A kind of method for preparing type I clopidogrel bisulfate

A technology of clopidogrel bisulfate and clopidogrel free base, which is applied in organic chemistry and other fields, and can solve problems such as cumbersome operation, unguaranteed crystal purity, and high residual solvent

Active Publication Date: 2016-06-22
ZHEJIANG HUAHAI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] 2. Since the crystal form I is a process of instant precipitation and then solidification, a large amount of residual solvent is often contained in the obtained product, which will cause the product to dry for a long time and still have a high residual solvent
[0014] 3. Both need to add high-purity type I (+)-(S)-clopidogrel bisulfate seed crystals, which is cumbersome to operate, and the purity of the crystal form cannot be guaranteed

Method used

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  • A kind of method for preparing type I clopidogrel bisulfate
  • A kind of method for preparing type I clopidogrel bisulfate
  • A kind of method for preparing type I clopidogrel bisulfate

Examples

Experimental program
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Effect test

Embodiment 1

[0046] Draw 3.83kg of clopidogrel free base and 45.0kg of methyl isobutyl ketone into a dry reaction kettle, stir to dissolve, cool to below -5°C, maintain T=-10±5°C, slowly drop to configure After dropping the good diluted methyl isobutyl ketone sulfate solution, slowly warm up to T=30±5°C, keep stirring for 2 to 4 hours, filter, and wash the filter cake with a small amount of methyl isobutyl ketone. Vacuum drying for 8 hours yielded 4.5 kg of white crystals.

[0047] Yield: 90%

Embodiment 2

[0049] Put 4.0 kg of the above clopidogrel bisulfate crystal form Form I into 20 L of acetone, cool to -10°C, stir for 1 to 2 hours, filter, wash the filter cake with a small amount of frozen acetone, and dry it in vacuum at 45°C for 8 hours to obtain Product: 3.6 kg.

[0050] Yield: 90% HPLC: 99.8% Optical purity: 99.85%

Embodiment 3

[0052] Put 4.0 kg of the above-mentioned clopidogrel bisulfate crystal form Form I into 12 L of butanone, cool to -10°C, stir for 1 to 2 hours, filter, wash the filter cake with a small amount of frozen acetone, and dry it in vacuum at 45°C for 8 hours. Product obtained: 3.68 kg.

[0053] Yield: 92% HPLC: 99.7% Optical purity: 99.85%

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Abstract

The invention provides a method for preparing (+)-(S)-clopidogrel bisulfate crystal form I, the method comprises first using methyl isobutyl ketone solvent, and adding methyl isobutyl ketone solvent dropwise Diluted sulfuric acid or undiluted concentrated sulfuric acid, stirred, filtered, after getting the wet product, add alcohol or ketone solvent to make a slurry, you can get high-purity (+)-(S)-clopidogrel bisulfate crystals Type I. The (+)-(S)-clopidogrel bisulfate crystal form I prepared by the method of the present invention has the advantages of no need to add seed crystals, high purity, high stability, and easy storage.

Description

technical field [0001] The present invention relates to a kind of stable method for preparing antithrombotic drug type I (+)-(S)-clopidogrel bisulfate, more specifically relates to a method for preparing type I (+)-clopidogrel bisulfate by clopidogrel free base The preparation method of (S)-clopidogrel bisulfate. Background technique [0002] The chemical name of clopidogrel hydrogen sulfate is: (S)-alpha-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)methyl acetate, its The structural formula is as follows: [0003] [0004] Clopidogrel was first successfully developed in 1986 by the French company Sanofi San Dela Fort (SANOFI), and was first listed in the United States in March 1998 by the US company Bristol-Myers Squibb. Clopidogrel is a platelet aggregation inhibitor with a unique mechanism of action (ADP receptor antagonism), which specifically and potently inhibits ADP-induced platelet aggregation. Its curative effect is superior to similar products, and ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D495/04
Inventor 向科
Owner ZHEJIANG HUAHAI PHARMA CO LTD
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