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Preparation methods for clopidogrel and its intermediates--methyl alpha-bromo-2-chloro-phenylacetate and thiophene ethylamino-substituted methyl acetate

A technology of thienylethylamine and methyl acetate, which is applied in the field of preparation of medicine and its intermediates, can solve the problems of high cost and complicated production steps, achieve high utilization rate, and avoid the use and reaction of highly toxic bromination reagents The effect of mild conditions

Inactive Publication Date: 2013-11-13
SHENZHEN SALUBRIS PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the prior art method, the α-bromo-o-chlorophenylacetic acid methyl ester separated from the reaction system needs to be post-treated before entering the next step of reaction, the production steps are complicated and the cost is high

Method used

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  • Preparation methods for clopidogrel and its intermediates--methyl alpha-bromo-2-chloro-phenylacetate and thiophene ethylamino-substituted methyl acetate
  • Preparation methods for clopidogrel and its intermediates--methyl alpha-bromo-2-chloro-phenylacetate and thiophene ethylamino-substituted methyl acetate
  • Preparation methods for clopidogrel and its intermediates--methyl alpha-bromo-2-chloro-phenylacetate and thiophene ethylamino-substituted methyl acetate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] α-Bromo-o-chlorophenylacetic acid methyl ester

[0052] Add 2.2g of methyl o-chlorophenylacetate into a 100ml round bottom flask, and add 8ml of dichloromethane to dissolve it completely. Add potassium bromide 1.7g, add dropwise 1.4g50%H 2 SO 4 , put a 25W fluorescent lamp (color temperature 6400K) at a distance of 20cm from the round bottom flask reactor to irradiate the reaction, and slowly add 3.0g16%H at room temperature 2 o 2 , the reaction solution turns brownish red. After about 8 hours, the color of the reaction solution gradually faded, and the reaction was detected by HPLC, and the reaction of the raw materials was basically complete. Stop stirring and let stand to separate layers. The organic phase was sequentially washed with 5ml 5% NaHCO 3 solution and washed with 5ml of water. After concentrating under reduced pressure and reclaiming the organic solvent, 3.0 g of brown-yellow oil was obtained, and the purity of the product detected by HPLC was 99.0%...

Embodiment 2

[0054] α-Bromo-o-chlorophenylacetic acid methyl ester

[0055] Add 2.2g of methyl o-chlorophenylacetate into a 100ml round bottom flask, and add 8ml of dichloromethane to dissolve it completely. Add 1.8g of 50%H successively under stirring 2 SO 4 and potassium bromide 2.1g, then slowly drop 3.8g16%H 2 o 2 , and at the same time place a 25W fluorescent lamp (color temperature 6400K) at room temperature at a distance of 20cm from the round bottom flask to irradiate the reaction. After about 8 hours, the color of the reaction solution gradually faded, and the reaction was detected by HPLC, and the reaction of the raw materials was basically complete. Stop stirring and let stand to separate layers. The organic phase was sequentially washed with 5ml 5% NaHCO 3 solution and washed with 5ml of water. After concentrating under reduced pressure to recover the organic solvent, 3.0 g of brown oil was obtained, and the purity of the product was 99.3% by HPLC (the chromatographic co...

Embodiment 3

[0057] α-Bromo-o-chlorophenylacetic acid methyl ester

[0058] Add 2.2g of methyl o-chlorophenylacetate into a 100ml round bottom flask, and add 8ml of dichloromethane to dissolve it completely. Add 3.9g30% hydrobromic acid aqueous solution, then add 1.5g16%H 2 o 2 , the reaction solution turns brownish red. At room temperature, place a 25W fluorescent lamp (color temperature 6400K) at a distance of 20cm from the round bottom flask to irradiate the reaction, and slowly add another batch of 1.5g16%H 2 o 2 . After about 8 hours, the color of the reaction solution gradually faded, and the reaction was detected by HPLC, and the reaction of the raw materials was complete. Stop stirring and let stand to separate layers. The organic phase was sequentially washed with 5ml 5% NaHCO 3 solution and washed with 5ml of water. After concentrating under reduced pressure to recover the organic solvent, 3.0 g of brown oil was obtained. The purity of the product detected by HPLC was 99...

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Abstract

The invention provides preparation methods for the drug clopidogrel used for resisting platelet aggregation and intermediates thereof. According to a technical scheme provided by the invention, reaction conditions are mild, the utilization rate of a brominating agent is high, usage of a high-toxicity brominating agent is avoided; and compared to the prior art, the preparation methods have the beneficial effects of low cost, low pollution, low energy consumption, high yield and the like, provide high purity intermediates for preparation of clopidogrel and effectively reduce preparation cost for clopidogrel products.

Description

technical field [0001] The present invention relates to a preparation method of a medicine and its intermediate, specifically, the present invention relates to an anti-platelet aggregation drug clopidogrel and its intermediate α-bromo-o-chlorophenylacetic acid methyl ester and D-(+)- A preparation method of α-(2-thienylethylamino)-α-(2-chlorophenyl)acetic acid methyl ester hydrochloride. Background technique [0002] Clopidogrel (CAS: 113665-84-2), molecular formula: C 16 h 16 ClNO 2 S, is an inducible platelet aggregation inhibitor, which reduces the chance of arterial blockage by inhibiting platelet aggregation, achieves the effect of preventing stroke and heart attack, and can effectively treat and prevent atherosclerosis. Clopidogrel is usually given in its bisulfate form. Clopidogrel can be resolved by reacting with 4,5,6,7-tetrahydrothiophene[3,2-c]pyridine using α-bromo-o-chlorophenylacetic acid methyl ester as raw material to generate racemic clopidogrel Prepare...

Claims

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Application Information

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IPC IPC(8): C07C69/65C07C67/307C07D333/20C07D495/04
Inventor 谭端明李海冬
Owner SHENZHEN SALUBRIS PHARMA CO LTD
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