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Preparation method for preparing high-purity II type (+)-(s)-clopidogrel bisulfate

A clopidogrel bisulfate, high-purity technology, applied in directions such as organic chemistry, to achieve the effects of improving yield, reducing production costs, and reducing environmental pollution

Active Publication Date: 2010-02-10
ESTEVE HUAYI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The original compound patent of clopidogrel is the European patent EP281459. Although this patent does not clearly indicate the crystal form of clopidogrel bisulfate, the crystal form I is synthesized according to the described process

Method used

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  • Preparation method for preparing high-purity II type (+)-(s)-clopidogrel bisulfate
  • Preparation method for preparing high-purity II type (+)-(s)-clopidogrel bisulfate
  • Preparation method for preparing high-purity II type (+)-(s)-clopidogrel bisulfate

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Embodiment 1

[0041] Embodiment 1: Preparation of type I (+)-(S)-clopidogrel bisulfate

[0042]Put 130g of clopidogrel free base and 700mL of ethyl acetate into a 1L three-necked flask, stir at room temperature until dissolved and clear, add 40g of concentrated sulfuric acid dropwise, and complete the dropwise addition in 30 minutes. The reaction solution continued to stir for 2 hours, solids precipitated, filtered; washed with ethyl acetate (50mL×3), and dried in vacuo at 50°C to obtain 148g of type I (+)-(S)-clopidogrel hydrogensulfate, collected The yield is 87%, the purity is 97.4%, and the impurity C content is 1.5%.

Embodiment 2II

[0043] Preparation of Example 2 Type II (+)-(S)-clopidogrel bisulfate

[0044] Put 80g type I clopidogrel bisulfate and 120mL methanol into a 1L three-necked flask, stir at room temperature until dissolved and clarified, add 480mL of ethyl formate, stir for 6 hours, a small amount of solid precipitates, remove by filtration; put the mother liquor into a 1L three-necked flask, Cool down to 0°C, stir for 5 hours, a large amount of solid precipitates, filter, wash with ethyl formate (30mL×3), and dry in vacuum at 50°C to obtain 67g I II(+)-(S)-type clopidogrel hydrogen sulfate Salt, the refined yield is 84%, the purity is 99.8%, and the impurity C content is 0.07%.

Embodiment 3II

[0045] The preparation of embodiment 3II type (+)-(S)-clopidogrel bisulfate

[0046] Put 80g of type I clopidogrel bisulfate and 120mL of methanol into a 1L three-necked flask, stir at room temperature until dissolved and clarified, add 680mL of ethyl acetate, stir for 30 minutes, a small amount of solid precipitates, remove by filtration; put the mother liquor into a 1L three-necked flask, Cool down to -15°C and stir for 7 hours, a large amount of solid precipitated, filtered, washed with ethyl acetate (30mL×3), and dried in vacuum at 50°C to obtain 65g of type III (+)-(S)-clopidogrel hydrogen sulfate Salt, the refined yield is 81%, the purity is 101.1%, and the impurity C content is 0.09%.

[0047] According to the detection method of United States Pharmacopoeia (USP) to the detection method of clopidogrel bisulfate, the product prepared in this embodiment is fully inspected (but the infrared is the II crystal form), and the specific results are as follows:

[0048] ...

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Abstract

The invention provides a preparation method for preparing high-purity II type (+)-(S)-clopidogrel bisulfate. The preparation method comprises the following steps of: dissolving I type (+)-(S)-clopidogrel bisulfate in C1-C3 lower alcohol, adding a poor solvent, stirring and precipitating little amount of crystal, filtering and removing; and continuously stirring the mother liquor, crystallizing, filtering, vacuum-drying and obtaining the high-purity II type (+)-(S)-clopidogrel bisulfate. The product produced by the method has high purity and high yield, the technique condition is mild, and themethod is applicable industrial production.

Description

(1) Technical field: [0001] The invention belongs to the technical field of chemical industry and pharmacy, and relates to a preparation method of type II (+)-(S)-clopidogrel hydrogen sulfate. More specifically, it relates to a process for refining and crystallizing type I (+)-(S)-clopidogrel hydrogen sulfate into high-purity type II (+)-(S)-clopidogrel hydrogen sulfate. (two) background technology: [0002] The chemical name of clopidogrel is (S)-(+)-(2-chlorophenyl)-2-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl- Methyl acetate, its structural formula is as follows: [0003] [0004] To distinguish it from its enantiomers, clopidogrel is often written as (+)-(S)-clopidogrel, and (+)-(S)-clopidogrel hydrogen sulfate is often abbreviated as clopidogrel hydrogen sulfate Salt. [0005] Clopidogrel is an anti-platelet coagulant drug developed by the French pharmaceutical company Sanofi (Sanofi). It was originally launched in the form of clopidogrel bisulfate with the trade n...

Claims

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Application Information

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IPC IPC(8): C07D495/04
Inventor 赵胜贤夏炯赵立强张艳艳郑国荣董金卢桂娟
Owner ESTEVE HUAYI PHARMA
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