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Method for preparing high-optical purity pitavastatin calcium

A technology of pitavastatin calcium and optical purity, applied in the field of preparation of cholesterol-lowering drugs

Inactive Publication Date: 2012-05-02
ZHEJIANG GUOBANG PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] EU patents EP0535548, EP0304063, Chinese patents CN101219991, CN1876633 report: take anthranilic acid as starting material, protect the amino group of anthranilic acid with p-toluenesulfonyl chloride , and then through Friedel-Crafts acylation reaction, deprotection group to obtain benzophenone, benzophenone and β-cyclopropyl-β-oxopropionic acid ethyl ester are cyclized by Friedl?nder reaction to obtain ethyl quinoline carboxylate, Then use LiAlH4 or DIBAL to reduce to quinoline methanol, quinoline methanol is oxidized by PCC to quinoline formaldehyde, quinoline formaldehyde is reacted by Witting-Horner to obtain quinoline acrylonitrile, and then reduced by DIBAL to quinoline acrolein, quinoline acrolein Condensation with methyl acetoacetate by Aldol to obtain methyl quinoline oxone heptenate, stereoselective reduction with NaBH4 at low temperature to obtain erythroquinoline dihydroxyheptenate methyl ester, finally hydrolyzed into calcium salt and freeze-dried to obtain Pitavastatin calcium (see Scheme 2), this method has complex reactions, harsh reaction conditions, two chiral centers are obtained by reduction, and four chiral isomers are produced, which is not easy to purify, and the yield is low

Method used

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  • Method for preparing high-optical purity pitavastatin calcium
  • Method for preparing high-optical purity pitavastatin calcium
  • Method for preparing high-optical purity pitavastatin calcium

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] In a 1000ml four-neck flask, add 600ml methanol, 33g (0.0638mol) (3R,5S)-dihydroxy-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinoline base]-3,5-dihydroxy-3,5-Oisopropylidene-6-heptenoic acid tert-butyl ester (I), at 10°C, add 85ml of 1mol / L hydrochloric acid, and react for 1 hour to obtain (3R ,5S)-dihydroxy-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-6-(E)-heptenoic acid tert-butyl ester (Ⅱ) methanol solution .

[0038] Add 85ml of 1mol / L sodium hydroxide solution to the methanol solution of (II) above, stir for 2 minutes, then add 64ml of 1mol / L sodium hydroxide solution, and react for 2 hours. Recover under reduced pressure at 55°C, stop recovery when about 100-200ml remains, add water to 250ml, extract twice with 300ml dichloromethane each, adjust the acidity of the water layer to pH 4-5, extract with 300ml dichloromethane , washed with 50ml of purified water to obtain (3R,5S)-dihydroxy-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-6-(E)-heptenoic acid (Ⅲ) i...

Embodiment 2

[0042] In a 1000 ml four-necked flask, add 600 ml of tetrahydrofuran, 33 g (0.0638 mol) (3R,5S)-dihydroxy-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinoline base]-3,5-dihydroxy-3,5-Oisopropylidene-6-heptenoic acid tert-butyl ester (I), at 50°C, add 100ml of 1mol / L sulfuric acid, and react for 1 hour to obtain (3R ,5S)-dihydroxy-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-6-(E)-heptenoic acid tert-butyl ester (Ⅱ) tetrahydrofuran solution .

[0043]Add 85 ml of 1 mol / L sodium hydroxide solution to the tetrahydrofuran solution of (II) above, stir for 2 minutes, then add 64 ml of 1 mol / L sodium hydroxide solution, and react for 2 hours. Recover under reduced pressure at 55°C, stop the recovery when there are about 100-200ml remaining, add water to 250ml, extract twice with 300ml methyl tert-butyl ether, adjust the acidity of the water layer to about 5, and use 300mM methyl Extracted with tert-butyl ether, washed with 50ml of purified water to obtain (3R,5S)-dihydroxy-7-[2-cyclo...

Embodiment 3

[0047] In a 1000ml four-neck flask, add 600ml of ethanol, 33g (0.0638mol) (3R,5S)-dihydroxy-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinoline base]-3,5-dihydroxy-3,5-Oisopropylidene-6-heptenoic acid tert-butyl ester (Ⅰ), at 25°C, add 85ml of 1mol / L hydrochloric acid, and react for 1 hour to obtain (3R ,5S)-dihydroxy-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-6-(E)-heptenoic acid tert-butyl ester (Ⅱ) ethanol solution .

[0048] Add 85ml of 1mol / L sodium hydroxide solution to the ethanol solution of (II) above, stir for 2 minutes, then add 64ml of 1mol / L sodium hydroxide solution, and react for 2 hours. Recover under reduced pressure at 55°C, stop recovery when about 100-200ml remains, add water to 250ml, extract twice with 300ml toluene each, adjust the acidity of the aqueous layer to pH 2-3, extract with 300ml dichloromethane, 50ml Purified and washed with water to obtain (3R,5S)-dihydroxy-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-6-(E)-heptenoic acid (Ⅲ ) in dichl...

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Abstract

The invention relates to a method for preparing high-optical purity pitavastatin calcium. The method comprises the following steps of: deprotecting (3R,5S)-dyhydroxyl-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dyhydroxyl-3,5-Oisopropylidene-6-tert-butyl heptenoate (I) serving as an initial raw material by using acid, and removing impurities under a certain pH value; adding excessive D-(+)benzyl methylamine, and crystallizing to extract heptenoic acid amine salt (IV); and adding calcium chloride to obtain the pitavastatin calcium. The method has the advantages that the reaction condition is mild, the purity of the product is high, the optical purity is more than or equal to 99.5 percent, the yield is more than or equal to 50 percent, the problems of high difficulty of separation and purification and low yield in the conventional method for synthesizing the pitavastatin calcium, and the method is suitable for industrialization.

Description

technical field [0001] The invention relates to a preparation method of a cholesterol-lowering drug, in particular to a preparation method of the cholesterol-lowering drug pitavastatin calcium. Background technique [0002] Pitavastatin Calcium (Pitavastatin Calcium) is the first fully synthetic HMG-CoA reductase inhibitor jointly developed by Nissan Chemical Co., Ltd. On the 17th, it was approved for listing in Japan for the first time. Foreign countries are known as "super statins" for their powerful lipid-lowering effects shown in clinical trials. According to the results of the existing clinical trials and the comparison with similar foreign products already on the market, its lipid-lowering effect is very good, and it is the most powerful lipid-lowering drug so far. [0003] The chemical name of pitavastatin calcium is (+)-bis{(3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3, 5-dihydroxy-6-heptenoic acid} calcium salt, its chemical structure is: [000...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/14
Inventor 邱家军单继雷侯仲轲汤旗单国洋
Owner ZHEJIANG GUOBANG PHARMA
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