Method for preparing high optical purity pitavastatin calcium raw material drug

A technology of pitavastatin calcium and optical purity, which is applied in the field of preparation of cholesterol-lowering drugs, can solve problems such as low yield and difficult separation and purification, and achieve low-cost effects

Active Publication Date: 2006-12-13
CHINA RESOURCES DOUBLE CRANE PHARMA COMPANY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Solve the technical problems of the existing preparation of pitavastatin calcium raw material drug separation and purification difficulty, low yield

Method used

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  • Method for preparing high optical purity pitavastatin calcium raw material drug
  • Method for preparing high optical purity pitavastatin calcium raw material drug
  • Method for preparing high optical purity pitavastatin calcium raw material drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] 1: (E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinoline]-5-carbonyl-(3R)-3-(tert-butyldimethylsiloxane base)-6-heptenoic acid methyl ester preparation

[0033] Reaction formula:

[0034]

[0035]Steps

[0036] Put 27g of compound II and 62.5g (1.25eq) of phosphorus ylide 1 into a 1L single-port reaction flask, add 680ml of anhydrous acetonitrile, stir, heat to 70-80°C for 24 hours, and TLC monitors that the reaction is basically complete. The solvent was distilled off, and the residue was 45.7 g of a slurry separated by column. Yield 90%.

[0037] [α] D 25 : -8.29 (c, 1.2; MeOH))

[0038] HNMR (CDCl 3 )δ: 0.00(s, 3H), 0.05(s, 3H), 0.8(s, 9H), 1.10(q, 2H), 1.40(s, 2H), 2.30(m, 1H), 2.46(m, 2H ), 2.69(m, 2H), 4.57(p, 1H), 3.66(s, 3H), 6.3(d, 1H), 7.63(d, 1H), 7.1-8.0(8H)

[0039] MASS: (Base)548.7(M+1)

[0040] C 32 h 38 FNO 4 Si: cal.547.7

[0041] 2: Preparation of (E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinoline]-5-carbonyl-(3R)-hydroxy-6-heptenoic a...

Embodiment 2

[0082] 1: (E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinoline]-5-carbonyl-(3R)-3-(tert-butyldimethylsiloxane ) Preparation of ethyl 6-heptenoate

[0083] Reaction formula:

[0084]

[0085] Steps

[0086] Put 18g of compound II and 66.01 (2.0eq) of phosphorus ylide 1 into a 1L single-port reaction flask, add 700ml of anhydrous THF, stir, heat to 60-70°C for 48 hours, and TLC monitors that the reaction is basically complete. The solvent was distilled off, and the residue was 27.4 g of slurry separated by column, but the yield decreased to 81%.

[0087] [α] D 25 : -8.10 (c, 1.1; MeOH).

Embodiment 3

[0089] 1: (E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinoline]-5-carbonyl-(3R)-3-(tert-butyldimethylsiloxane ) Preparation of ethyl 6-heptenoate

[0090] Reaction formula:

[0091]

[0092] Steps

[0093]Put 18g of compound II and 59.4 (1.8eq) of phosphorus ylide 1 into a 1L single-port reaction flask, add 600ml of anhydrous toluene and stir, heat to 100°C for 12 hours, and TLC monitors that the reaction is basically complete. The solvent was distilled off, and the residue was 28.4 g of slurry separated by column, the yield was 85%.

[0094] [α] D 25 : -8.10 (c, 1.1; MeOH)

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Abstract

The invention relates the method of preparing the raw material of high optical purity pravastatin calcium. The method comprises the following steps: adding the 2- cyclopropyl-4-(4- fluorophenyl)-3-quinoline aldehyde II and (3R)-3- alkoxy silane-5- carbonyl-6- triphenyl phosphor heptene acid ester III in dissolvent, getting (E)-7- [2-2- cyclopropyl-4-(4- fluorophenyl)-3- chinoline]-5- carbonyl-(3R)-3- alkoxy silane-6- triphenyl phosphor heptene acid ester IV, removing the protection of IV, getting (E)-7- [2-2- cyclopropyl-4-(4- fluorophenyl)-3- chinoline]-5- carbonyl-(3R)- hydroxyl -6- triphenyl phosphor heptene acid ester V, deacidizing it in the mixture dissolvent of alcohol and ether with NaBH4 or KBH4 at -100-0Deg.C, getting (E)-7- [2-2- cyclopropyl-4-(4- fluorophenyl)-3- chinoline]-(3R, 5S)- dihydroxy -6- triphenyl phosphor heptene acid ester VI, hydrolyzing it with alkali, and getting pravastatin calcium. The material is used to prepare HMG-CoA reductase inhibiting agent.

Description

Technical field: [0001] The present invention relates to a kind of preparation method of cholesterol-lowering medicine, is the new preparation method of cholesterol-lowering medicine (HMG-CoA reductase inhibitor) pitavastatin calcium crude drug (I): [0002] technical background: [0003] Pitavastatin calcium (I) is Japanese Patent Application No. 1-279866, EP304063, disclosed in U.S. Patent No. 5,011,930 as a hypolipidemic drug (HMG-CoA reductase inhibitor), and pitavastatin calcium is produced by Japan Nissan Chemical Industry Co., Ltd. Researched and developed, and jointly applied by Nissan Chemical Industry Co., Ltd., Kowa Co., Ltd. and Sankyo Co., Ltd., it was approved for marketing in Japan in July 2003 for the treatment of hypercholesterolemia. The trade name is LIVALO®, and the preparation specification is 1mg and 2 mg film-coated tablet. [0004] Since the first statin drug lovastatin was launched in 1987, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductas...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/14
Inventor 吴颢胡国平杜晓行李革
Owner CHINA RESOURCES DOUBLE CRANE PHARMA COMPANY
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