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Preparation method of clopidogrel and salts thereof

A technology of clopidogrel and o-chloro, which is applied in the field of preparation of clopidogrel and its salts, and can solve the problems of complex reaction, low yield of clopidogrel and low optical purity

Inactive Publication Date: 2011-03-23
BEIJING WANQUAN SUNSHINE MEDICAL TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But above-mentioned method, reaction is complicated, and the yield and optical purity of obtaining clopidogrel are not high

Method used

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  • Preparation method of clopidogrel and salts thereof
  • Preparation method of clopidogrel and salts thereof
  • Preparation method of clopidogrel and salts thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0013] The synthesis of embodiment 1 (R)-o-chloromandelic acid methyl ester

[0014] Add 15 g of (R)-o-chloromandelic acid, 46.08 g of methanol, and 0.8 g of concentrated sulfuric acid into a 250 ml three-necked flask, and react under reflux for 3 hours. After the completion of the reaction, it was naturally cooled to room temperature, and the reaction system was heated with 10% K 2 CO 3 The solution was neutralized to neutral, the solvent was evaporated to dryness under reduced pressure, 100ml of dichloromethane was added, and 100ml×3 saturated NaHCO 3 The solution was washed, the organic phases were combined, and the solvent was evaporated to dryness under reduced pressure to obtain 15.9 g of relatively pure (R)-methyl o-chloromandelate, with a yield of 99% and an optical purity of 99.8%.

Embodiment 2

[0015] The synthesis of embodiment 2α-chloro-(2-chlorophenyl) methyl acetate

[0016] Add 20 g of (R)-methyl-o-chloromandelate and 17.8 g of thionyl chloride into a 250 ml three-neck flask, stir at room temperature for 16 hours, then heat and reflux for 2 hours. After the reaction is complete, pour the reaction solution into 100ml of ice water, stir until no gas is produced, extract with 100ml×2 dichloromethane, combine the organic phases, and wash the organic phases with saturated NaHCO 3 The solution and water were washed once respectively, and the solvent was evaporated to dryness under reduced pressure to obtain 21.1 g of a light yellow oily liquid with a yield of 97% and an optical purity of 99.6%.

Embodiment 3

[0017] Example 3 Synthesis of Clopidogrel

[0018] Add 219.06 g of α-chloro-(2-chlorophenyl) methyl acetate, 210.8 g of 4,5,6,7-tetrahydrothieno[3,2c]hexahydropyridine hydrochloride, and K 2 CO 3 276.4g, DMF1.3L, heated to 90°C, and kept for 4 hours. After the reaction was completed, the solid was filtered off, 6L of dichloromethane was added to the filtrate, washed with 6L×3 water, and the organic phase was spin-dried to obtain 310 g of clopidogrel free base with a yield of 92.3% and an optical purity of 99.4% ee.

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Abstract

The invention relates to a preparation method of a compound clopidogrel represented in the formula I and salts thereof, which comprises the following steps of: firstly, reacting methyl (R)-o-chloromandelate with thionyl chloride to obtain alpha-chloro-(2-chlorphenyl) methyl acetate, and condensing with 4,5,6,7-thiophane and [3,2c] hexahydropyridine hydrochloride in a solvent under alkaline catalytic action to produce the clopidogrel. The clopidogrel and salts thereof can be applied to medicines for inhibiting platelet aggregation.

Description

technical field [0001] The present invention relates to a new method for preparing clopidogrel and its salts: (S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H) The preparation method of methyl acetate and its salt, and its use as platelet aggregation inhibitor drugs. Background technique [0002] Ischemic heart disease and cerebrovascular disease have become the main causes of death in humans. In my country, especially cerebrovascular disease, the prevalence is as high as 490 per 100,000 people per year. Studies have shown that arteriosclerosis is the underlying cause of such diseases, and platelet inhibitors can effectively fight against atherosclerosis and thromboembolic diseases. [0003] Although both Aspirin and Ticlopidine are effective in inhibiting thrombosis, both have potential adverse reactions. Clopidogrel is a new type of thienopyridine derivative; It binds to the ADP receptor coupled with adenylate cyclase on the surface of platelets and irrevers...

Claims

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Application Information

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IPC IPC(8): C07D495/04A61P7/02
Inventor 高晓婷张志强卢文
Owner BEIJING WANQUAN SUNSHINE MEDICAL TECH CO LTD
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