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Method for preparing clevidipine butyrate

A technology of ammonium acetate and dichlorophenyl, applied in the field of preparation of clevidipine butyrate, can solve the problems of slow reaction speed, low total yield, low melting point, etc. The effect of reaction yield

Active Publication Date: 2012-05-02
ZHEJIANG JIUXU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But, there are following problems in this method: (1) concentrated ammonia water has strong pungent odor, and is volatile, and under heating state, ammonia water is mostly volatilized, can't participate in reaction, so the consumption of ammonia water is bigger; (2) environmental protection The condensation reaction time is 8~15h, and the reaction speed is relatively slow; (3) the selectivity of methyl ester hydrolysis is poor under alkaline conditions, resulting in low overall yield of the preparation method; (4) the prepared intermediate 4-(2 , 3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-3-pyridinecarboxylic acid fusing point is lower, suggesting that the impurity content of product is higher, to final The quality of clevidipine butyrate has great influence

Method used

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  • Method for preparing clevidipine butyrate
  • Method for preparing clevidipine butyrate
  • Method for preparing clevidipine butyrate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Add 2,3-dichlorobenzaldehyde (17.5g, 0.1mol), ammonium acetate (11.6g, 0.15mol), methyl acetoacetate (17.3g, 0.15mol) to the ultrasonic reactor, set the reaction power to 100W, and react 5h. Release the reaction liquid from the ultrasonic reactor, cool to below 10°C, stir for 2 hours to precipitate crystals, filter, and wash the crystals with water three times. Then, the obtained crystals were completely dissolved in 100ml of absolute ethanol at 50-60°C, placed at room temperature for 1 hour, and then placed in a refrigerator at 0-5°C for 8 hours. Filter, and dry the obtained crystals in an oven at 70-80° C. for 6 hours to obtain 33.2 g of light yellow sand-like crystals (Intermediate I) (content: 98.4%, yield: 89.5%).

[0025] Melting point: 187.0~188.5℃

[0026] IR (KBr, cm -1 ): 3336, 2948, 1704, 1680, 1651, 1620, 1502, 1286, 779, 732.

[0027] Utilize HPLC to carry out assay, detection condition is as follows:

[0028] Column: C 8 (250mm×4.6mm, 5um) (Welch Mat...

Embodiment 2

[0034] Add 2,3-dichlorobenzaldehyde (17.5g, 0.1mol), ammonium acetate (11.6g, 0.15mol), methyl acetoacetate (17.3g, 0.15mol) to the ultrasonic reactor, set the reaction power to 500W, and react 1h. Release the reaction liquid from the ultrasonic reactor, cool to below 10°C, stir for 2 hours to precipitate crystals, filter, and wash the crystals with water three times. Then, the obtained crystals were completely dissolved in 100ml of absolute ethanol at 50-60°C, placed at room temperature for 1 hour, and then placed in a refrigerator at 0-5°C for 8 hours. Filter and dry the obtained crystals in an oven at 70-80°C for 6 hours to obtain 30.2 g of light yellow sandy crystals (Intermediate I) (content: 98.9%, yield: 81.4%).

[0035] Melting point: 186.9~187.9℃

[0036] IR (KBr, cm -1 ): 3334, 2949, 1705, 1681, 1651, 1620, 1502, 1286, 779, 733.

[0037] Utilize HPLC to carry out content determination, and determination condition is identical with embodiment 1.

Embodiment 3

[0039] Add 2,3-dichlorobenzaldehyde (17.5g, 0.1mol), ammonium acetate (23.2g, 0.30mol), methyl acetoacetate (17.3g, 0.15mol) to the ultrasonic reactor, set the reaction power to 250W, and react 2h. Release the reaction liquid from the ultrasonic reactor, cool to below 10°C, stir for 2 hours to precipitate crystals, filter, and wash the crystals with water three times. Then, the obtained crystals were completely dissolved in 100ml of absolute ethanol at 50-60°C, placed at room temperature for 1 hour, and then placed in a refrigerator at 0-5°C for 8 hours. Filter, and dry the obtained crystals in an oven at 70-80° C. for 6 hours to obtain 34.8 g of light yellow sand-like crystals (Intermediate I) (content: 98.6%, yield: 93.8%).

[0040] Melting point: 187.0~188.2℃

[0041] IR (KBr, cm -1 ): 3336, 2949, 1704, 1680, 1651, 1620, 1502, 1286, 779, 732.

[0042] The HPLC detection conditions were the same as in Example 1.

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Abstract

The invention relates to a method for preparing clevidipine butyrate and also relates to a method for preparing 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-methoxycarbonyl-3-picolinic acid methyl ester (an intermediate I) and 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-methoxycarbonyl-3-pyridine carboxylic acid (an intermediate II) which are used as intermediates of the clevidipine butyrate. The intermediate I is prepared by using 2,3-dichlorobenzaldehyde, ammonium acetate and methyl acetoacetate as raw materials and performing a reaction by using ultrasound. The intermediate II is prepared by carrying out enzyme hydrolysis on the intermediate I. When the clevidipine butyrate is prepared by using the method disclosed by the invention, ammonia water is not used as the raw material, so that no irritant gas is generated. Moreover, the cyclizative condensation is carried out by using ultrasonic waves and the hydrolysis is carried out by using carboxy lesterase, so that the reaction time can be shortened and the reaction yield is increased.

Description

technical field [0001] The present invention relates to a preparation method of clevidipine butyrate, and also relates to 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl as an intermediate of clevidipine butyrate -5-methoxycarbonyl-3-picolinic acid methyl ester and 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl- The preparation method of 3-pyridinecarboxylic acid. Background technique [0002] Clevidipine butyrate (clevidipine butyrate), the chemical name is 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid methyl (1-butyryloxy)methyl ester, the structural formula is as follows. Clevidipine butyrate is a new type of dihydropyridine calcium channel blocker for intravenous injection, mainly used for blood pressure control in hospitalized patients, including the treatment of acute hypertension, as well as heart surgery, percutaneous coronary intervention and other operations subsequent blood pressure control. Compared with many...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/90C12P17/12
Inventor 潘自国李宏岳昌林于自勋王超蒋斌
Owner ZHEJIANG JIUXU PHARMA
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