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Synthesis method of clopidogrel isomer (+)-(R-)-clopidogrel hydrochloride

A technology of clopidogrel hydrochloride and clopidogrel, which is applied in the field of medicine, can solve the problems of many steps and low product purity, and achieve the effect of mild conditions, simple synthesis steps and high purity of prepared samples

Inactive Publication Date: 2014-04-09
吉林修正药业新药开发有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The foregoing method has many steps, and the resulting product has low purity

Method used

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  • Synthesis method of clopidogrel isomer (+)-(R-)-clopidogrel hydrochloride
  • Synthesis method of clopidogrel isomer (+)-(R-)-clopidogrel hydrochloride
  • Synthesis method of clopidogrel isomer (+)-(R-)-clopidogrel hydrochloride

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Embodiment Construction

[0015] Weigh 20.0 g of vortex clopidogrel into a 500 ml three-necked flask, add (S+)-camphor-10-sulfonic acid 22 g and acetone 150 ml, heat and reflux at 60 ° C for 3 h, cool down to 0-20 ° C and stir after the reaction is completed After 3 hours, filter, adjust the pH of the filtrate to 7.0-7.2 with aqueous sodium bicarbonate solution, extract with ethyl acetate, and concentrate to obtain an oil.

[0016] Add 20 g of D-di-p-toluoyl tartaric acid and 150 ml of isopropanol to the oil, react at 80°C for 4 hours, cool down to 0-20°C and stir for 3 hours, filter, and dry the crude product.

[0017] Add 150 ml of isopropanol to 20 g of the crude product, and heat to dissolve. Then cool down to 0-10°C for crystallization for 3 hours, and filter. The filter cake was adjusted to pH 7.0-7.2 with aqueous sodium bicarbonate solution, extracted with ethyl acetate, hydrogen chloride gas was passed through, and crystallized at 0-10°C for 3-10 hours. Filter and dry to obtain a white solid ...

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Abstract

The invention discloses a synthesis method of clopidogrel isomer (+)-(R-)-clopidogrel hydrochloride. The synthesis method comprises the following steps: I, adding (S+)- camphor-10-sulfonic acid and acetone into a hybrid clopidogrel free basic group, filtering after reacting, regulating pH value by saturated sodium bicarbonate aqueous liquor, extracting by ethyl acetate and obtaining an oily matter after concentrating; II, adding D-di-p-toluene formyl tartaric acid and isopropanol into the oily matter, and filtering after reacting, and drying to obtain a crude product; and III, adding isopropanol into the crude product, heating and dissolving, filtering, regulating the pH value of a filter cake by sodium bicarbonate aqueous liquor, extracting by ethyl acetate, ventilating a hydrogen chloride gas, crystallizing, filtering and drying to obtain white solid-state clopidogrel isomer (+)-(R-)-clopidogrel hydrochloride. The synthesis method disclosed by the invention has positive effect that the clopidogrel isomer with higher purity is obtained. The clopidogrel isomer is taken as a known impurity for accurately analyzing quality of the clopidogrel. The synthesis method disclosed by the invention is gentle in conditions, simple in synthesis steps, stable in product quality and simple in experimental operation; the prepared sample is higher in purity.

Description

Technical field: [0001] The invention belongs to the field of medicine, and in particular relates to a synthesis method of an isomer impurity (R-)-clopidogrel hydrochloride of an anticoagulant drug clopidogrel. Background technique: [0002] Clopidogrel is an anticoagulant drug whose structural formula is: [0003] [0004] With the mass production of clopidogrel, the quality control of clopidogrel products has become an important link. As a chiral compound, the control of the R-isomer has always been the key to the quality control of clopidogrel. Therefore, we have been trying to obtain a high-purity R-isomer as an impurity reference substance for its content determination to ensure the quality of clopidogrel products. Most of the existing technologies use the corresponding camphorsulfonic acid for resolution to directly obtain the corresponding R-type isomer camphorsulfonate, and then go through repeated single recrystallization processes to reduce the content of S-ty...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D495/04
CPCC07D495/04
Inventor 林子琦阎君曹翠高陆白冰王化录刘学峰
Owner 吉林修正药业新药开发有限公司
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