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Method for synthesizing clopidogrel hydrogen sulfate intermediate by adopting solid acid catalytic esterification

A technology of clopidogrel hydrogen sulfate, acid catalyzed ester, applied in chemical instruments and methods, physical/chemical process catalysts, organic compound/hydride/coordination complex catalysts, etc. Difficulty in product separation

Active Publication Date: 2012-07-04
TIANJIN CENT PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] Regarding the synthetic method of clopidogrel, currently there are U.S. Patent No. 5204469 using chiral o-chlorophenylglycine as a raw material, and U.S. Patent No. 48747265, which synthesizes a clopidogrel racemate and then splits it. The yield and optical purity of pidogrel are not high; there is another Chinese patent CN1775782 that uses α-bromo-o-chlorophenylacetic acid as the starting material to synthesize clopidogrel, but the catalyst sulfuric acid of the esterification reaction mentioned in the article, thionyl chloride And other traditional catalysts are all liquid inorganic acids, because the inorganic acids are highly corrosive to the equipment, resulting in many side reactions, in industry, the process is cumbersome and the product separation is difficult, and the use of solid acids instead of liquid inorganic acids not only has better Catalytic esterification performance, and cheap and easy to get, has a good application prospect

Method used

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  • Method for synthesizing clopidogrel hydrogen sulfate intermediate by adopting solid acid catalytic esterification
  • Method for synthesizing clopidogrel hydrogen sulfate intermediate by adopting solid acid catalytic esterification

Examples

Experimental program
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Effect test

Embodiment 1

[0020] Put 25g of α-bromo-o-chlorophenylacetic acid (0.1mol), 150ml of methanol (6 times), 12.5g of solid acid (0.5 times) into the reaction bottle, reflux for 8 hours, and add K after cooling down to room temperature 2 CO 3 Adjust pH=8, add 13.9ml (0.11mol) thienylethylamine, reflux reaction for 5 hours, add 100ml water and 125ml ethyl acetate for extraction, add hydrochloric acid to adjust pH=3, crystallize at 0°C for 10 hours. 29.5 g of α-(2-thienylethylamine)-2-chlorophenylacetic acid methyl ester hydrochloride was obtained, with a melting point of 174-175° C., an HPLC of 99.5%, and a yield of 85.01%.

Embodiment 2

[0022] Put 25g of α-bromo-o-chlorophenylacetic acid (0.1mol), 50ml of methanol (2 times), 2.5g of solid acid (0.1 times) into the reaction bottle, reflux for 16 hours, and add NaHCO after cooling down to room temperature 3 Adjust pH=4, add 10.1ml (0.08mol) thienylethylamine, reflux reaction for 10 hours, add 50ml water and 75ml ethyl acetate for extraction, add hydrochloric acid to adjust pH=5, crystallize at -20°C for 1 hour. 27.2 g of α-(2-thiopheneethylamine)-2-chlorophenylacetic acid methyl ester hydrochloride was obtained, with a melting point of 173-174° C., an HPLC of 98.3%, and a yield of 78.39%.

Embodiment 3

[0024] Put 25g of α-bromo-o-chlorophenylacetic acid (0.1mol), 250ml of methanol (10 times), 20g of solid acid (0.8 times) into the reaction bottle, reflux for 2 hours, and add Na 2 CO 3 Adjust pH=10, add 18.9ml (0.15mol) thienylethylamine, reflux reaction for 1 hour, add 200ml water and 250ml ethyl acetate for extraction, add hydrochloric acid to adjust pH=1, crystallize at 10°C for 20 hours. 29.1 g of α-(2-thiopheneethylamine)-2-chlorophenylacetic acid methyl ester hydrochloride was obtained, with a melting point of 174-175° C., an HPLC of 99.4%, and a yield of 83.86%.

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Abstract

The invention discloses a method for synthesizing a clopidogrel hydrogen sulfate intermediate by adopting solid acid catalytic esterification, comprising the following steps of: esterifying solid acid catalytic alpha-bromo-2-chlorophenylacetic acid and methanol, and then carrying out condensation reaction with thiopheneethylamine to obtain the clopidogrel hydrogen sulfate intermediate (clopidogrel hydrochloric acid). In the method, solid acid (CT-450) is used for replacing liquid strong-acid catalysts comprising sulfuric acid, phosphoric acid, p-toluenesulfonic acid and the like; tested by a high performance liquid chromatography (HPLC) normalization method, the purity of the obtained product is greater than 99%, and the yield can be greater than 90%. The synthesis method of the inventionhas the advantages of simple and convenient industrial operation, repeatable use of the adopted solid acid catalyst and environmental protection and is beneficial to large-scale industrial production.

Description

technical field [0001] The invention belongs to the technical field of organic chemical synthesis, and relates to a preparation method of a pharmaceutical intermediate, in particular to a method for synthesizing a clopidogrel hydrogen sulfate intermediate catalyzed by a solid acid for esterification. Background technique [0002] Clopidogrel sulfate 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 thrombotic complications after coronary stent implantation, etc. . Compared with other antiplatelet drugs, clopidogrel sulfate has the advantages of strong curative effect, low cost, and few side effects. The combination of clopidogrel sulfate and aspirin is gradually becoming the standard of antithrombotic therapy in cardiovascular and cerebrovascular diseases. Clopidogrel (Clopidogrel), chemical name (S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyrid...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D333/20B01J31/10
Inventor 孟庆礼杨冠宇王学元宋风武李玉梅马琳
Owner TIANJIN CENT PHARM CO LTD
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