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Preparation method of clevidipine butyrate

A technology of clevidipine butyrate and dichlorobenzaldehyde, which is applied in the direction of organic chemistry, can solve the problems of long reaction steps, high price, cumbersome operation, etc., and achieve the effects of low cost, low environmental pollution and simple process

Inactive Publication Date: 2013-08-14
SHANGHAI INST OF PHARMA IND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method has the following disadvantages: (1) the preparation of raw material acetoacetate (2-methylmercapto) ethyl ester needs to use poisonous and malodorous 2-methylmercaptoethanol, and the yield is low, not easy to obtain
(2) Use expensive methyl iodide
(3) The reaction steps are long and the operation is cumbersome

Method used

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  • Preparation method of clevidipine butyrate
  • Preparation method of clevidipine butyrate
  • Preparation method of clevidipine butyrate

Examples

Experimental program
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Effect test

Embodiment 1

[0047] Preparation of (±)-4-(2′,3′-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-5-carboxylic acid methyl-3-carboxylic acid (II)

[0048] Method A:

[0049]Add 2,3-dichlorobenzaldehyde (1.75g, 10mmol), methyl acetoacetate (1.16g, 10mmol) and cyanoethyl 3-aminocrotonate (1.54g, 10mmol) successively in a round bottom flask, triethyl Amine (0.10g, 1mmol) and ethanol (50ml) were used as solvent, and reacted at 75°C for 8h. Cooling and cooling, suction filtration to obtain a solid, the resulting solid was recrystallized by adding ethanol (30ml), and suction filtration to obtain the compound (±)-3-(2-cyanoethyl)-5-methyl-4-(2',3'- Dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid (III) (3.3 g, 8 mmol). Compound III (3.3g, 8mmol) was dissolved in ethanol (50ml), 8.8ml (8.8mmol) of 1M lithium hydroxide solution was added at 0°C, stirred for 2h, the solvent was evaporated, water (33ml) was added, and dilute Adjust the pH to 5-6 with hydrochloric acid (1M), an...

Embodiment 2

[0056] (±)-4-(2′,3′-dichlorophenyl)-2,6,-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid methyl (butyryloxy Methyl) ester (I)

[0057] Method A:

[0058] Add (±)-4-(2′,3′-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-5-carboxylic acid methyl-3- Formic acid (3.1g, 8.7mmol), sodium bicarbonate (1.46g, 17.4mmol), potassium iodide (0.14g, 0.87mmol) and acetonitrile (30ml), then added chloromethyl n-butyrate (1.30g, 9.6mmol), Stirring and reflux reaction at 80°C for 6h. Cool to 50°C, heat filter, add isopropanol (10ml) and water (50ml) to the filtrate successively at 40°C, stir for 1 hour, then cool down to room temperature and stir overnight, a solid precipitates, filters to obtain a light yellow solid, filter cake Recrystallize with 20ml of isopropanol / water (2 / 1, volume ratio) to obtain 3.1g of solid with a yield of 77.5%.

[0059] mp.136.3~138.4℃; m / z: 478 (M+Na + ), 494 (M+K + ); 1 H NMR (DMSO, ppm): 9.03(s, 1H7.23-7.39(m, 3H), 5.67(dd, 2H, J=5.5Hz, J=5.38Hz), 5.3...

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Abstract

The invention discloses a preparation method of clevidipine butyrate, comprising the following steps: (1) carrying out one-pot reaction by putting 2,3-dichlorobenzaldehyde, methyl acetoacetate and 3-amino crotonic acid ethyl cyanide in a solvent under the action of a catalyst; (2) carrying out recrystallization to obtain a pure product (+ / -)-3-(2-cyanoethyl)-5-methyl-4-(2',3'-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid; (3) carrying out a reaction between the pure product and alkali; (4) adding water and hydrochloric acid, and collecting an intermediate from reaction products; and (5) carrying out a reaction between the intermediate and n-chloromethyl butyrate in the presence of an alkaline substance and an iodide catalyst, and finally collecting the target product clevidipine butyrate from reaction products. The preparation method provided by the invention has advantages of high yield, stable product quality and low cost, is simple to operate, and is suitable for industrial product of clevidipine butyrate.

Description

technical field [0001] The invention designs a preparation method of a novel antihypertensive drug clevidipine butyrate. Background technique [0002] Clevidipine butyrate, the chemical name is 4-(2′,3′-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Acid methyl (butyryloxymethyl) ester (I), is a new type of dihydropyridine calcium channel blocker for intravenous injection, which can selectively inhibit the influx of calcium ions outside the arterial smooth muscle cells, so that Blood vessels relax and blood pressure drops. Developed by the Medicines Company, it was approved for marketing by the US FDA on August 1, 2008. It is the first antihypertensive drug for intravenous injection in foreign countries in the past ten years. It is suitable for the treatment of high blood pressure when oral preparations are not applicable or desired. It is also used in the treatment of acute blood pressure elevation after cardiac surgery. This product has a quick onset...

Claims

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Application Information

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IPC IPC(8): C07D211/90
Inventor 李建其郑永勇方干张莉
Owner SHANGHAI INST OF PHARMA IND
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