxyl group phenoxy) quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
A23: (4R, 6S)-6-{ (E)-2-[2-cyclopropyl-6,7-two fluoro-4-(4-methoxyl group phenoxy) quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
A24: (4R, 6S)-6-{ (E)-2-[2-cyclopropyl-6,7-two fluoro-4-(4-sec.-propyl phenoxy) quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
A25: (4R, 6S)-6-{ (E)-2-[2-cyclopropyl-6-fluoro-4,7-two (phenoxy)-quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
A26: (4R, 6S)-6-{ (E)-2-[2-cyclopropyl-6-fluoro-4,7-two (3-fluorophenoxy) quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
A27: (4R, 6S)-6-{ (E)-2-[2-cyclopropyl-6-fluoro-4,7-two (4-fluorophenoxy) quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
A28: (4R, 6S)-6-{ (E)-2-[2-cyclopropyl-6-fluoro-4,7-two (3-methoxyl group phenoxy) quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
A29: (4R, 6S)-6-{ (E)-2-[2-cyclopropyl-6-fluoro-4,7-two (4-methoxyl group phenoxy) quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
A30: (4R, 6S)-6-{ (E)-2-[2-cyclopropyl-6-fluoro-4,7-two (4-sec.-propyl phenoxy) quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
A31: (4R, 6S)-6-{ (E)-2-[2-cyclopropyl-4,6-two (phenoxy) quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
A32: (4R, 6S)-6-{ (E)-2-[2-cyclopropyl-4,6,7-three (phenoxy)-quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
Or A33: (4R, 6S)-6-{ (E)-2-[2-cyclopropyl-4,6,7-three (4-fluorophenoxy)-6-methoxy yl-quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one.
Among the present invention, described suc as formula the cyclopropyl of the 2-shown in the A-4-substituted phenoxyl quinoline verivate better for comprising following compounds:
A1: (4R, 6S)-6-{ (E)-2-[2-cyclopropyl-4-(phenoxy) quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
A3: (4R, 6S)-6-{ (E)-2-[2-cyclopropyl-4-(4-fluorophenoxy) quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
A6: (4R, 6S)-6-{ (E)-2-[2-cyclopropyl-4-(2-sec.-propyl phenoxy) quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
A7: (4R, 6S)-6-{ (E)-2-[2-cyclopropyl-4-(4-sec.-propyl phenoxy) quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
A8: (4R, 6S)-6-{ (E)-2-[2-cyclopropyl-6-fluoro-4-(phenoxy)-quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
A12: (4R, 6S)-6-{ (E)-2-[2-cyclopropyl-6-fluoro-4-(4-methoxyl group phenoxy) quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
A13: (4R, 6S)-6-{ (E)-2-[2-cyclopropyl-6-fluoro-4-(2-sec.-propyl phenoxy) quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
A15: (4R, 6S)-6-{ (E)-2-[2-cyclopropyl-6-methoxyl group-4-(4-methoxyl group phenoxy)-quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
A16: (4R, 6S)-6-{ (E)-2-[2-cyclopropyl-6-methoxyl group-4-(2-sec.-propyl phenoxy)-quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
A17: (4R, 6S)-6-{ (E)-2-[2-cyclopropyl-5,6-two fluoro-4-(phenoxy)-quinoline-3-yls] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
A18: (4R, 6S)-6-{ (E)-2-[2-cyclopropyl-5,6-two fluoro-4-(4-methoxyl group phenoxy)-quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
A20: (4R, 6S)-6-{ (E)-2-[2-cyclopropyl-6,7-two fluoro-4-(3-fluorophenoxy) quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
Or A22: (4R, 6S)-6-{ (E)-2-[2-cyclopropyl-6,7-two fluoro-4-(3-methoxyl group phenoxy) quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one.
The invention further relates to the preparation method suc as formula the cyclopropyl of the 2-shown in the A-4-substituted phenoxyl quinoline verivate, it comprises the following step: will get final product suc as formula lactonizing behind the compound deprotection shown in the I;
Wherein, radicals R
1, R
2, R
3And R
4Definition ditto said.
Wherein, The method of described deprotection and lactonization reaction and condition all can be the ordinary method and the condition of this type of reaction of this area; Preferred especially following method of the present invention and condition: in the organic solvent, under the effect of acid, react, get final product suc as formula the compound shown in the I.
Wherein, described organic solvent can be the conventional solvent of this type of reaction of this area, one or more that preferable is in THF, MTBE, toluene, methylene dichloride and the chloroform; The volume mass of described organic solvent and chemical compounds I than preferable be 5～50ml/g, that better is 10ml/g; Described acid can be the conventional acid of this type of reaction of this area, one or more that preferable is in acetate, trifluoroacetic acid and the hydrochloric acid; What the concentration of described acid in organic solvent was preferable is volume percent 5～66%, and better is 20%; What the temperature of described reaction was preferable is 0～80 ℃, and better is 20～30 ℃; The time of described reaction is preferable accomplish with detection reaction till.
Chemical compounds I described in the present invention can be made by following method: will carry out the Wittig-Hornor reaction suc as formula the compound shown in the II with suc as formula the compound shown in the B, and get final product;
Wherein, radicals R
1, R
2, R
3And R
4Definition ditto said.
Wherein, Ordinary method and condition that the method for described Wittig-Hornor reaction and condition all can be this type of reaction of this area; Preferred especially following method of the present invention and condition: in the organic solvent; In the presence of alkali, will react suc as formula the compound shown in the II with suc as formula the compound shown in the B, get final product.
Wherein, described organic solvent can be the conventional solvent of this type of reaction of this area, one or more that preferable is in THF, ether and the MTBE, and better is THF; The volume mass of described organic solvent and compound ii than preferable be 10～50ml/g, that better is 10ml/g; Described alkali can be the conventional alkali of this type of reaction of this area, and preferable is 2,2,6, one or more in 6-tetramethyl piperidine lithium, diisopropylamine lithium, two-(trimethyl silicon based) amine lithium, n-Butyl Lithium and the sodium hydride, and better is n-Butyl Lithium; What the mol ratio of described alkali and compound ii was preferable is 1: 1～4: 1, and better is 1.2: 1; What the mol ratio of described compd B and compound ii was preferable is 1: 1～2: 1, and better is 1.2: 1; What the temperature of described reaction was preferable is-100～50 ℃, and better is-78～25 ℃; The time of described reaction is preferable accomplish with detection reaction till, be generally 10～48 hours.
Compound ii described in the present invention can be made by following method: in the organic solvent, compound VIII and phenylbenzene oxyethyl group phosphine are reacted, get final product;
Wherein, radicals R
1, R
2, R
3And R
4Definition ditto said.
Wherein, described organic solvent can be the conventional solvent of this type of reaction of this area, one or more that preferable is in THF, MTBE, methylene dichloride, chloroform and the toluene, and better is toluene; What the temperature of described reaction was preferable is 20～150 ℃, and better is 100～120 ℃.
Compound VIII described in the present invention can be made by following method: in the organic solvent, with compound VII and PBr
3Carry out bromination reaction, get final product;
Wherein, radicals R
1, R
2, R
3And R
4Definition ditto said.
Wherein, described organic solvent can be the conventional solvent of this type of reaction of this area, one or more that preferable is in THF, MTBE, methylene dichloride, chloroform and the toluene, and better is methylene dichloride; What the temperature of described reaction was preferable is 0～100 ℃, and better is 0～30 ℃.
Compound VII described in the present invention can be made by following method: in the organic solvent, compound VI and diisobutyl aluminium hydride (DIBAL-H) are carried out reduction reaction, get final product;
Wherein, radicals R
1, R
2, R
3And R
4Definition ditto said.
Wherein, described organic solvent can be the conventional solvent of this type of reaction of this area, one or more that preferable is in benzene, toluene and the THF; What the temperature of described reaction was preferable is 0～30 ℃.
Compound VI described in the present invention can be made by following method: in the organic solvent, under the effect of alkali, with compound V and compound XI (R
4H) carry out substitution reaction, get final product;
Wherein, radicals R
1, R
2, R
3And R
4Definition ditto said; R
5Be H, halogen or C
1～C
4Alkoxyl group; R
6Be H or halogen.
Wherein, work as R
5During for halogen, that described halogen is preferable is F, Cl, Br or I, and that better is F; Work as R
5Be C
1～C
4Alkoxyl group the time, described C
1～C
4Alkoxyl group preferable be methoxyl group.
Wherein, work as R
6During for halogen, that described halogen is preferable is F, Cl, Br or I, and that better is F.
Wherein, described organic solvent can be the conventional solvent of this type of reaction of this area, one or more that preferable is in THF, N (DMF) and the DMSO 99.8MIN. (DMSO); What described alkali was preferable is yellow soda ash, salt of wormwood, sodium hydride or butyllithium; What the temperature of described reaction was preferable is 0～60 ℃.Select different reaction conditions,, can obtain polysubstituted respectively or the mono-substituted product in 4-position like different substrates, different feed ratio, different alkali, different solvent and different temperature of reaction etc.
Compound V described in the present invention can be made by following method: in the organic solvent, compound IV and POCl3 are carried out chlorination, get final product;
Wherein, radicals R
1, R
5And R
6Definition ditto said.
Wherein, described organic solvent can be the conventional solvent of this type of reaction of this area, one or more that preferable is in methylene dichloride, toluene and the POCl3; What the temperature of described reaction was preferable is 20～120 ℃; What the mol ratio of described compound IV and POCl3 was preferable is 1: 1.4～1: 5.
Compound IV described in the present invention can be made by following method: in the organic solvent, the compound III is carried out ring-closure reaction, get final product;
Wherein, radicals R
1, R
5And R
6Definition ditto said.
Wherein, described organic solvent is preferable is in whiteruss, biphenyl and the thermal oil one or more; What the temperature of described reaction was preferable is 150～180 ℃.
Compound III described in the present invention can be made by following method: in the organic solvent, under the effect of alkali, compound IX and compound X are carried out condensation reaction, get final product; But (preparing method's 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 said.
Wherein, described organic solvent is preferable is in triethylamine, pyridine, toluene and the N (DMF) one or more; What described alkali was preferable is triethylamine, pyridine or salt of wormwood; What the temperature of described reaction was preferable is 55～110 ℃.
On the basis that meets this area general knowledge, but above-mentioned each preferred feature arbitrary combination among the present invention promptly gets each preferred embodiments of the present invention.
The present invention also further relates to suc as formula the midbody compound of the preparation shown in I, II, IV, V, VI, VII or the VIII suc as formula the cyclopropyl of the 2-shown in the A-4-substituted phenoxyl quinoline verivate;
Wherein, radicals R
1, R
2, R
3, R
4, R
5And R
6Definition all ditto said.
The invention still further relates to suc as formula the cyclopropyl of the 2-shown in the A-4-substituted phenoxyl quinoline verivate and suppress the HMG-CoA reductase enzyme or treat the application in the diseases related medicine of hyperlipidemia in preparation.
2-cyclopropyl of the present invention-4-substituted phenoxyl quinoline verivate can be processed pharmaceutical composition with any pharmaceutically acceptable carrier.The pharmaceutical carrier that described carrier such as pharmaceutical field are conventional: thinner or vehicle, like water etc.; Tackiness agent is like derivatived cellulose, gelatin or Vinylpyrrolidone polymer etc.; Weighting agent is like starch etc.; The agent of bursting apart is like lime carbonate or sodium hydrogencarbonate.In addition, also can in pharmaceutical composition, add other auxiliarys such as flavouring agent and/or sweeting agent.
With 2-cyclopropyl of the present invention-4-substituted phenoxyl quinoline verivate is that the pharmaceutical composition of activeconstituents can adopt the conventional method of medical field to process various formulations.Be used for when oral, can be made into conventional solid preparation such as tablet, pulvis or capsule etc.; When being used to inject, can be made into injection liquid.In various preparations, 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 2-cyclopropyl of the present invention-4-substituted phenoxyl quinoline verivate is the pharmaceutical prepn of activeconstituents; Can put on the patient who needs this treatment through intravenous injection, subcutaneous injection or oral form; General dosage is 1～100mg/ kg body weight/sky, specifically can select according to patient's age, the state of an illness etc.
Raw material described in the present invention or reagent except that specifying, all commercially available getting.
Positive progressive effect of the present invention is: compare with HMG-CoA reductase inhibitor Rosuvastatin in the prior art; 2-cyclopropyl of the present invention-4-substituted phenoxyl quinoline verivate has the activity of preferable inhibition HMG-CoA reductase enzyme, for the diseases related medicine of preparation treatment hyperlipidemia provides a new approach.
Embodiment
Further specify the present invention with embodiment below, but the present invention is not limited.
Used raw material or reagent is except that specifying among the embodiment, all commercially available getting.
Room temperature described in the following embodiment all refers to 20～30 ℃ of temperature.
Embodiment 1 preparation 2-cyclopropyl-4-phenoxy-6-fluorine quinoline-3-carboxylic acid ethyl ester (VI 8)
N
2Protection down, 1.13g (12mmol) phenol is dissolved among the 30ml exsiccant DMSO, under 0 ℃; (60%, 12mmol) sodium hydride stirs 0.5h to add 0.48g; Add 2.94g (10mmol) 2-cyclopropyl-4-chloro-6-fluorine quinoline-3-carboxylic acid ethyl ester again, be warming up to 80 ℃, reaction 2h.Cooling is poured reaction solution in the 50ml frozen water into, ethyl acetate extraction, and organic phase is water, saturated common salt water washing successively, anhydrous sodium sulfate drying.Filter, concentrate, column chromatography purification obtains the pure article compound of white solid VI 83.28g, yield 93.4%.
With 2-cyclopropyl-4-chloro-quinoline-3-carboxylic acid ethyl ester is raw material, adopts aforesaid method can make compound VI 1～7; With 2-cyclopropyl-4-chloro-6-fluorine quinoline-3-carboxylic acid ethyl ester is raw material, adopts aforesaid method can make VI 9～14; With 2-cyclopropyl-4-chloro-6-methoxy quinoline-3-carboxylic acid, ethyl ester is raw material, adopts aforesaid method can make VI 15 and VI 16.
The structure appraising datum of compound VI 1～7 is seen table 1; The structure appraising datum of compound VI 8～14 is seen table 2; The structure appraising datum of compound VI 15～16 is seen table 3.
Embodiment 2 preparation 2-cyclopropyl-4-phenoxys-6,7-difluoro-quinoline-3-carboxylic acid, ethyl ester (VI 19)
N
2Under the protection, 0.50g (5.29mmol) phenol is dissolved among the anhydrous THF of 15ml, under the ice bath; (60%, 5.29mmol) sodium hydride stirs 0.5h to add 0.212g; Add 1.5g (4.81mmol) 2-cyclopropyl-4-chloro-6 again; 7-difluoro-quinoline-3-carboxylic acid, ethyl ester (Rf=0.30, sherwood oil: ETHYLE ACETATE=20: 1 (v/v)), back flow reaction 9h.Cooling is poured reaction solution in the 50ml frozen water into, ethyl acetate extraction, and organic phase is water, saturated common salt water washing successively, anhydrous sodium sulfate drying.Filter, concentrate, the sherwood oil recrystallization obtains colorless, crystalline compound VI191.45g, yield 81.4% (Rf=0.25, sherwood oil: ETHYLE ACETATE=20: 1 (v/v)).
The compound method of compound VI 20～24 is the same.
With 2-cyclopropyl-4-chloro-6-methoxy quinoline-3-carboxylic acid, ethyl ester is raw material, adopts aforesaid method can make compound VI 17～18.
The structure appraising datum of compound VI 19～24 is seen table 4; The structure appraising datum of compound VI 17～18 is seen table 3.
Embodiment 3 preparation 2-cyclopropyl-4,7-two phenoxys-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 among the 20ml DMF successively, are warming up to 100 ℃ of reaction 4h.Cooling is poured reaction solution in the 50ml frozen water into, ethyl acetate extraction, and organic phase is water, saturated common salt water washing successively, anhydrous sodium sulfate drying.Filter, concentrate, the sherwood oil recrystallization obtains colorless, crystalline compound VI 251.79g, yield 83.8%, mp:102-4 ℃.
The compound method of compound VI 26～30 is the same.
The structure appraising datum of compound VI 25～30 is seen table 5.
Embodiment 4 preparation 2-cyclopropyl-4,6-hexichol oxy-quinoline-3-carboxylic acid, ethyl ester (VI 31)
2.82g (30mmol) phenol is dissolved among the 30ml exsiccant DMSO, under 0 ℃, (60%, 29mmol) sodium hydride stirs 1h, adds 2.94g (10mmol) 2-cyclopropyl-4-chloro-6-fluorine quinoline-3-carboxylic acid ethyl ester again, is warming up to 140 ℃, reaction 6h to add 1.16g.Cooling is poured reaction solution in the 50ml frozen water into, ethyl acetate extraction, and organic phase is water, saturated common salt water washing successively, anhydrous sodium sulfate drying.Filter, concentrate column chromatography purification (sherwood oil: ETHYLE ACETATE=100: 1 (v/v)), obtain white solid compound VI 8 1.48g (yield 42.2%) and colourless liquid compound VI 31 2.02g (yield 47.5%).
The structure appraising datum of compound VI 31 is seen table 5.
Embodiment 5 preparation 2-cyclopropyl-4,6,7-triple phenoxyl-quinoline-3-carboxylic acid ethyl ester (VI 32)
2.94g (31.2mmol) phenol is dissolved among the 30ml exsiccant DMSO, under 0 ℃, adds 1.25g (60%; 31.2mmol) sodium hydride, stir 1h, add 2.78g (8.92mmol) 2-cyclopropyl-4-chloro-6 again; 7-difluoro-quinoline-3-carboxylic acid, ethyl ester is warming up to 100 ℃, reaction 18h.Cooling is poured reaction solution in the 50ml frozen water into, ethyl acetate extraction, and organic phase is water, saturated common salt water washing successively, anhydrous sodium sulfate drying.Filter; Concentrate, through column chromatography purification (sherwood oil: ETHYLE ACETATE=100: 1 (v/v)), obtain colourless liquid compound VI 322.53g (yield 54.8%; Rf=0.33; ETHYLE ACETATE=10: 1 (v/v)) and compound VI 250.455g (yield 11.5%, Rf=0.39, sherwood oil: ETHYLE ACETATE=10: 1 (v/v)) sherwood oil:.
The compound method of compound VI 33 is the same.
The structure appraising datum of compound VI 32～33 is seen table 6.
Embodiment 6 preparation 2-cyclopropyl-4-phenoxy-6-fluorine quinoline-3-methyl alcohol (VII 8)
N
2Under the protection, (2.57g 7.32mmol) is dissolved in the anhydrous THF of 30ml to compound VI 8, is chilled to-70 ℃, adds LiAlH
4(0.278g 7.32mmol), changes cryosel immediately into and bathes, and reacts 4h about-15 ℃, and hydrochloric acid to the system that drips 6mol/L is acid.ETHYLE ACETATE (100ml) extraction, organic phase is water, saturated sodium bicarbonate solution, saturated common salt water washing successively, anhydrous sodium sulfate drying.Filter, concentrate,, obtain colorless, crystalline compound VII 81.58g, yield 69.9% with ETHYLE ACETATE and sherwood oil mixed solvent crystallization.
The compound method of compound VII 1～7 and compound VII 9～14 is the same.
The structure appraising datum of compound VII 1～7 is seen table 7; The structure appraising datum of compound VII 8～14 is seen table 8.
Embodiment 7 preparation 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 the 35ml dry toluene, under-10 ℃, drip diisobutyl aluminium hydride toluene solution (8.72ml, 21.8mmol), 0 ℃ of following stirring reaction 4h.Splash into the hydrochloric acid of 6mol/L, be neutralized to acidity, ethyl acetate extraction, organic phase is water, saturated sodium bicarbonate solution, saturated common salt water washing successively, anhydrous sodium sulfate drying.Filter, concentrate,, obtain white crystal compound VII 152.028g, yield 65.7% with the mixed solvent recrystallization of ETHYLE ACETATE and sherwood oil.
The compound method of compound VII 16～33 is the same.
The structure appraising datum of compound VII 15～18 is seen table 9; The structure appraising datum of compound VII 19～24 is seen table 10; The structure appraising datum of compound VII 25～31 is seen table 11; The structure appraising datum of compound VII 32～33 is seen table 12.
Embodiment 8 preparation 2-cyclopropyl-4-phenoxy-6-fluorine quinoline-3-methyl bromides (VIII 8)
(1.58g 5.11mmol) is dissolved in 10ml CH to compound VII 8
2Cl
2, under 0 ℃, dropwise add 0.96ml (2.77g, 10.2mmol) PBr
35ml CH
2Cl
2React 2h under the solution, room temperature, reaction solution is poured in the 30ml saturated sodium bicarbonate solution, stir 0.5h.Ethyl acetate extraction, organic phase are used the saturated common salt water washing, concentrate, and obtain white solid compound VIII 81.81g, yield 95.2%.
The compound method of compound VIII 1～7 and compound VIII 9～33 is the same.
The structure appraising datum of compound VIII 1～7 is seen table 13; The structure appraising datum of compound VIII 8～14 is seen table 14; The structure appraising datum of compound VIII 15～18 is seen table 15; The structure appraising datum of compound VIII 19～24 is seen table 16; The structure appraising datum of compound VIII 25～31 is seen table 17; The structure appraising datum of compound VIII 32～33 is seen table 18.
Embodiment 9 preparation 2-cyclopropyl-4-phenoxy-6-fluoro-3-(diphenyl phosphate oxygen methyl) quinoline (II 8)
(1.81g 4.87mmol) is dissolved in 10ml toluene to compound VIII 8, and (2.24g, 9.7mmol) ethoxy diphenyl base phosphine is warming up to backflow, reaction 2h, crystallisation by cooling dropwise to add 2.1ml.Filter, obtain white solid compound ii 8 2.2g, yield 91.7%.
The compound method of compound ii 1～7 and compound ii 9～33 is the same.
The structure appraising datum of compound ii 1～7 is seen table 13; The structure appraising datum of compound ii 8～14 is seen table 14; The structure appraising datum of compound ii 15～18 is seen table 15; The structure appraising datum of compound ii 19～24 is seen table 16; The structure appraising datum of compound ii 25～31 is seen table 17; The structure appraising datum of compound ii 32～33 is seen table 18.
Embodiment 10 preparations (3R, 5S, 6E)-and 7-[2-cyclopropyl-4-phenoxy-6-fluorine quinoline-3-]-3,5-dihydroxyl-3, the 5-O-isopropylidene-6-heptenoic acid tert-butyl ester (I 8)
N
2Under the protection, (2.2g 4.46mmol) is dissolved among the anhydrous THF of 20ml compound ii 8; Under 0 ℃, and dropping 1.87ml n-BuLi solution (2.86mol/L, 5.35mmol); Stir 1h, splash into 1.38g (5.35mmol) (3R, 5S)-6-oxo-3; 5-O-isopropylidene-3, the 7mlTHF solution of 5-dihydroxyl hecanoic acid t-butyl ester, stirred overnight under the room temperature.System is placed ice-water bath, drip the hydrochloric acid of 6mol/L, be neutralized to solution and be acid, water, saturated sodium bicarbonate solution, saturated common salt water washing successively, anhydrous sodium sulfate drying.Filter, concentrate column chromatography purification (sherwood oil: ETHYLE ACETATE=20: 1～10: 1 (v/v)), obtain white solid chemical compounds I 81.044g, yield 43.9%.
The compound method of chemical compounds I 1～7 and chemical compounds I 9～33 is the same.
The structure appraising datum of chemical compounds I 1～7 is seen table 19; The structure appraising datum of chemical compounds I 8～14 is seen table 20; The structure appraising datum of chemical compounds I 15～18 is seen table 21; The structure appraising datum of chemical compounds I 19～24 is seen table 22; The structure appraising datum of chemical compounds I 25～31 is seen table 23; The structure appraising datum of chemical compounds I 32～33 is seen table 24.
Embodiment 11 preparations (4R, 6S)-6-{ (E)-2-[2-cyclopropyl-6-fluoro-4-(phenoxy)-quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one (A8)
(0.5g 0.94mmol) is dissolved in 10.5ml CH to chemical compounds I 8
2Cl
2, under 0 ℃, splash into 1.4ml (18.7mmol) trifluoroacetic acid, stirring at room 24h.Reaction solution is poured in the 20ml saturated sodium bicarbonate solution, ethyl acetate extraction, organic phase is used saturated common salt water washing, anhydrous sodium sulfate drying.Filter, concentrate column chromatography purification (sherwood oil: ETHYLE ACETATE=2: 1 (v/v)), obtain white solid compound A-28 0.256g, yield 65.2%.
The compound method of compd A 1～7 and compd A 9～33 is the same.
The structure appraising datum of compd A 1～7 is seen table 25; The structure appraising datum of compound A-28～14 is seen table 26; The structure appraising datum of compd A 15～18 is seen table 27; The structure appraising datum of compd A 19～24 is seen table 28; The structure appraising datum of compd A 25～31 is seen table 29; The structure appraising datum of compound A-13 2～33 is seen table 30.
Embodiment 12 preparations (4R, 6S)-6-{ (E)-2-[2-cyclopropyl-6-fluoro-4-(4-fluorophenoxy) quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one (A10)
Under 0～5 ℃, (1.20g 2.1mmol) is dissolved in 24ml CH to chemical compounds I 10
2Cl
2In, drip 4.8ml (63mmol) CF
3COOH reacts 4h under the room temperature, pours reaction solution into 50ml saturated NaHCO
3In the solution, ethyl acetate extraction, organic phase is with saturated NaCl solution washing, anhydrous Na
2SO
4Drying is filtered, and concentrates column chromatography purification (ETHYLE ACETATE: sherwood oil=1: 2 (v/v)), obtain faint yellow solid 0.652g, yield 68.0%.
Embodiment 13 preparations (4R, 6S)-6-{ (E)-2-[2-cyclopropyl-6-fluoro-4-(4-fluorophenoxy) quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one (A10)
Under 0～5 ℃, (1.20g 2.1mmol) is dissolved in the 15ml toluene chemical compounds I 10, adds 10ml acetate, reacts 8h under the room temperature, pours reaction solution into 50ml saturated NaHCO
3In the solution, ethyl acetate extraction, organic phase is with saturated NaCl solution washing, anhydrous Na
2SO
4Drying is filtered, and concentrates column chromatography purification (ETHYLE ACETATE: sherwood oil=1: 2 (v/v)), obtain faint yellow solid 0.461g, yield 48.0%.
Embodiment 14 preparations (4R, 6S)-6-{ (E)-2-[2-cyclopropyl-6-fluoro-4-(4-fluorophenoxy) quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one (A10)
Under 0～5 ℃, (0.65g 1.2mmol) is dissolved in the 20ml THF chemical compounds I 10, adds the hydrochloric acid of 1ml 36%, reacts 8h down in 80 ℃.Pour reaction solution into 20ml saturated NaHCO
3In the solution, ethyl acetate extraction, organic phase is with saturated NaCl solution washing, anhydrous Na
2SO
4Drying is filtered, and concentrates column chromatography purification (ETHYLE ACETATE: sherwood oil=1: 2 (v/v)), obtain faint yellow solid 0.215g, yield 41.7%.
Embodiment 15 preparations (4R, 6S)-6-{ (E)-2-[2-cyclopropyl-4-(phenoxy) quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one (A1)
Under 0～5 ℃, (0.76g 1.32mmol) is dissolved in the 15ml chloroform chemical compounds I 1, adds the 5ml trifluoroacetic acid, reacts 8h down in 0～5 ℃.Pour reaction solution into 50ml saturated NaHCO
3In the solution, ethyl acetate extraction, organic phase is with saturated NaCl solution washing, anhydrous Na
2SO
4Drying is filtered, and concentrates column chromatography purification (ETHYLE ACETATE: sherwood oil=1: 2 (v/v)), obtain faint yellow solid 0.321g, yield 52.7%.
The vitro inhibition HMG-CoA reductase activity test of effect embodiment part quinoline A
Among the present invention; But the TP reference Kim HJ et al:Characterization of β-hydroxy-β of quinoline A vitro inhibition HMG-CoA reductase activity-methylglutarylcoenzyme A reductase inhibitor from Pueraria thunbergiana.J Agric Food Chem2005,53:5882-5888.
The HMG-CoA reductase enzyme extracts from the male Sprague-Dawley rat liver and obtains.
With the positive contrast of Rosuvastatin, do not add the negative contrast of any suppressor factor, be blank with no HMG-CoA and unrestraint agent simultaneously.
3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) consumes two molecule reduced form two nucleoside of nicotinamide adenine phosphoric acid (NADPH) under the catalysis of HMG-CoA reductase enzyme, generate 3-methyl-3,5-dihydroxy valeric acid and Reduced nicotinamide-adenine dinucleotide (NADP).NADPH has maximum absorption at ultraviolet 340nm place, and NADP does not have absorption in this wavelength, and the lowering speed of mensuration system ultraviolet absorption value at the 340nm place can be known the speed that this reduction reaction is carried out.After adding suppressor factor, can calculate the inhibition activity of this suppressor factor to the HMG-CoA reductase enzyme by the variation of system ultraviolet absorption value at 340nm place.
Active with part of compounds A among the present invention of aforesaid method mensuration to the inhibition of HMG-CoA reductase enzyme.Quinoline A to be measured is respectively chosen eight suitable concns, measure its restraining effect to the HMG-CoA reductase enzyme, match suppresses curve, obtains half-inhibition concentration (IC
50).The IC of Rosuvastatin that records and part quinoline A
50Value is seen table 31.
Data in the table 31 show: compare with Rosuvastatin of the prior art, part quinoline of the present invention has the activity of better inhibition HMG-CoA reductase enzyme.
Claims (19)
1. one type suc as formula the cyclopropyl of the 2-shown in the A-4-substituted phenoxyl quinoline verivate;
Wherein, R
1Be H or halogen; R
2Be H, halogen, C
1～C
4Alkoxyl group or suc as formula the group shown in the Q; R
3For H, halogen or suc as formula the group shown in the Q; R
4For suc as formula the group shown in the Q;
Among the 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, works as R
1During for halogen, described halogen is F.
3. quinoline as claimed in claim 1 is characterized in that, works as R
2During for halogen, described halogen is F; Work as R
2Be C
1～C
4Alkoxyl group the time, described alkoxyl group is a methoxyl group.
4. quinoline as claimed in claim 1 is characterized in that, works as R
3During for halogen, described halogen is F.
5. quinoline as claimed in claim 1 is characterized in that, among the described formula Q, when R was halogen, described halogen was F; When R is C
1～C
4Alkyl the time, described alkyl is a sec.-propyl; When R is C
1～C
4Alkoxyl group the time, described alkoxyl group is a methoxyl group.
6. quinoline as claimed in claim 1 is characterized in that, described quinoline comprises following compounds:
(4R, 6S)-6-{ (E)-2-[2-cyclopropyl-4-(phenoxy) quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
(4R, 6S)-6-{ (E)-2-[2-cyclopropyl-4-(4-fluorophenoxy) quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
(4R, 6S)-6-{ (E)-2-[2-cyclopropyl-4-(2-sec.-propyl phenoxy) quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
(4R, 6S)-6-{ (E)-2-[2-cyclopropyl-4-(4-sec.-propyl phenoxy) quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
(4R, 6S)-6-{ (E)-2-[2-cyclopropyl-6-fluoro-4-(phenoxy)-quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
(4R, 6S)-6-{ (E)-2-[2-cyclopropyl-6-fluoro-4-(4-methoxyl group phenoxy) quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
(4R, 6S)-6-{ (E)-2-[2-cyclopropyl-6-fluoro-4-(2-sec.-propyl phenoxy) quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
(4R, 6S)-6-{ (E)-2-[2-cyclopropyl-6-methoxyl group-4-(4-methoxyl group phenoxy)-quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
(4R, 6S)-6-{ (E)-2-[2-cyclopropyl-6-methoxyl group-4-(2-sec.-propyl phenoxy)-quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
(4R, 6S)-6-{ (E)-2-[2-cyclopropyl-5,6-two fluoro-4-(phenoxy)-quinoline-3-yls] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
(4R, 6S)-6-{ (E)-2-[2-cyclopropyl-5,6-two fluoro-4-(4-methoxyl group phenoxy)-quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
(4R, 6S)-6-{ (E)-2-[2-cyclopropyl-6,7-two fluoro-4-(3-fluorophenoxy) quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
(4R, 6S)-6-{ (E)-2-[2-cyclopropyl-6,7-two fluoro-4-(3-methoxyl group phenoxy) quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
(4R, 6S)-6-{ (E)-2-[2-cyclopropyl-6-fluoro-4,7-two (phenoxy)-quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
(4R, 6S)-6-{ (E)-2-[2-cyclopropyl-6-fluoro-4,7-two (3-fluorophenoxy) quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
(4R, 6S)-6-{ (E)-2-[2-cyclopropyl-6-fluoro-4,7-two (3-methoxyl group phenoxy) quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one;
Or (4R, 6S)-6-{ (E)-2-[2-cyclopropyl-4,6-two (phenoxy) quinoline-3-yl] vinyl }-3,4,5,6-tetrahydrochysene-4-hydroxyl-2H-pyran-2-one.
7. like the preparation method of each described formula A compound of claim 1～6, it is characterized in that comprising the following step: will get final product suc as formula lactonizing behind the compound deprotection shown in the I;
Wherein, radicals R
1, R
2, R
3And R
4Definition such as claim 1～5 each is said.
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 the organic solvent, will under the effect of acid, react suc as formula the compound shown in the I, and get final product.
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 THF, MTBE, toluene, methylene dichloride and the 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 acetate, trifluoroacetic acid and the hydrochloric acid.
11. the preparation method of formula A compound as claimed in claim 8 is characterized in that: the concentration of described acid in organic solvent is volume percent 5～66%.
12. the preparation method of formula A compound as claimed in claim 11 is characterized in that: the concentration of described acid in organic solvent is volume percent 20%.
13. the preparation method of formula A compound as claimed in claim 8 is characterized in that: the temperature of described reaction is 0～80 ℃.
14. the preparation method of formula A compound as claimed in claim 13 is characterized in that: the temperature of described reaction is 20～30 ℃.
15. the preparation method of formula A compound as claimed in claim 7 is characterized in that: described chemical compounds I is made by following method: compound ii and compd B are carried out the Wittig-Hornor reaction, get final product;
Wherein, radicals R
1, R
2, R
3And R
4Definition such as claim 1～5 each is said.
16. midbody compound suc as formula the preparation shown in I, II, IV, V, VI, VII or the VIII such as each described formula A compound of claim 1～6;
Wherein, radicals R
1, R
2, R
3And R
4Definition such as claim 1～5 each is said; R
5Be H, halogen or C
1～C
4Alkoxyl group; R
6Be H or halogen.
17. midbody compound as claimed in claim 16 is characterized in that, works as R
5During for halogen, described halogen is F; Work as R
5Be C
1～C
4Alkoxyl group the time, described C
1～C
4Alkoxyl group be methoxyl group.
18. midbody compound as claimed in claim 16 is characterized in that, works as R
6During for halogen, described halogen is F.
19. suppress the HMG-CoA reductase enzyme or treat the application in the diseases related medicine of hyperlipidemia in preparation like each described quinoline of claim 1～6.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002092570A1 (en) * | 2001-05-15 | 2002-11-21 | Ube Industries, Ltd. | Process for producing (3r,5s)-7-substituted-3,5-dihydroxyhept-6-enoic acid |
| CN101210011A (en) * | 2006-12-27 | 2008-07-02 | 上海医药工业研究院 | Quinolines compounds and their intermediates, preparation method and application |
| CN101220021A (en) * | 2007-01-12 | 2008-07-16 | 上海医药工业研究院 | 4-substituted phenoxyl quinoline compounds and midbody, production method, application thereof |
| CN101570510A (en) * | 2008-04-30 | 2009-11-04 | 上海医药工业研究院 | Quinoline compound, pharmaceutical composition, preparation method and application thereof |
| WO2010098583A2 (en) * | 2009-02-24 | 2010-09-02 | 한미약품 주식회사 | Novel method for preparing statin compounds or salts thereof, and intermediate compounds used in same |
-
2010
- 2010-11-26 CN CN201010567219.1A patent/CN102477032B/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002092570A1 (en) * | 2001-05-15 | 2002-11-21 | Ube Industries, Ltd. | Process for producing (3r,5s)-7-substituted-3,5-dihydroxyhept-6-enoic acid |
| CN101210011A (en) * | 2006-12-27 | 2008-07-02 | 上海医药工业研究院 | Quinolines compounds and their intermediates, preparation method and application |
| CN101220021A (en) * | 2007-01-12 | 2008-07-16 | 上海医药工业研究院 | 4-substituted phenoxyl quinoline compounds and midbody, production method, application thereof |
| CN101570510A (en) * | 2008-04-30 | 2009-11-04 | 上海医药工业研究院 | Quinoline compound, pharmaceutical composition, preparation method and application thereof |
| WO2010098583A2 (en) * | 2009-02-24 | 2010-09-02 | 한미약품 주식회사 | Novel method for preparing statin compounds or salts thereof, and intermediate compounds used in same |
Non-Patent Citations (1)
| Title |
|---|
| 蔡正艳，等: "3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂的构效关系研究进展", 《中国新药杂志》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106749403A (en) * | 2016-12-08 | 2017-05-31 | 广东省测试分析研究所（中国广州分析测试中心） | A kind of flame-retardant luminous bifunctional material of difluorophenyl quinoline phosphine oxide and preparation method thereof |
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