Preparation method of clopidogrel intermediate compound

The technology of an intermediate, clopyrrole, is applied in the field of preparation of pharmaceutical intermediates, and can solve the problems of high toxicity of sodium cyanide, unsafe production activities, environmental pollution, etc., achieve low price, maintain dyeing quality, and avoid environmental pollution. effect of the problem

Inactive Publication Date: 2014-09-17
沈健芬
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These two synthetic routes all can use sodium cyanide, because sodium cyanide is highly toxic, cause production activity unsafe, and can cause very big pollution to the environment, so it is very important to develop a synthetic route that does not need to use highly toxic cyanide Significant

Method used

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  • Preparation method of clopidogrel intermediate compound
  • Preparation method of clopidogrel intermediate compound
  • Preparation method of clopidogrel intermediate compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] The synthetic route is as follows:

[0023]

[0024] In a 100ml three-neck flask, add potassium ferrocyanide (1.69g, 4mmol) and p-chlorobenzoyl chloride (3.50g, 20mmol), heat and stir to 180°C for 2 hours, cool to 50°C, and then add o-chlorobenzene dropwise A 30ml mixed solution of formaldehyde (2.81g, 20mmol) and thienopyridine hydrochloride (3.51g, 20mmol) was heated and stirred to 80°C for 8 hours. Suction filtration, the filtrate was concentrated under reduced pressure to remove ethanol, 20ml of water was added, extracted with 20ml*3 dichloromethane, the organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain (±)-(2-chlorophenyl)- (6,7-Dihydro-4H-thieno[3,2- c ]pyridin-5-yl) acetonitrile crude product, recrystallized from methanol to obtain 4.91 g of off-white product, yield 85%. The resulting product was analyzed by IR and 1 H-NMR identification is as follows: IR spectrum (cm-1): 2227 (-CN); 1 H-NMR (CDCl 3...

Embodiment 2

[0026] The synthetic route is the same as above.

[0027] In a 100ml three-necked flask, add potassium ferrocyanide (1.69g, 4mmol) and benzoyl chloride (2.81g, 20mmol), heat and stir to 160°C for 2 hours, cool to 50°C, and then add o-chlorobenzaldehyde ( 2.81g, 20mmol) and thienopyridine hydrochloride (3.51g, 20mmol) in 30ml of methanol mixed solution, continue heating and stirring to 80 ° C for 8 hours. Suction filtration, the filtrate was concentrated under reduced pressure to remove methanol, 20ml of water was added, extracted with 20ml*3 dichloromethane, the organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain (±)-(2-chlorophenyl)- (6,7-Dihydro-4H-thieno[3,2- c ] pyridin-5-yl) acetonitrile crude product, recrystallized from methanol to obtain 4.62 g of off-white product, yield 80%.

Embodiment 3

[0029] In a 100ml three-necked flask, add potassium ferrocyanide (1.69g, 4mmol) and benzoyl chloride (2.81g, 20mmol), heat and stir to 160°C for 2 hours, cool to 50°C, and then add o-chlorobenzaldehyde ( 2.81g, 20mmol) and tetrahydrothienopyridine (2.78g, 20mmol) in 30ml of methanol mixed solution, continue heating and stirring to 80 ° C for 8 hours. Suction filtration, the filtrate was concentrated under reduced pressure to remove methanol, 20ml of water was added, extracted with 20ml*3 dichloromethane, the organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain (±)-(2-chlorophenyl)- (6,7-Dihydro-4H-thieno[3,2- c ]pyridin-5-yl) acetonitrile crude product, recrystallized from methanol to obtain 4.95 g of off-white product, yield 86%.

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Abstract

The invention provides a method for preparing a clopidogrel intermediate compound (+/-)-(2-chlorphenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyridyl-5-yl) acetonitrile. Compared with the prior art, the method shortens the synthesis step of the clopidogrel intermediate compound (+/-)-(2-chlorphenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyridyl-5-yl) acetonitrile, increases the overall yield and lowers the synthesis cost of clopidogrel; and meanwhile, the use of virulent sodium cyanide is avoided, so that the safety problem and environmental pollution problem in the original production route can be avoided, thereby generating equivalent social benefits and economic benefits.

Description

technical field [0001] The present invention relates to a preparation method of a pharmaceutical intermediate, in particular to a method for preparing a clopyrrole intermediate (±)-(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2 - c ]pyridin-5-yl) acetonitrile method. Background technique [0002] Cardiovascular and cerebrovascular thrombotic diseases are common diseases in my country. Clopyrrole is an acetic acid derivative of ticlopidine, which has the advantages of strong curative effect, low cost, and small side effects. It is mainly used for the treatment of atherosclerosis, acute coronary syndrome, and prevention of coronary stent implantation. internal restenosis and thrombotic complications. The combination of clopidogrel and aspirin is gradually becoming the standard of antithrombotic therapy in cardiovascular and cerebrovascular diseases. [0003] Clopidogrel (Clopidogrel) is a new generation of platelet inhibitors researched and developed by Sanofi Sandela Fort Ph...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D495/04
CPCC07D495/04
Inventor 沈健芬郑睿
Owner 沈健芬
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