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A kind of preparation method of clopidogrel bisulfate

A technology of clopidogrel hydrogen sulfate and concentrated sulfuric acid, applied in the field of preparation of clopidogrel hydrogen sulfate, can solve the problems of limited heating and reflux temperature, long route and the like, and achieve the effects of cost reduction, easy availability of raw materials and cost reduction

Active Publication Date: 2017-09-19
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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  • A kind of preparation method of clopidogrel bisulfate
  • A kind of preparation method of clopidogrel bisulfate
  • A kind of preparation method of clopidogrel bisulfate

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Effect test

Embodiment 1

[0035] A kind of preparation method of clopidogrel bisulfate of the present invention comprises the following steps:

[0036] 1) Weigh 12.6g of 2-thiopheneacetaldehyde and 20.0g of S-o-chlorophenylglycine methyl ester, add them into a 250mL three-necked reaction flask, then add 100mL of organic solvent toluene and 0.4g of catalyst ammonium acetate, heat and stir under reflux for reaction, the reaction The temperature was 110°C. TLC tracking and monitoring showed that the raw materials disappeared. The reaction solution was cooled to 25° C., 100 mL of water was added, stirred, and left to stand for separation. 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 solid imine intermediate crude product, which was recrystallized with ethanol to obtain 28.7 g of pure imine intermediate, with a yield of 93.2%.

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

Embodiment 2

[0041] A kind of preparation method of clopidogrel bisulfate of the present invention comprises the following steps:

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

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

Embodiment 3

[0047] A kind of preparation method of clopidogrel bisulfate of the present invention comprises the following steps:

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

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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 medicine synthesis, and relates to a preparation method of clopidogrel bisulfate. Background technique [0002] Clopidogrel bisulfate, 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 Sanofi (sanofic) in France in 1986. Its trade name is Plavix, and its structural formula is: [0003] [0004] Clopidogrel bisulfate is a new type of thienopyridine derivatives, which can irreversibly inhibit the aggregation of platelets by selectively binding to the ADP receptors coupled with adenylase on the surface of platelets, and can reduce the occurrence of thrombus in blood vessels. Formation, clinically used to prevent atherosclerosis in patients with myocardial infarction, stroke, or patients with a history of peripheral arterial disease, combined with aspirin, for patients wi...

Claims

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Application Information

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Patent Type & Authority Patents(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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