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Clopidogrel hydrogen sulfate preparation method

A technology of clopidogrel hydrogen sulfate and concentrated sulfuric acid is applied in the field of preparation of clopidogrel hydrogen sulfate, can solve the problems of long route, limited heating and reflux temperature, etc., and achieves the effects of easy availability of raw materials, reduced cost and short synthesis route

Active Publication Date: 2015-02-25
HENAN PURUI PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Using dichloromethane as a solvent, the heating and reflux temperature is limited, and the route is long

Method used

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  • Clopidogrel hydrogen sulfate preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] The preparation method of clopidogrel hydrogen sulfate of the present invention includes the following steps:

[0036] 1) Weigh 12.6 g of 2-thiophene acetaldehyde and 20.0 g of S-o-chlorophenylglycine methyl ester, add them to a 250 mL three-necked reaction flask, add 100 mL of organic solvent toluene and 0.4 g of catalyst ammonium acetate, heat and stir to reflux for reaction. The temperature is 110°C. TLC tracking monitoring showed that the raw materials disappeared. The reaction solution was cooled to 25° C., 100 mL of water was added, and the mixture was allowed to stand for separation after stirring. The toluene layer was dried with anhydrous sodium sulfate. Then it was filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain a crude solid imine intermediate product, which was recrystallized with ethanol to obtain 28.7 g of pure imine intermediate, with a yield of 93.2%.

[0037] 2) Take 15.4g of the imine intermediate obtained in step 1) i...

Embodiment 2

[0041] The preparation method of clopidogrel hydrogen sulfate of the present invention includes the following steps:

[0042] 1) Weigh 12.6g of 2-thiopheneacetaldehyde and 20.0g of S-o-chlorophenylglycine methyl ester, add them to a 250mL three-necked reaction flask, add 100mL of solvent chloroform and 0.6g of catalyst ammonium chloride, heat and stir to reflux, reaction temperature The temperature was 60°C and TLC tracking monitoring showed that the raw materials disappeared. The reaction solution was cooled to 20°C, 100 mL of water was added, and the mixture was stirred and left to stand for separation. The chloroform layer was dried with anhydrous sodium sulfate. Then filtered, the filtrate was evaporated to dryness under reduced pressure to obtain a crude solid imine intermediate product, which was recrystallized with ethanol to obtain 27.9 g of a pure imine intermediate, with a yield of 90.6%.

[0043] 2) Take 15.4g of the imine intermediate obtained in step 1) and add it to a...

Embodiment 3

[0047] The preparation method of clopidogrel hydrogen sulfate of the present invention includes the following steps:

[0048] 1) Weigh 12.6g of 2-thiopheneacetaldehyde and 20.0g of S-o-chlorophenylglycine methyl ester, add them to a 250mL three-necked reaction flask, add 100mL of solvent dichloromethane and 0.4g of catalyst ammonium acetate, heat and stir to reflux, react The temperature was 40°C and TLC tracking monitoring showed that the raw materials disappeared. The reaction solution was cooled to 30°C, 100 mL of water was added, and the mixture was stirred and left to stand for separation. The methylene chloride layer was dried with anhydrous sodium sulfate. Then it is filtered, and the filtrate is evaporated to dryness under reduced pressure to obtain a crude solid imine intermediate product. The crude product is recrystallized from ethanol to obtain 28.8 g of pure imine intermediate with a yield of 93.5%.

[0049] 2) Weigh 15.4g of the imine intermediate obtained in step 1) ...

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Abstract

The present invention relates to a clopidogrel hydrogen sulfate preparation method. According to the clopidogrel hydrogen sulfate preparation method, 2-thiophene aldehyde is adopted as a basic starting material, the 2-thiophene aldehyde and o-chlorophenylglycine methyl ester are subjected to a condensation reaction to produce the corresponding imine intermediate, the imine intermediate is reduced into the corresponding secondary amine intermediate by adopting sodium borohydride or by directly adopting sodium cyanoborohydride intermediate, the secondary amine intermediate and formaldehyde are subjected to reaction ring closure to obtain clopidogrel, and the clopidogrel is acidified with sulfuric acid to obtain the target compound clopidogrel hydrogen sulfate. According to the present invention, the provided synthesis route is short, the related reactions are classical organic reactions, the reaction conditions are mild, the operation is simple, the total yield is high, the cost is low, and the preparation method is suitable for industrial production.

Description

Technical field [0001] The invention belongs to the technical field of drug synthesis and relates to a preparation method of clopidogrel hydrogen sulfate. Background technique [0002] Clopidogrel hydrogen sulfate, chemical name (S)-(+)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H) methyl acetate Bisulfate is a new generation of platelet aggregation inhibitor researched and developed by the French company Sanofic in 1986. The brand name is Plavix, and the structural formula: [0003] [0004] Clopidogrel bisulfate is a new type of thienopyridine derivative, which irreversibly inhibits platelet aggregation by selectively binding to the ADP receptor coupled with adenylate enzyme on the platelet surface, and can reduce blood clots. It is clinically used to prevent myocardial infarction, stroke or atherosclerosis in patients with a history of peripheral arterial disease, combined with aspirin, for patients with non-ST-segment elevation acute coronary syndrome. [0005] A la...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D495/04
CPCC07D495/04
Inventor 栗金梁乔爱红张福义郭永慧
Owner HENAN PURUI PHARMA TECH CO LTD
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