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Method for synthesizing related substance C of clopidogrel hydrogen sulfate

A technology of clopidogrel bisulfate and clopidogrel hydrochloride, which is applied in the field of organic chemical synthesis, can solve the problems of high material cost, achieve short reaction time, reduce the emission of three wastes, and achieve the effects of high yield

Active Publication Date: 2011-08-31
TIANJIN CENT PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] The invention provides an economical, convenient and environment-friendly synthesis method for preparing clopidogrel hydrogen sulfate related substance C, greatly reduces the production cost of clopidogrel hydrogen sulfate under the premise of ensuring quality, and solves the problem of high cost of related substances problems, reduce the discharge of three wastes, and realize a sustainable new reaction mode

Method used

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  • Method for synthesizing related substance C of clopidogrel hydrogen sulfate
  • Method for synthesizing related substance C of clopidogrel hydrogen sulfate

Examples

Experimental program
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Effect test

Embodiment 1

[0022] Put 35.8g (0.1mol) of clopidogrel hydrochloride, 71.6ml (twice) of ethyl acetate, and 100ml of water into the reaction flask, adjust the pH to neutral with sodium bicarbonate for dissociation, dry the obtained organic layer and add 9.3 g (0.04mol) left-handed camphorsulfonic acid, crystallized for 4 hours at 0°C, filtered to obtain the left-handed camphorsulfonate of dextro-clopidogrel, added 13.9g (0.06mol) right-handed camphorsulfonic acid in the clopidogrel mother liquor, Crystallization at -20°C for 2 hours, filtered to obtain 16.6 g of dextrocamphorsulfonate of clopidogrel, mp 184-186°C, [α] D =-56.0° HPLC 98.73%, yield 29.96%. Salt with sulfuric acid to obtain the related substance C.

Embodiment 2

[0024] Put 35.8g (0.1mol) of clopidogrel hydrochloride, 71.6ml (2 times) of ethyl acetate, and 100ml of water into the reaction flask, adjust the pH to neutral with sodium bicarbonate for freeing, dry the organic layer and concentrate it into an oily substance, add 143.2 ml (4 times) of acetone, 11.6g (0.05mol) of L-camphorsulfonic acid, crystallized at 0°C for 4 hours, filtered to obtain the L-camphorsulfonate of D-clopidogrel, and 11.6g (0.05mol) of L-camphorsulfonic acid was added to the mother liquor. Rotate camphorsulfonic acid, crystallize at -10°C for 4 hours, filter to obtain 16.9 g of D-camphorsulfonate of L-clopidogrel, mp184-186°C, [α] D =-56.0° HPLC 98.88%, yield 30.50%. Salt with sulfuric acid to obtain the related substance C.

Embodiment 3

[0026] Put 35.8g (0.1mol) of clopidogrel hydrochloride, 214.8ml (6 times) of ethyl acetate, and 100ml of water into the reaction flask, adjust the pH to neutral with sodium bicarbonate for freeing, and add 13.9g (0.06mol) after drying the organic layer Left-handed camphorsulfonic acid, crystallization at 0°C for 4 hours, filtered to obtain the left-handed camphorsulfonate of dextroclopidogrel, 9.3g (0.04mol) of right-handed camphorsulfonic acid was added to the mother liquor, crystallization at 5°C for 6 hours, filtered Obtain 17.3g of D-camphorsulfonate of L-clopidogrel, mp184-186℃, [α] D =-56.0° HPLC 99.44%, yield 31.22%. Salt with sulfuric acid to obtain the related substance C.

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Abstract

The invention discloses a method for synthesizing a related substance C of clopidogrel hydrogen sulfate, which comprises the step of reacting split mother solution of racemic clopidogrel hydrochloride as a raw material with d-camphorsulfonic acid to generate sulphate and thereby obtaining L-clopidogrel bisulphate which is the related substance C. The invention repeatedly utilizes reaction waste liquid of clopidogrel bisulphate, greatly reduces the cost, has simple industrial operation and is more beneficial to industrial production on a large scale.

Description

technical field [0001] The invention belongs to the technical field of organic chemical synthesis, and relates to a method for preparing pesticides and pharmaceutical intermediates, in particular to a method for synthesizing related substance C of clopidogrel hydrogen sulfate. Background technique [0002] Cardiovascular and cerebrovascular thrombosis is a common disease in my country and an important cause of death. Especially in recent years, the incidence of thromboembolic diseases, mainly coronary thrombosis and cerebral thrombosis, is on the rise, seriously endangering human health. Clopidogrel sulfate (Clopidogrel) is a new type of high-efficiency antiplatelet drug, which is clinically used in the treatment of atherosclerosis, acute coronary syndrome, prevention of in-stent restenosis and thrombosis after coronary stent implantation. Complications etc. Compared with other antiplatelet drugs, clopidogrel sulfate has the advantages of strong curative effect, low cost, ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D495/04
Inventor 孟庆礼杨冠宇王学元宋风武李玉梅季娟张旭婷
Owner TIANJIN CENT PHARM CO LTD
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