Method for producing pitavastatin calcium raw material

A technology for pitavastatin calcium and raw materials, which is applied in the field of preparation of cholesterol-lowering drugs, can solve the problems of difficult separation of pitavastatin calcium raw materials, and achieves the effects of low raw material requirements, high product conversion rate and simple preparation process.

Inactive Publication Date: 2008-07-16
JIANGSU WANBANG BIOPHARMLS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] The technical problem to be solved by the present invention is to provide a method for preparing pitavastatin calcium bulk drug with high optical purity, using raw materials without special isomerization requireme

Method used

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  • Method for producing pitavastatin calcium raw material
  • Method for producing pitavastatin calcium raw material
  • Method for producing pitavastatin calcium raw material

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] A method for preparing pitavastatin calcium raw material, with (E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-5-hydroxyl-3-carbonyl- 6-heptenoic acid ethyl ester (I) is starting raw material, comprises the following steps:

[0031] The first step: (+)-3,5-dihydroxy-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-6-heptenoic acid ethyl The preparation of ester, reaction formula:

[0032]

[0033] Operation process:

[0034] Add 770ml of anhydrous methanol, 5060ml of anhydrous tetrahydrofuran, and 253g of (E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-5-hydroxyl to a 10L three-necked flask -3-carbonyl-6-heptenoic acid ethyl ester, under the protection of nitrogen, add dropwise 240ml of 50% diethylmethoxyborane / tetrahydrofuran solution, drop the temperature of the reaction solution to -50°C, and stir for 1 hour , add 42.8g of sodium borohydride, add dropwise 6150ml of ethyl acetate to the reaction liquid for extraction, wash with 5600ml of saturated salt ...

Embodiment 2

[0044] The first step: (+)-3,5-dihydroxy-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-6-heptenoic acid ethyl Preparation of esters:

[0045] Operation process:

[0046] Add 770ml of anhydrous methanol, 5060ml of anhydrous tetrahydrofuran, and 253g of (E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-5-hydroxyl to a 10L three-necked flask -3-carbonyl-6-heptenoic acid ethyl ester, under the protection of nitrogen, add 240ml of 50% trimethylborane / tetrahydrofuran solution dropwise, after dropping, cool the reaction solution to -100°C, stir for 1 hour, add 42.8 g potassium borohydride, add dropwise to the reaction solution, add 6150ml ethyl acetate to extract, wash with 5600ml saturated salt and 5600ml saturated aqueous sodium bicarbonate solution, concentrate under reduced pressure to remove solvent, add 4500ml methanol to dissolve, concentrate again, repeat the above steps three times , to obtain solid (+) (E)-3,5-dihydroxy-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl...

Embodiment 3

[0054] The first step: (+)-3,5-dihydroxy-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-6-heptenoic acid ethyl Preparation of esters:

[0055] Operation process:

[0056] Add 770ml of anhydrous methanol, 5060ml of anhydrous tetrahydrofuran, and 253g of (E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-5-hydroxyl to a 10L three-necked flask -Ethyl 3-carbonyl-6-heptenoate, under the protection of nitrogen, add 240ml of 50% trimethoxyborane / tetrahydrofuran solution dropwise, after dropping, cool the reaction solution to -50°C, stir for 1 hour, and add 42.8g of boron Add potassium hydride dropwise to the reaction solution, add 6150ml of ethyl acetate for extraction, wash with 5600ml of saturated salt and 5600ml of saturated aqueous sodium bicarbonate solution. Concentrate under reduced pressure to remove solvent, add 4500ml of methanol to dissolve, concentrate again, repeat the above steps three times to get Solid (+) (E)-3,5-dihydroxy-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-...

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Abstract

The invention relates to a method for preparing the raw materials of pitavastatin calcium, which uses an (E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-5-hydroxyl-3- carbonyl-6-heptene acid ester as a beginning raw material to generate a heptenoic acid through being reduced and reacted by adding an alkali and an acid; a D-(+) benzyl methylamine is added to generate a mixture of a benzyl methylamine salt, and crystallize to separate out a (3R, 5S)-dihydroxy-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-6- heptenoic acid D-(+) benzyl methylamine through the different solubility of the mixtures in a separating agent, and the separating agent is a mixed liquid of a methyl isobutyl ketone and an acetone or an ethanol; finally adds lye to hydrolyze and prepare the pitavastatin calcium salt. The method of the invention is selectively reduced to a pair of isomers by using a determined reduction agent, generates salt by reacting with the D-(+) benzyl methylamine and effectively separates a needed isomer by utilizing the different solubility of various isomers to the separating agent. The invention has the advantages of simple preparing technique, low requirements for the raw materials and high conversion rate of the obtained products.

Description

technical field [0001] The invention relates to a method for preparing a cholesterol-lowering drug, in particular to a method for preparing a raw material of pitavastatin calcium. The pitavastatin calcium is an HMG-CoA reductase inhibitor of the cholesterol-lowering drug. Background technique [0002] Pitavastatin Calcium is a third-generation statin drug jointly developed by Nissan Chemical Industry Co., Ltd. and Kowa Co., Ltd., which was registered and listed in Japan in July 2003. The trade name is LIVALO, and the preparation specifications are 1mg and 2mg. [0003] The chemical name of pitavastatin calcium is (E)-3,5-dihydroxy-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-6-heptenoic acid Calcium salt, its chemical structural formula is: [0004] [0005] The pharmacological effects of pitavastatin calcium are: (1) Inhibiting HMG-CoA reductase, pitavastatin calcium has a strong antagonistic inhibitory effect on HMG-CoA enzyme, with an IC50 value of 6.8nM, which is ...

Claims

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Application Information

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IPC IPC(8): C07D215/06
Inventor 李孝成乔德水高雪芹
Owner JIANGSU WANBANG BIOPHARMLS
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