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

The technology of a methacryl group and a synthetic method is applied in the field of preparation of 1--L-proline, which can solve the problems of many side reactions, long reaction time, difficulty in control, etc., achieve mild reaction conditions, short reaction time, Simple operation effect

Active Publication Date: 2014-07-09
HUAZHONG PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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

Method used

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

Examples

Experimental program
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Effect test

Embodiment 1

[0029] Adopt a 2L three-necked flask equipped with a stirring blade and a thermometer, and the reaction temperature is controlled by an oil bath, and operates as follows:

[0030] (1) Add 43.1g (0.51mol) sodium bicarbonate solid in a three-necked flask, add 392mL of water and stir to dissolve (the mass concentration of sodium bicarbonate solution is 11%), then add 135g (0.51mol) of 1-(3 -Bromo-2-D-methylpropionyl)pyrrolidine-2-carboxylic acid, reacted at room temperature for 5 minutes, and then heated to 70°C;

[0031] (2) Add 139g (0.56mol) sodium thiosulfate pentahydrate (NaS 2 o 3 .5H 2O) solid, reacted at 70° C. for 2 hours, then cooled to room temperature;

[0032] (3) 223 g (0.29 mol) of sodium sulfide solution with a mass concentration of 10% was added to the above reaction solution, and reacted at room temperature for 25 minutes;

[0033] (4) acidify the above reaction solution with hydrochloric acid to pH=2, react at room temperature for 25 minutes, and filter to ...

Embodiment 2

[0038] Reaction device, technological process are with embodiment 1. Other steps processing conditions are with embodiment 1. Only the process conditions of step (1) are adjusted to: add 43.1g (0.51mol) of sodium bicarbonate solid in a three-necked flask, add water 287mL and stir to dissolve (the mass concentration of sodium bicarbonate solution is 20%). Finally, 119.8 g (0.55 mol) of disulfide solids of 1-(3-mercapto-2-D-methylpropionyl)-L-proline were obtained, yield: 108%; 1-(3-mercapto-2 -D-methylpropionyl)-L-proline solid 88.3g (0.41mol), yield: 74%, content: 97.3%, total yield: 80%.

Embodiment 3

[0040] Reaction device, technological process are with embodiment 1. Other steps processing conditions are with embodiment 1. Only the process condition of step (2) is adjusted to: react at 80° C. for 1 hour. Finally, 120.0 g (0.55 mol) of disulfide solids of 1-(3-mercapto-2-D-methylpropionyl)-L-proline were obtained, yield: 108%; 1-(3-mercapto-2 -D-methylpropionyl)-L-proline solid 89.5g (0.41mol), yield: 75%, content: 97.5%, total yield: 81%.

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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, ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D207/16
Inventor 李海玲张晓利杨真付林徐勇高中洪
Owner HUAZHONG PHARMA
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