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A kind of preparation method of clevidipine butyrate

A technology of clevidipine butyrate and ethyl acetate is applied in the preparation of short-acting dihydropyridine calcium channel blocker clevidipine butyrate and in the field of medicine preparation, which can solve the problems of cumbersome operation, low purity and production cycle. Long-term problems, to achieve the effect of improving product purity, simplifying process steps, and saving production costs

Active Publication Date: 2019-01-25
HEFEI JIUNUO MEDICAL TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] The resulting formula (III) synthesized by the above three methods has low purity, large impurities, especially excessive feed intake and large residual amount of unreacted raw materials, and the product is dark in color, which requires further refining and decolorization treatment (such as patent CN201210027889.3), or in In the subsequent synthesis process of formula (II), hydrolysis into salt and acidification crystallization are carried out step by step (such as patent CN201310017727.6), the production cycle is long and the operation is cumbersome
[0016] In the process of synthesizing clevidipine butyrate in the prior art, especially in the synthesis process of formula (II), step-by-step refining, impurity removal and decolorization are required, the operation is cumbersome, the industrial production efficiency is low, and the cost is high

Method used

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  • A kind of preparation method of clevidipine butyrate
  • A kind of preparation method of clevidipine butyrate
  • A kind of preparation method of clevidipine butyrate

Examples

Experimental program
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Effect test

Embodiment 1

[0056] 1. Preparation of 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-3-pyridinecarboxylic acid intermediate

[0057] Put 25.0g (162.16mmol) of cyanoethyl 3-aminocrotonate into 125ml of isopropanol, add 50.0g (183.08mmol) of methyl 2,3-dichlorobenzylidene acetoacetate while stirring, and heat to reflux for reaction 6 -8h, after the reaction is finished, cool down to 35-45°C, put 13.8g (245.95mmol) of potassium hydroxide into the reaction liquid, keep stirring for 2-4h, then put in 1.3g of activated carbon for decolorization for 5-15min, filter, and the filtrate is placed in 30- Add 0.5mol / L hydrochloric acid solution dropwise at 40°C to adjust the pH value to 5-6, filter, and dry under reduced pressure at 40-50°C to obtain the intermediate - 4-(2,3-dichlorophenyl)-1,4 - 51.3 g of dihydro-2,6-dimethyl-5-methoxycarbonyl-3-pyridinecarboxylic acid, yield 88.81%.

[0058] 2, the preparation of clevidipine butyrate

[0059] Put 51.3g (144.02mmol) of the interm...

Embodiment 2

[0061] 1. Preparation of 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-3-pyridinecarboxylic acid intermediate

[0062] Put 25.0 g (162.16 mmol) of cyanoethyl 3-aminocrotonate into 150 ml of isopropanol, add 53.0 g (194.06 mmol) of methyl 2,3-dichlorobenzylidene acetoacetate while stirring, and heat to reflux for reaction 6 -8h, after the reaction, cool down to 35-45°C, put 12.9g (322.50mmol) of sodium hydroxide into the reaction liquid, keep stirring for 2-4h, then throw in 3.0g of activated carbon for decolorization for 5-15min, filter, and the filtrate is placed in 30- Add 1mol / L hydrochloric acid solution dropwise at 40°C to adjust the pH value to 5-6, filter, and dry under reduced pressure at 40-50°C to obtain the intermediate - 4-(2,3-dichlorophenyl)-1,4- 50.6 g of dihydro-2,6-dimethyl-5-methoxycarbonyl-3-pyridinecarboxylic acid, yield 87.60%.

[0063] 2, the preparation of clevidipine butyrate

[0064] Put 50g (140.37mmol) of the intermediate prepar...

Embodiment 3

[0066] 1. Preparation of 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-3-pyridinecarboxylic acid intermediate

[0067] Put 1.0kg (6.49mol) of cyanoethyl 3-aminocrotonate into 5.5L isopropanol, add 2.0kg (7.32mol) of methyl 2,3-dichlorobenzylidene acetoacetate under stirring, and heat to reflux for reaction 6-8h, after the reaction is over, cool down to 35-45°C, put in 550.0g (9.80mol) of potassium hydroxide, keep stirring for 2-4h, then put in 60.0g of activated carbon for decolorization for 5-15min, filter, and drop the filtrate at 30-40°C Add 1mol / L hydrochloric acid solution to adjust the pH value to 5-6, filter, and dry under reduced pressure at 40-50°C to obtain the intermediate - 4-(2,3-dichlorophenyl)-1,4-dihydro-2 , 6-dimethyl-5-methoxycarbonyl-3-pyridinecarboxylic acid 2.11kg, yield 91.32%.

[0068] 2, the preparation of clevidipine butyrate

[0069] Put 2.0kg (5.61mol) of the intermediate prepared in step 1 into 10L of acetonitrile, add 850g (6....

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Abstract

The invention discloses a method for preparing high-purity cleviprex. 3-amino crotonic acid cyanoacetate and 2,3-dichloro benzal methyl acetoacetate serve as initial raw materials, and an intermediate 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-5-methoxy carbonyl-3-picolinic acid is obtained through cyclization, hydrolysis, decoloration and acidification crystallization; and the intermediate undergoes condensation with n-chloromethyl butyrate and refining to obtain the high-purity cleviprex. The method is simple in process, convenient to operate, high in yield and low in cost, and the product is pure and more suitable for industrial production.

Description

1. Technical field [0001] The invention relates to a preparation method of fine chemicals, in particular to a preparation method of medicines, in particular to a preparation method of short-acting dihydropyridine calcium channel blocker clevidipine butyrate. 2. Background technology [0002] Clevidipine butyrate, the chemical name is 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Base (butyryloxymethyl) ester, its structural formula is as shown in formula (I): [0003] [0004] Clevidipine butyrate is a short-acting dihydropyridine calcium channel blocker developed by AstraZeneca, and its injectable emulsion was first launched in the United States in August 2008 under the trade name Cleviprex. It is used to reduce the blood pressure of patients who are not suitable for oral administration or oral treatment is ineffective. It can also be used to treat blood pressure control during surgery and acute blood pressure increase after surgery. Clevidi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D211/90
CPCC07D211/90
Inventor 吴标凌林王周红戴一
Owner HEFEI JIUNUO MEDICAL TECH