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Calcium ion channels antagonist manidipine preparation method

A technology of calcium ion channel and manidipine, which is applied in the field of drug preparation, can solve the problems of complex by-products of reaction products, difficulty in obtaining intermediates, unsuitable for industrial production, etc., and achieve less impurities in the reaction process, simple post-treatment, and technological conditions mild effect

Inactive Publication Date: 2013-11-27
ZHANG JIA GANG VINSCE BIO PHARM
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But, this method is difficult to obtain purer intermediate 2-(4-benzhydrylpiperazine) ethyl acetoacetate in the preparation process, and, if the impurity that this intermediate exists is directly separated with The subsequent material reaction will bring complex by-products to the reaction product, which has higher requirements for post-treatment, and generally must be separated by column chromatography, so it is not suitable for industrial production

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0018] Preparation of benzhydrylpiperazine ethyl β-aminocrotonate (3)

[0019] Dissolve methyl β-aminocrotonate (20g, 0.174mol) in chloroform (100ml), add sodium methoxide (11.28g, 0.209mol), and add 1-benzhydryl-4-(2- Hydroxyethyl)piperazine (77.17g, 0.260mmol) in chloroform (50ml) was heated to reflux for 6h. Water (50ml×3) was added for extraction, the organic phase was evaporated under reduced pressure to remove the organic solvent, and petroleum ether was added for crystallization to obtain 55.10 g of solid, with a yield of 83.58%.

Embodiment 2

[0021] Preparation of benzhydrylpiperazine ethyl β-aminocrotonate (3)

[0022] Methyl β-aminocrotonate (20g, 0.174mol) was dissolved in toluene (100ml), potassium carbonate (24.05g, 0.174mol) was added, and 1-benzhydryl-4-(2- Hydroxyethyl) piperazine (56.68g, 0.191mmol) in toluene (50ml) solution, keep warm for 4h. The solvent was evaporated under reduced pressure, extracted with water (300ml) and dichloromethane (80ml×3), the organic phases were combined, dried, and the organic solvent was evaporated to remove the organic solvent. The resulting product was crystallized with petroleum ether to obtain 52.66g of solid, with a yield of 79.88%.

Embodiment 3

[0024] Preparation of benzhydrylpiperazine ethyl β-aminocrotonate (3)

[0025] Methyl β-aminocrotonate (20g, 0.174mol) was dissolved in toluene (100ml), sodium methoxide (11.28g, 0.209mol) was added, and 1-benzhydryl-4-(2- Hydroxyethyl) piperazine (51.53g, 0.174mmol) in toluene (50ml) solution, keep warm for 4h. The solvent was evaporated under reduced pressure, extracted with water (150ml) and dichloromethane (50ml×3), the organic phases were combined, dried, and the organic solvent was evaporated to remove the organic solvent. The resulting product was crystallized with petroleum ether to obtain 53.89g of solid, with a yield of 81.75%.

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Abstract

The present invention provides a calcium ion channel antagonist manidipine preparation method, which comprises that: methyl 2-(3-nitrobenzylidene)acetoacetate 2 and beta-amino crotonic acid diphenylmethyl piperazine ethyl ester 3 are subjected to a cyclization reaction in an alcohol solvent to obtain a manidipine 1 crude product, and re-crystallization is performed to obtain the manidipine 1. The preparation method has advantages of short reaction period, simple synthesis route, less impurities in a reaction process, simple post-treatment, mild process conditions and the like, and is suitable for industrial production, wherein a yield is more than 68%.

Description

technical field [0001] The invention relates to medicine preparation, in particular to a preparation method of manidipine, a dihydropyridine calcium ion dual channel antagonist. Background technique [0002] With the development of social economy and the improvement of people's living standards, cardiovascular disease has become one of the main diseases affecting the health of the general public. Hypertension is the main factor of death from cardiovascular and cerebrovascular diseases. The world dies of cardiovascular and cerebrovascular diseases every year. About 15 million people, accounting for 30% of the total death toll, pose a great threat to people's life and life. According to the estimates of relevant departments, the number of hypertensive patients over the age of 15 in my country has reached 130 million, and it is expected to increase by more than 64% by 2015. It can be seen that antihypertensive drugs have huge market potential and good economic and social benef...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/90C07D295/088
Inventor 赵金召张梅彭学东
Owner ZHANG JIA GANG VINSCE BIO PHARM
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