Synthetic method of 1-(3-mercapto-2-D-methyl propionyl)-L-proline

Abstract

The invention provides a synthetic method of 1-(3-mercapto-2-D-methyl propionyl)-L-proline which comprises the following process steps: a. allowing 1-(3-bromo-2-D-methyl propionyl)pyrrolidine-2-carboxylic acid to react with a sodium bicarbonate solution to obtain 1-(3-bromo-2-D-methyl propionyl)pyrrolidine-2-sodium carboxylate; b. allowing 1-(3-bromo-2-D-methyl propionyl)pyrrolidine-2-sodium carboxylate to react with sodium hyposulfite to synthesize Bunte salt; c. allowing the Bunte salt to react with a sodium sulfide solution, performing acidification and filtration to directly obtain a disulphide solid of 1-(3-mercapto-2-D-methyl propionyl)-L-proline; d. reducing the disulphide solid with zinc powder in a sulfuric acid solution, performing extraction and recrystallization to obtain the disulphide 1-(3-mercapto-2-D-methyl propionyl)-L-proline product. The invention overcomes the disadvantage of low yield of original process, and is suitable for industrial production.

Description

technical field [0001] The invention relates to a method for synthesizing chemical drugs, in particular to a method for preparing 1-(3-mercapto-2-D-methylpropionyl)-L-proline. Background technique [0002] 1-(3-mercapto-2-D-methylpropionyl)-L-proline (common name: captopril) is the first one developed according to the structural characteristics of angiotensin-converting enzyme (ACE) Orally effective inhibitory antihypertensive drugs. Pharmacological studies have confirmed that this compound not only has high inhibitory enzyme activity in vitro, but also has good pharmacokinetic properties. It is a new type of antihypertensive drug with a unique mechanism of action. It was first introduced in Germany in 1980 listed. The successful research and development of 1-(3-mercapto-2-D-methylpropionyl)-L-proline has greatly promoted the development of non-peptide angiotensin-converting enzyme inhibitors, enalapril, Alapril, cilazapril, ramipril and other new drugs are on the market, ...

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Problems solved by technology

There is only the report of relevant documents, such as Zhao Ruodong reported the method for synthesizing thioglycolic acid by Bunte salt method [referring to 1. Zhao Ruodong. Bunte salt method to prepare thioglycolic acid experimental synthesis new method. Journal of Lanzhou Petrochemical Vocational and Technical College, 2006, 1], but this Method for synthesizing 1-(3-mercapto-2-D-methylpropionyl)-L-proline has many side reactions, is difficult to control, and the yield is low; The obtained acetyl captopril dicyclohexylamine salt is oxidized to the disulfide of captopril [see 2. Liu Renyong, Chen Yubin. A new method for the preparation of captopril. Journal of Shenyang Pharmaceutical University, 1999, 2 ], and then reduce it to obtain 1-(3-mercapto-2-D-methylpropionyl)-L-proline, but the reaction time of this method is long (9 hours), and the yield is low (68.5%); For example, Liu Renyong, Li Huiqin, etc. reported the preparation of 1-(3-mercapto-2-D-methylpropionyl)-L-proline using sodium trithiocarbonate [see 3. Liu Renyong, Li Huiqin, Liu Chunqing, Fu Jun. Improvement of captopril synthesis method. Journal of Shenyang Pharmaceutical University, 1997, 4], but the yield is only 65.9%

[0005] The method for synthesizing 1-(3-mercapto-2-D-methylpropionyl)-L-proline in the existing technology has a yield lower than 70%, which is unfavorable for improving the competitiveness of the drug in the market

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