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Preparation method of cardiovascular drug nilvadipine

A nilvadipine and cardiovascular technology, which is applied in the field of preparation of cardiovascular drugs, can solve the problems of difficult purification, low purity, and difficulty in obtaining pure solids, and achieves the effects of simplified procedure, improved purity and simple process

Inactive Publication Date: 2013-08-21
HUNAN NORMAL UNIVERSITY
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AI Technical Summary

Problems solved by technology

The intermediate 2-(3-nitrobenzylidene)-4,4-dimethoxyacetoacetate methyl ester obtained in the route is an oily substance, which often contains unreacted m-nitrobenzaldehyde and other by-products, It is not easy to purify, and its purity directly affects the quality of subsequent products. If you want to obtain high-purity intermediates, you can only purify them by column chromatography, which is not suitable for industrial production. If you directly put them into the next step reaction, the obtained intermediate The purity of 3-methoxycarbonyl-2,2-dimethoxymethyl-4-(3-nitrophenyl)-6-methyl-1,4-dihydropyridine-5-carboxyisopropyl ester is not High, it is difficult to obtain a solid with higher purity and better shape by recrystallization
In the final step, the formation of 3-methoxycarbonyl-6-methyl-4-(3-nitrophenyl)-2-formyl-1,4-dihydropyridine-5-carboxylic acid isopropyl ester and hydroxylamine hydrochloride The intermediate oxime is dehydrated at high temperature in an acidic environment, and it is easy to form 3-methoxycarbonyl-6-methyl-4-(3-nitrophenyl)-2-carbamoyl-1,4-dihydropyridine-5 Acids such as isopropyl carboxylate and 3-methoxycarbonyl-6-methyl-4-(3-nitrophenyl)-2-carboxy-1,4-dihydropyridine-5-carboxylate By-products, and these by-products can be removed from the final product nilvadipine through multiple recrystallizations, and multiple recrystallizations reduce the yield and increase the production cost

Method used

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  • Preparation method of cardiovascular drug nilvadipine
  • Preparation method of cardiovascular drug nilvadipine
  • Preparation method of cardiovascular drug nilvadipine

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preparation example Construction

[0031] Preparation of methyl 4,4-dimethoxyacetoacetate:

[0032] Dissolve 9.6g (0.4mol) of sodium hydride with a content of 60wt%, 36.0g (0.4mol) of dimethyl carbonate, and 23.6g (0.2mol) of dimethyl acetal in 100ml of benzene to obtain a mixed solution. Reflux at 110°C for 10 h, cool the reaction solution in an ice bath, add 23 ml of glacial acetic acid dropwise, then add 62 ml of water dropwise, stir for 10 min, leave to separate layers, separate the organic layer, extract the aqueous layer with 60 ml of toluene, combine the organic layer, washed with water, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was rectified under reduced pressure to obtain 19.5g of methyl 4,4-dimethoxyacetoacetate, boiling range 65-68°C / 3mmHg, yield 55.3%.

[0033]

Embodiment 1

[0035] This embodiment includes the following steps:

[0036] (1) 3-methoxycarbonyl-2,2-dimethoxymethyl-4-(3-nitrophenyl)-6-methyl-1,4-dihydropyridine-5-carboxyisopropyl ester (Compound Ⅰ) Preparation

[0037]5.01g (33.1mmol) m-nitrobenzaldehyde, 5.21g (36.41mmol) isopropyl 3-aminocrotonate, 6.41g (36.41mmol) methyl 4,4-dimethoxyacetoacetate and 55ml isopropyl Alcohol was mixed, heated to reflux for 10 h, the solvent was spin-dried, and the residue was recrystallized with isopropyl ether to obtain 10.4 g of white solid, yield 72.3%, m.p.110-112°C;

[0038] (2) 3-methoxycarbonyl-6-methyl-4-(3-nitrophenyl)-2-formyl-1,4-dihydropyridine-5-carboxylic acid isopropyl ester (compound Ⅱ) preparation

[0039] Dissolve 7.60g (17.5mmol) of compound I in 84ml of acetone, add 10ml of 6mol / L hydrochloric acid, stir at room temperature for 5h, then add 20ml of water, stir for 20min, filter, filter cake with acetone / water (V / V=1:1 ) washing, vacuum drying to obtain 5.88g yellow powdery sol...

Embodiment 2

[0053] This embodiment includes the following steps:

[0054] (1) 3-methoxycarbonyl-2,2-dimethoxymethyl-4-(3-nitrophenyl)-6-methyl-1,4-dihydropyridine-5-carboxyisopropyl ester (Compound Ⅰ) Preparation

[0055] Mix 10.0 g (66.2 mmol) m-nitrobenzaldehyde, 10.4 g (72.8 mmol) isopropyl 3-aminocrotonate, 12.8 g (72.8 mmol) methyl 4,4-dimethoxyacetoacetate and 100 ml tetrahydrofuran , the temperature was raised to reflux for 10 h, and the solvent was removed under reduced pressure to obtain 15.0 g of a light yellow oil, which was directly used in the next step without purification;

[0056] (2) 3-methoxycarbonyl-6-methyl-4-(3-nitrophenyl)-2-formyl-1,4-dihydropyridine-5-carboxylic acid isopropyl ester (compound Ⅱ) preparation

[0057] Dissolve 15.0g of the oily compound obtained in step (1) in 120ml of acetone, add 20ml of 6mol / L hydrochloric acid, stir at room temperature for 5h, add 40ml of water, stir for 20min, filter, and wash the filter cake with acetone / water (volume ratio ...

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Abstract

A preparation method of a cardiovascular drug nilvadipine comprises the following steps of (1) cyclizing isopropyl 3-aminocrotonate, methyl 4,4-dimethoxyacetylacetate and m-nitrobenzaldehyde without a solvent or in an organic solvent I to obtain an intermediate compound I, (2) dissolving the compound I in an organic solvent II, adding 2-6 equivalents of acid, stirring for hydrolysis reaction for 1-12h to generate an intermediate compound II, (3) dissolving the intermediate compound II, 1.1-1.3 equivalents of hydroxylamine hydrochloride and 1.4-1.6 equivalents of alkali in the organic solvent III for reaction for 2.5-4h, adding water, stirring and filtering to obtain an intermediate compound III, and (4) dehydrating the compound III in an alkaline environment to obtain nilvadipine IV. The preparation method is simple in process, low in cost, can greatly improve the purity of a nilvadipine intermediate, and is suitable for large-scale industrial production, and the yield of nilvadipine is higher.

Description

technical field [0001] The invention relates to a preparation method of cardiovascular medicine, in particular to a preparation method of cardiovascular medicine nilvadipine. Background technique [0002] Nilvadipine, the molecular formula is C 19 h 19 N 3 o 6 , the chemical name is 3-methoxycarbonyl-6-methyl-4-(3-nitrophenyl)-2-cyano-1,4-dihydropyridine-5-carboxylic acid isopropyl ester, namely 2- cyano-1,4-dihydro-6-methy-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-methyl-5-(1-methylethyl) diester, the structural formula is as follows: [0003] Nilvadipine is a novel dihydropyridine calcium antagonist used in the treatment of cerebrovascular diseases, ischemic heart disease and hypertension. its and Ca 2+ The binding force of the specific part of the channel is 10 times stronger than that of nitrobedipine, and the duration of action is 2-3 times longer. It has anti-angina pectoris and anti-arteriosclerosis effects. [0004] Nilvadipine was first launched in J...

Claims

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Application Information

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IPC IPC(8): C07D211/90
Inventor 徐广宇宋耀平沈栋国邓华峰
Owner HUNAN NORMAL UNIVERSITY
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