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Novel method for synthesizing clopidogrel bisulphate and intermediate thereof

A technology of clopidogrel and a new method, which is applied in the field of synthesizing clopidogrel hydrogen sulfate and its intermediates, can solve the problems of non-compliance with the green development strategy, waste of configuration isomers, etc., and is beneficial to the industrial production of products, The effect of short synthetic route and high conversion number

Active Publication Date: 2019-04-05
SOUTH UNIVERSITY OF SCIENCE AND TECHNOLOGY OF CHINA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] The above process routes all need to use the step of chiral resolution, which will inevitably cause waste of another configuration isomer, which is not in line with the national green development strategy

Method used

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  • Novel method for synthesizing clopidogrel bisulphate and intermediate thereof
  • Novel method for synthesizing clopidogrel bisulphate and intermediate thereof
  • Novel method for synthesizing clopidogrel bisulphate and intermediate thereof

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Experimental program
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Effect test

preparation example Construction

[0070] Catalyst preparation: [Ir(COD)Cl] 2 (1eq.), (R)-f-amphox (2eq.) were mixed in methanol, stirred at room temperature for 2.5 hours and then directly used for asymmetric hydrogenation catalytic reaction;

[0071] [Rh(COD)Cl] 2 (1eq.), (R)-BINAP (2.2eq.) were mixed in methanol, stirred at room temperature for 2 hours and then directly used for asymmetric hydrogenation catalytic reaction;

Embodiment 1

[0072] Embodiment 1 The preparation method of the chiral secondary amine compound shown in a kind of formula (II)

[0073]

[0074] Add 12.3g (0.04mol) of imine (I) into a 200mL stainless steel autoclave, then add 80mL of methanol and stir to dissolve, add 652mg of cesium carbonate (5mol%, 0.002mol), and then add (R) with a concentration of 0.01mol / L -f-amphox / [Ir(COD)Cl] 2 Catalyst 0.8mL, the molar ratio of imine (I) and catalyst is 5000 / 1. 4 MPa of hydrogen gas was introduced into the reactor, the reaction was stirred at 25°C for 24 hours, and the solvent was distilled off. After separation and purification by column chromatography, 12.1 g of chiral secondary amine (II) was obtained, with a yield of 97.9% and an enantiomeric excess of more than 99%.

Embodiment 2

[0075] Embodiment 2 The preparation method of the chiral secondary amine compound shown in a kind of formula (II)

[0076]

[0077] Add 12.3g (0.04mol) of imine (I) into a 200mL stainless steel autoclave, then add 80mL of methanol and stir to dissolve, add 14mg(R)-BINAP-[Rh(COD)Cl] 2 The molar ratio of catalyst to substrate catalyst is 5000 / 1. 4 MPa of hydrogen gas was introduced into the reaction vessel, the reaction was stirred at 25°C for 24 hours, and the solvent was distilled off. After separation and purification by column chromatography, 11.9 g of chiral secondary amine (II) was obtained, with a yield of 96.3% and an enantiomeric excess of more than 99%.

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Abstract

The invention relates to a novel method for synthesizing clopidogrel bisulphate and an intermediate thereof. The novel method includes subjecting 2-thiophenethylamine and N-benzyl-2-(2-chlorophenyl)-2-carbonyl acetamide to a condensation reaction to generate imine; reducing the imine into corresponding secondary amine through asymmetric hydrogenation; cyclizing the secondary amine and formaldehyde under acidic conditions to obtain clopidogrel free base, and acidifying the clopidogrel free base by sulfuric acid to obtain the clopidogrel bisulphate. The novel method has the advantages that thesynthetic route is short, the reactions involved are classical organic chemical reactions, reaction conditions are moderate, and the method is simple to operate and has high enantioselectivity, yieldand conversion number; most substrates have the conversion rate of 99% or more and the ee value of 97-99% when the millionth of catalysts is used, the highest conversion number reaches 100,000, and accordingly, the method has extremely high industrial application value.

Description

technical field [0001] The invention belongs to the field of synthesis of pharmaceutical and chemical intermediates, and provides a new method for synthesizing clopidogrel hydrogen sulfate and its intermediates. 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 in 1986, and its structural formula is as follows: [0003] [0004] Clopidogrel bisulfate is widely used clinically in the treatment and prevention of cardiovascular diseases such as myocardial infarction, atherosclerosis, and acute coronary syndrome. Compared with other drugs with the same curative effect, clopidogrel bisulfate has the advantages of good curative effect, low price, and few side effects, and its clinical usage is larger. [0005] In the prior art, the synthesis of clopidogrel bisulfate all has low overa...

Claims

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Application Information

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IPC IPC(8): C07D333/20C07D495/04
CPCC07B2200/07C07D333/20C07D495/04
Inventor 邵攀霖马保德王江丁小兵张绪穆
Owner SOUTH UNIVERSITY OF SCIENCE AND TECHNOLOGY OF CHINA
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