Synthesis method of high-purity I-type (+)-(S)-clopidogrel hydrogen sulfate

A technology of clopidogrel hydrogen sulfate and a synthesis method, which is applied in the synthesis field of high-purity type I clopidogrel hydrogen sulfate, can solve the problems of low product purity and high cost, and achieve high product yield, low cost, and improved The effect of purity

Active Publication Date: 2013-04-17
SHANGHAI MODERN HASEN SHANGQIU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

At present, the synthesis of clopidogrel bisulfate has been reported in many patent documents

Method used

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  • Synthesis method of high-purity I-type (+)-(S)-clopidogrel hydrogen sulfate
  • Synthesis method of high-purity I-type (+)-(S)-clopidogrel hydrogen sulfate
  • Synthesis method of high-purity I-type (+)-(S)-clopidogrel hydrogen sulfate

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Experimental program
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Effect test

Embodiment 1

[0030] A high-purity type I (+)-(S)-clopidogrel bisulfate synthetic method, which comprises the following steps:

[0031] 1) Add the (+)-(S)-clopidogrel crude acetone solution (18.8kg (58.5 mol) clopidogrel dissolved in 99 L acetone) dropwise to the acetone solution of L-camphorsulfonic acid under stirring at room temperature (12.9kg (55.5mol) levocamphorsulfonic acid dissolved in 99L acetone), the dropwise addition was completed in about 30 minutes. Then stirred and reacted at 40° C. for 8 h. After the reaction was completed, the reaction product was filtered, and the obtained filter cake was washed with acetone and dried to obtain 20.5 kg of white solid (+)-(S)-clopidogrel levocamphorsulfonate;

[0032] 2) Add 60L of dichloromethane and 40L of water into the reaction kettle, then add 20.5kg of (+)-(S)-clopidogrel levocamphorsulfonate, mix well, and use saturated sodium bicarbonate at a temperature of 15°C Adjust the pH of the aqueous solution to 7-8, then stir for 30 minute...

Embodiment 2

[0039] A high-purity type I (+)-(S)-clopidogrel bisulfate synthetic method, which comprises the following steps:

[0040] 1) Add the (+)-(S)-clopidogrel crude acetone solution (18.8kg (58.5 mol) clopidogrel dissolved in 99 L acetone) dropwise to the acetone solution of L-camphorsulfonic acid under stirring at room temperature (14.27kg (61.4mol) L-camphorsulfonic acid dissolved in 99L acetone), about 30min to complete the dropwise addition. Then stirred and reacted at 40° C. for 8 h. After the reaction was completed, the reaction product was filtered, and the obtained filter cake was washed with acetone and dried to obtain 21.0 kg of white solid (+)-(S)-clopidogrel levocamphorsulfonate;

[0041] 2) Add 60 L of ethyl acetate and 40 L of water into the reaction kettle, stir, then add 20.5 kg of white clopidogrel levocamphorsulfonate, mix well, cool down to 15°C, and adjust the pH to 7~8 with saturated sodium bicarbonate solution , stirred for 30 minutes, stood still, separated t...

Embodiment 3

[0048] A high-purity type I (+)-(S)-clopidogrel bisulfate synthetic method, which comprises the following steps:

[0049] 1) Add (+)-(S)-clopidogrel crude acetone solution (18.8kg (58.5mol) clopidogrel in 99L acetone) dropwise to the acetone solution of levocamphorsulfonic acid ( 10.9kg (46.8mol) of levocamphorsulfonic acid was dissolved in 99L of acetone), and the addition was completed in about 30 minutes. Then stirred and reacted at 40° C. for 8 h. After the reaction was completed, the reaction product was filtered, and the obtained filter cake was washed with acetone and dried to obtain 19.8 kg of white solid (+)-(S)-clopidogrel levocamphorsulfonate;

[0050] 2) Add 60L of ethyl acetate and 40L of water into the reaction kettle, stir, then add 20.5kg of white clopidogrel levocamphorsulfonate, mix well, cool down to 15°C, and adjust the pH to 7~8 with saturated sodium bicarbonate solution , stirred for 30 minutes, stood still, separated the organic layer, extracted the aqu...

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Abstract

The invention discloses a synthesis method of high-purity I-type (+)-(S)-clopidogrel hydrogen sulfate, which comprises the following steps: 1) mixing an acetone solution of L(-)-camphorsulfonic acid and an acetone solution of (+)-(S)-clopidogrel crude product to carry out salification reaction for 6-10, filtering after the reaction finishes, and treating the filter cake to obtain (+)-(S)-clopidogrel L(-)-camphorsulfonate; 2) dissolving the product obtained in the step 1) in a mixture of dichloromethane or ethyl acetate and water, regulating the pH value to 7-8, stirring for 10-60 minutes, standing to stratify, and treating the organic layer to obtain a (+)-(S)-clopidogrel pure product; and 3) dissolving the product obtained in the step 2) in an organic solvent, adding a crystal seed, stirring, adding an organic solvent solution of sulfuric acid, heating to 50-60 DEG C, stirring for 1-3 hours, cooling to room temperature, filtering, and treating the filter cake to obtain the high-purity I-type (+)-(S)-clopidogrel hydrogen sulfate. The method has the advantages of simple technique, high product yield and high product purity, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of chemical industry and pharmacy, and in particular relates to a method for synthesizing high-purity type I (+)-(S)-clopidogrel bisulfate. Background technique [0002] The chemical name of clopidogrel is (+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetic acid methyl ester, Pharmaceutically used in the form of bisulfate, its structure is as follows. To distinguish its enantiomers, clopidogrel is often written as (+)-(S)-clopidogrel. [0003] [0004] Clopidogrel is an anti-platelet aggregation drug developed on the basis of ticlopyridine. It is launched in the form of its bisulfate, and its trade name is "Plavix". Its curative effect is better than that of aspirin, and it has been widely used in It is one of the best-selling drugs in the world for the treatment of myocardial infarction and cardiovascular and cerebrovascular diseases. [0005] With the advancement of civilization,...

Claims

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Application Information

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IPC IPC(8): C07D495/04
Inventor 王英利陈洪刘砺李新柱刁文瑞唐秋玲刘统斌
Owner SHANGHAI MODERN HASEN SHANGQIU PHARMA
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