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Method for preparing high optical purity pitavastatin calcium raw material drug

A technology of pitavastatin calcium and raw materials, 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: 2009-07-01
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 ac...

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 to a method for preparing a raw material drug of pitavastatin calcium with high optical purity, which mainly solves the technical problems of high difficulty in separation and purification of the raw material drug of pitavastatin calcium and low yield. The method comprises the following steps: 2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinecarbaldehyde II and (3R)-3-alkylsilyloxy-5-carbonyl-6-triphenyl (E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinoline]-5-carbonyl-(3R)- 3-Alkylsilyloxy-6-heptenoate IV, IV is deprotected with a deprotecting agent to obtain (E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3- Quinoline]-5-carbonyl-(3R)-hydroxyl-6-heptenoic acid ester V, which was mixed with NaBH in a mixed solvent of an alcohol and an ether compound 4 or KBH 4 And selective reduction under the action of the ligand, the reaction temperature is -100 ° C to 0 ° C, to obtain (E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinoline] -(3R,5S)-dihydroxy-6-heptenoic acid ester VI, which is hydrolyzed into calcium salt with alkali to obtain pitavastatin calcium. It is mainly used in the preparation of HMG-CoA reductase inhibitors, a drug for lowering blood lipids.

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. It was developed and jointly applied by Nissan Chemical Industry Co., Ltd., Kowa Co., Ltd. and Sankyo Co., Ltd., and was approved for marketing in Japan in July 2003 for the treatment of hypercholesterolemia. The product name is , film-coated tablets with formulation specifications of 1 mg and 2 mg. [0004] Since the first statin drug lovastatin was launched in 1987, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors...

Claims

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Application Information

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Patent Type & Authority Patents(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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