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Synthetic method of racemic clopidogrel

A technology of racemic clopidogrel and synthesis method, which is applied in the field of drug synthesis, can solve the problems of rising overall cost and high market price, and achieve the effects of stable properties, mild and easy-to-control reaction conditions, and cost reduction

Active Publication Date: 2020-09-01
WUHAN UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This method is relatively simple, but the market price of tetrahydrothieno[3,2-c]pyridine hydrochloride is relatively high, which will cause an increase in the overall cost

Method used

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  • Synthetic method of racemic clopidogrel
  • Synthetic method of racemic clopidogrel
  • Synthetic method of racemic clopidogrel

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] A kind of synthetic method of racemic clopidogrel, concrete steps are as follows:

[0033] Step 1: Add 1.5mmol N-chlorosuccinimide, 0.1mmol palladium acetate and 2mL 1,2-dichloroethane to a pressure-resistant reaction tube and mix to obtain a solution, add 1mmol benzoylformate to the solution ester, add 0.2mmol ligand 3,5-bis(trifluoromethyl)aniline, add 10mmol trifluoroacetic acid, react at 80°C for 24 hours, dilute the resulting reaction solution with dichloromethane to 50mL, and then add 50mL saturated bicarbonate Quenched by sodium solution, then extracted three times with dichloromethane, combined the organic phases, added anhydrous sodium sulfate to dry, and removed the solvent by rotary evaporation under reduced pressure at 40 ° C, and carried out column chromatography separation in 200-300 mesh silica gel (eluent Petroleum ether:ethyl acetate=40:1, v / v) to obtain methyl o-chlorobenzoylformate. The yield of this step is 65%.

[0034] The second step: Add 1.1 mm...

Embodiment 2

[0043] A kind of synthetic method of racemic clopidogrel, concrete steps are as follows:

[0044] The first step: add 1.5mmol N-chlorosuccinimide to the pressure-resistant reaction tube, add 0.1mmol palladium acetate, add 2mL solvent 1,2-dichloroethane, add 1mmol 3-methyl Methyl benzoylformate, add 0.3mmol ligand 3,5-bis(trifluoromethyl)aniline, add 10mmol trifluoroacetic acid, react at 80°C for 24 hours, dilute the obtained reaction solution to 50mL with dichloromethane, Quench with 50 mL of saturated sodium bicarbonate solution, then extract three times with dichloromethane, combine the organic phases, add anhydrous sodium sulfate to dry, remove the solvent by rotary evaporation under reduced pressure at 40°C, and conduct column layer in 200-300 mesh silica gel Analysis and separation (eluent: petroleum ether: ethyl acetate = 40:1, v / v) gave methyl o-chlorobenzoylformate. The yield of this step is 71%.

[0045] The second step: Add 1.1 mmol 2-thienylethylamine to 2 mL of d...

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Abstract

The invention relates to a synthesis method of racemic clopidogrel, which comprises the following steps: 1) uniformly mixing methyl benzoylformate, N-chlorosuccinimide, palladium acetate, a ligand andtrifluoroacetic acid, and carrying out ortho-chlorination to obtain methyl o-chlorobenzoylformate; 2) uniformly mixing methyl o-chlorobenzoylformate with 2-thiopheneethylamine, then adding sodium cyanoborohydride and a small amount of acetic acid, and carrying out a reductive amination reaction to obtain 2-(2-thiopheneethylamino) (2-chlorphenyl) methyl acetate; and 3) uniformly mixing 2-(2-thiopheneethylamino) (2-chlorphenyl) methyl acetate with paraformaldehyde and an acid solution, and carrying out a cyclization reaction to obtain racemic clopidogrel. The synthetic method provided by the invention has the advantages of low cost, mild and easily controllable reaction conditions, a whole process yield of about 50%, and good industrial production prospects.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a synthesis method of racemic clopidogrel. Background technique [0002] Clopidogrel is the original drug of Sanofi, France, and is usually used as an antithrombotic drug. Mechanistically, clopidogrel is an adenosine diphosphate inhibitor that binds to P2Y on platelets 12 Receptor binding inhibits the release of the first messenger ADP, thereby reducing platelet aggregation and preventing thrombus formation. It is widely used clinically and has important medical value and economic value. [0003] Clopidogrel is a chiral drug molecule, and the pure product can be obtained by preparing racemic clopidogrel and performing resolution, or performing chiral resolution on raw materials and then synthesizing clopidogrel step by step. There are a few reports about the synthetic method of racemic clopidogrel, such as Sanofi company in patents US4529596, US5036156 a...

Claims

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Application Information

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IPC IPC(8): C07D495/04
CPCC07B2200/07C07D495/04
Inventor 黄志军王云芳孙兵张方林
Owner WUHAN UNIV OF TECH
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