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Method for synthesizing captopril and ceptopril

A synthesis method and technology of propionyl chloride are applied in the synthesis field of captopril and acyltopril, and can solve the problems of many steps of the splitting method, low product yield and high production cost, and achieve low production cost and high reaction yield. The effect of high and three wastes is small

Inactive Publication Date: 2012-02-15
ZHEJIANG UNIV OF TECH +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Phosphorus trichloride method produces phosphorous acid, a by-product that is difficult to remove, and generally requires rectification, so the yield of the product is low and the purity is poor; the sulfur oxychloride method produces unpleasant sulfur dioxide gas, corrodes equipment, and pollutes Environment; phosgene method, the prepared product has good purity and high yield, but phosgene is a highly toxic gas, which is a fixed-point production substance, and its source is limited
And in the traditional method, 3-acetylthio-2-methylpropionyl-L-proline must be resolved to obtain optically pure acyltopril D-3-acetylthio-2-methylpropionyl -L-proline, the resolution method has many steps, and the production cost is high

Method used

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  • Method for synthesizing captopril and ceptopril
  • Method for synthesizing captopril and ceptopril
  • Method for synthesizing captopril and ceptopril

Examples

Experimental program
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Effect test

Embodiment 1

[0034]Add 200g (1.23mol) D-3-acetylthio-2-methyl-propionic acid, 110g (0.37mol) bis(trichloromethyl)carbonic acid to a 500mL three-necked flask equipped with mechanical stirring, a thermometer and a drying tube Esters and 2g (0.023mmol) N,N-dimethylacetamide, stirred and heated to 30°C for 50h, after the reaction, control the vacuum degree to 5mmHg, first remove the low boilers at 90-100°C by vacuum distillation, The fractions at 110-115°C were collected again to obtain 199.5 g of colorless liquid D-3-acetylthio-2-methyl-propionyl chloride, with a yield of 89.5% and a content detected by HPLC of 97.8%.

Embodiment 2

[0036] Add 200g (1.23mol) D-3-acetylthio-2-methyl-propionic acid, 183g (0.62mol) bis(trichloromethyl)carbonic acid to a 500mL three-necked flask equipped with mechanical stirring, a thermometer and a drying tube Ester and 0.1g (0.0014mol) N,N-dimethylformamide, stirred and heated to 60°C for 35h. After the reaction, control the vacuum degree to 5mmHg, first remove the low boilers at 90-100°C by vacuum distillation, and then collect the fraction at 110-115°C to obtain colorless liquid D-3-acetylthio-2-methyl-propane Acid chloride 188.5g, yield 84.6%, HPLC detection content 98.1%.

Embodiment 3

[0038] Add 200g (1.23mol) D-3-acetylthio-2-methyl-propionic acid, 129g (0.43mol) bis(trichloromethyl)carbonic acid to a 500mL three-necked flask equipped with mechanical stirring, a thermometer and a drying tube Ester and 9g (0.056mol) N, N-carbonyldiimidazole, stirred and heated to 70°C for 25h. After the reaction, control the vacuum degree to 5mmHg, first remove the low boilers at 90-100°C by vacuum distillation, and then collect the fraction at 110-115°C to obtain colorless liquid D-3-acetylthio-2-methyl-propane Acid chloride 193.6g, yield 86.9%, HPLC detection content 97.2%.

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Abstract

The invention discloses a method for synthesizing captopril and ceptopril. The method comprises the following steps of: reacting D-(-)-3-acetylthio-2-methylpropionic acid with bis(trichloromethyl) carbonate in the presence of a catalyst to obtain D-(-)-3-acetylthio-2-methylpropionyl chloride; dissolving L-proline in water, dripping the D-(-)-3-acetylthio-2-methylpropionyl chloride and a NaOH solution, controlling the pH to be equal to 8-9, and reacting to obtain D-(-)-3-acetylthio-2-methylpropionyl-L-proline; and adding the D-(-)-3-acetylthio-2-methylpropionyl-L-proline into a NH3.H2O solution with stirring, introducing nitrogen for protection, performing deacylation at the temperature of between 10 and 80DEG C, regulating the pH to be 2.0-2.5, keeping the temperature for 2 to 10 hours, and performing posttreatment on reaction liquid t obtain 1-[(2S)-2-methyl-3-thio-1-oxopropyl]-L-proline. Reaction conditions are mild and a period is short; in the reaction process, optical isomers are not required to be split, and the captopril product is obtained through separation directly; and the product has high optical purity, the production cost is low, and the reaction yield is high.

Description

(1) Technical field [0001] The present invention relates to a synthetic method of captopril and acyltopril, further, the present invention relates to a kind of 1-[(2S)-2-methyl-3-mercapto-1-oxopropyl] -Synthetic method of L-proline and D-3-acetylthio-2-methylpropionyl-L-proline. (2) Technical background [0002] Captopril is the first angiotensin-converting enzyme (ACE) inhibitor developed by Pepsi-Myers Squibb Company of the United States. Cardiovascular system diseases such as heart failure and myocardial infarction. Captopril is captopril, and its chemical name is 1-[(2S)-2-methyl-3-mercapto-1-oxopropyl]-L-proline, and its structural formula is as formula (I ) as shown: [0003] [0004] The traditional method of preparing captopril at present mainly uses 3-acetylthio-2-methyl-propionic acid as a raw material, and first obtains 3-acetylthio-2-methyl-propionyl chloride through chlorination, and then Condensate with L-proline to obtain 3-acetylthio-2-methylpropionyl-...

Claims

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Application Information

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IPC IPC(8): C07D207/16
Inventor 谢媛媛夏建胜夏旺施湘君苏为科
Owner ZHEJIANG UNIV OF TECH
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