Preparation method of nilvadipine intermediate

A technology of methyl and nitrophenyl, which is applied in the field of preparation of nilvadipine intermediates, can solve the problems of low purity, low yield, complicated preparation process, etc., and achieve the effect of improving purity, low cost and simple process

Inactive Publication Date: 2012-12-12
HUNAN FANGSHENG PHARMACEUTICAL CO LTD
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  • Abstract
  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

[0011] The object of the present invention is to provide a kind of nilvadipine intermediate and preparation method thereof, to solve the nilvadipine intermediate 3-methoxycarbonyl-6-methyl-4-(3-nitrophenyl)- The preparation process of isopropyl 2-formyl-1,4-dihydropyridine-5-carboxylate is complicated, the purity is not high, the yield is low and other technical problems

Method used

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  • Preparation method of nilvadipine intermediate
  • Preparation method of nilvadipine intermediate

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Embodiment 1

[0050] 1) Put sodium hydride with a molar mass of 0.2 mol, dimethyl carbonate with a molar mass of 0.2 mol, and aceguvaldehyde dimethyl acetal with a molar mass of 0.1 mol into 50 mL of toluene to obtain a mixed solution, and reflux the mixed solution at 120°C 10h to obtain a concentrated solution. Cool the concentrated solution in an ice bath, slowly add 23mL of glacial acetic acid dropwise, then dropwise add 62mL of water, stir for 10min, stand and separate to obtain the water layer and the first organic layer, wash the water layer with 30mL of benzene and stand to separate , to obtain the second organic layer; combine the first organic layer and the second organic layer to obtain the total organic solution; wash the total organic solution with water, dry the steps, and rectify under reduced pressure to obtain 4,4-dimethoxyacetoacetate methyl ester Pure product 10.61g, yield 60.2%, bp: 69~70℃ / 3mmHg.

[0051] 2) Take 4,4-dimethoxyacetoacetate methyl ester with a molar mass o...

Embodiment 2

[0056] 1) Sodium hydride with a molar mass of 0.2 mol, dimethyl carbonate with a molar mass of 0.2 mol, and aceguvaldehyde dimethyl acetal with a molar mass of 0.1 mol were dissolved in 50 mL of benzene to obtain a mixed solution, and the mixed solution was heated at 110°C Reflux for 10h to obtain a concentrated solution. Cool the concentrated solution in an ice bath, slowly add 23mL of glacial acetic acid dropwise, then dropwise add 62mL of water, stir for 10min, stand and separate to obtain the water layer and the first organic layer, wash the water layer with 30mL of benzene and stand to separate , to obtain the second organic layer; combine the first organic layer and the second organic layer to obtain the total organic solution; the total organic solution is washed and dried, and then concentrated under reduced pressure at 3 mmHg to obtain 4,4-dimethoxy The crude methyl acetoacetate was distilled under reduced pressure to obtain 9.58g pure product, bp: 69~70℃ / 3mmHg. .

...

Embodiment 3

[0062] 1) Dissolve butyl lithium with a molar mass of 0.2 mol, dimethyl carbonate with a molar mass of 0.2 mol, and aceguvaldehyde dimethyl acetal with a molar mass of 0.1 mol in 50 ml of toluene to obtain a mixed solution, and put the mixed solution at 100°C Under reflux for 5h to obtain a concentrated solution. Cool the concentrated solution in an ice bath, slowly add 23mL of glacial acetic acid dropwise, then dropwise add 62mL of water, stir for 10min, stand and separate to obtain the water layer and the first organic layer, wash the water layer with 30mL of benzene and stand to separate , to obtain the second organic layer and combine the first organic layer and the second organic layer to obtain the total organic solution; the total organic solution was washed with water and dried, and then concentrated under reduced pressure at 3 mmHg to obtain 18.5 g of 4,4-dimethoxy The crude methyl acetoacetate was then rectified under reduced pressure to obtain 10.0 g of pure product...

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Abstract

The invention provides a preparation method of 3-methoxycarbonyl-6-methyl-4-(3-nitrophenyl)-2-formyl-1, 4-dihydropyridine-5-isopropyl carbonate. The method comprises the following steps that condensation and amination reactions between pyruvic aldehyde dimethyl acetal and dimethyl carbonate are carried out under the catalysis of a strong base to obtain 3-amino-4, 4-dimethoxyl-methyl crotonate; dehydration condensation reaction between isopropyl acetoacetate and nitrobenzaldehyde is carried out under the catalysis of a weak base to obtain 2-(3-nitrobenzylidene)-isopropyl acetoacetate; dehydration condensation and hydrolysis reactions between 3-amino-4, 4-dimethoxyl-methyl crotonate and 2-(3-nitrobenzylidene)-isopropyl acetoacetate are carried out to obtain 3-methoxycarbonyl-6-methyl-4-(3-nitrophenyl)-2-formyl-1, 4-dihydropyridine-5-isopropyl carbonate. The method provided by the invention solves the technical problems in the prior art including complex preparation process, low purity and less yield during the preparation of nilvadipine intermediate 3-methoxycarbonyl-6-methyl-4-(3-nitrophenyl)-2-formyl-1, 4-dihydropyridine-5-isopropyl carbonate.

Description

technical field [0001] The invention relates to the field of chemical intermediates, in particular to a method for preparing a nilvadipine intermediate. Background technique [0002] Nilvadipine, molecular formula is C19H19N3O6, chemical name: 3-methoxycarbonyl-6-methyl-4-(3-nitrophenyl)-2-cyano-1,4-dihydropyridine-5-carboxylic acid Isopropyl ester, the structural formula is as follows: [0003] [0004] Nilvadipine is a dihydropyridine calcium antagonist used in the treatment of angina, cerebrovascular disease, ischemic heart disease and hypertension. its and Ca 2+ The binding force of the channel-specific site is 10 times stronger than that of nitrobedipine, and the duration of action is 2-3 times longer. It can selectively dilate coronary arteries and cerebral arteries, has strong vasodilator action, has little effect on the heart, and has obvious blood pressure lowering effect. The expansion effect on vertebral artery and coronary artery is stronger than that on o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/90
Inventor 张庆华徐广宇沈栋国
Owner HUNAN FANGSHENG PHARMACEUTICAL CO LTD
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