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Crystallizing method for obtaining I crystal form (+)-(S)-clopidogrel bisulfate

A technology of clopidogrel bisulfate and clopidogrel free base, which is applied in the field of antithrombotic drugs, can solve the problems of no obvious improvement in the crystallization process, difficult to precipitate solids, and harsh conditions, and achieve simple and easy-to-control crystallization process with high yield , good crystal fluidity effect

Inactive Publication Date: 2011-05-11
北京华禧联合科技发展有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] According to the method described in patent EP281459 and CN200610062880.0, ice acetone was used as solvent to prepare I crystal form clopidogrel. It was found that the repeatability was poor and the conditions were harsh. In patent CN200710069957.1, ketone solvent was used, but in the crystallization process A small amount of alcohol solvent was added, but from the experimental results, a small amount of alcohol solvent did not significantly improve the crystallization process
With reference to domestic patents CN200610051684.3 and CN200610023423.9, it is found that it mainly uses low-polarity solvents such as dichloromethane, ethers, and esters for crystallization process. Repeat the above patents and find that low-polarity solvents drop at low temperatures. Adding concentrated sulfuric acid will first form a white oil, and it is difficult to precipitate solids after stirring after heating, which cannot meet the production requirements

Method used

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  • Crystallizing method for obtaining I crystal form (+)-(S)-clopidogrel bisulfate
  • Crystallizing method for obtaining I crystal form (+)-(S)-clopidogrel bisulfate
  • Crystallizing method for obtaining I crystal form (+)-(S)-clopidogrel bisulfate

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Experimental program
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Effect test

Embodiment 1

[0017] In a 100ml three-necked flask, add (+)-(S)-clopidogrel free base 5.00g, propanol 25ml, stir to dissolve, ice bath controls temperature and slowly adds dropwise 1.5g of concentrated sulfuric acid (mass concentration is 98%) 25ml of propanol solution, after the dropwise addition, was incubated and stirred for 10h to obtain a large amount of white solid, which was filtered and dried under reduced pressure to constant weight to obtain 4.75g I crystal form (+)-(S)-clopidogrel hydrogensulfate. The rate is 73%.

Embodiment 2

[0019] In a 100ml three-necked flask, add (+)-(S)-clopidogrel free base 5.00g, butanol 25ml, stir and dissolve, and slowly add 1.5g of concentrated sulfuric acid (mass concentration is 98%) dropwise to control the temperature in an ice bath. 25ml of butanol solution, after the dropwise addition, was incubated and stirred for 10h to obtain a large amount of white solid, which was filtered and dried under reduced pressure to constant weight to obtain 5.01g I crystal form (+)-(S)-clopidogrel hydrogensulfate. rate of 77%.

Embodiment 3

[0021] In a 100ml three-necked flask, add (+)-(S)-clopidogrel free base 5.00g, butanol 100ml, stir to dissolve, control the temperature in an ice bath and slowly add 1.5g of concentrated sulfuric acid (mass concentration is 98%) dropwise 100ml of butanol solution, after the dropwise addition, was incubated and stirred for 12h to obtain a white solid, filtered, and dried under reduced pressure to constant weight to obtain 2.73g I crystal form (+)-(S)-clopidogrel hydrogensulfate, yield 41.96%.

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Abstract

The invention discloses a crystallizing method for obtaining I crystal form (+)-(S)-clopidogrel bisulfate. The method disclosed by the invention comprises the following steps: dissolving (+)-(S)-clopidogrel free alkali in an alcohol solvent, and dropwise adding an alcohol solution of concentrated sulfuric acid, thereby obtaining the I crystal form (+)-(S)-clopidogrel bisulfate by controlling the dropwise adding temperature, mixing time and recrystallization temperature.

Description

technical field [0001] The present invention relates to a crystallization method of antithrombotic drug (+)-(S)-clopidogrel bisulfate I crystal form with the following structure, that is, (+)-(S)-2-(2-chlorophenyl)- Crystallization method of 2-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl)acetate methyl sulfate salt I crystallization method. [0002] Background technique [0003] Clopidogrel bisulfate is a new-generation platelet aggregation inhibitor successfully developed by the French company Sanofi in 1986, and its trade name is "Polivi". It belongs to the thienopyridine class of drugs and is a new type of adenosine diphosphate receptor antagonist. Because of its good safety and rapid inhibition of platelets, it has replaced ticlopidine as the most widely used antiplatelet drug one. [0004] European Patent EP281459 and U.S. Patent US6429210 point out that there are different crystal forms of clopidogrel hydrogen sulfate, and the method for obtaining the I crystal fo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D495/04
Inventor 唐功秉张凯王玉莉王健航毕华张志芳
Owner 北京华禧联合科技发展有限公司
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