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Preparation method of D-3-bromine-2-methyl propionyl-L-proline

A technology of methylpropionyl and D-3-, which is applied in the field of preparation of D-3-bromo-2-methylpropionyl-L-proline, can solve the problems of high production cost, long reaction steps, and yield. Low efficiency and other problems, to achieve the effect of shortening the production cycle, simplifying the production process, and reducing production costs

Inactive Publication Date: 2012-05-16
HUAZHONG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But above-mentioned method reaction step is long, and needs to carry out the separation of optical isomers with dicyclohexylamine, and production cost height, the yield of D-3-bromo-2-methyl propionyl-L-proline (I) Lower and the purity is not high, therefore, the purity of captopril prepared by its hydrolysis is also affected

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  • Preparation method of D-3-bromine-2-methyl propionyl-L-proline
  • Preparation method of D-3-bromine-2-methyl propionyl-L-proline
  • Preparation method of D-3-bromine-2-methyl propionyl-L-proline

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Embodiment 1

[0028] Example 1 Preparation of D-3-bromo-2-methylpropionyl-L-proline (I)

[0029] Dissolve 57.5g (0.5mol) of L-proline in 200ml of water, cool to -5°C-0°C, add 20% NaOH solution dropwise under stirring conditions to adjust pH = 8.0-9.0, then add dropwise 3-bromo -2-Methylpropionyl chloride (IX) 92.7g (0.5mol), during the dropwise addition, continuously add NaOH solution to control the pH to remain at 8.0-9.0, after the dropwise addition, stir at this temperature for 0.5 hours, the reaction solution Wash 3 times with 200ml of ethyl acetate, remove the ethyl acetate layer, transfer the aqueous solution into a three-necked flask, acidify with concentrated hydrochloric acid to pH=2.0, react for 0.5 hours, let stand to separate layers, and separate to obtain the lower oil layer. Crystallize at 0°C to -5°C for 3-5 hours, then stand at -10°C for 10 hours, filter, wash the crystals with cold water, and dry at 55°C in a decompression oven to obtain D-3-bromo-2-methyl Propionyl-L-prol...

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Abstract

The invention discloses a preparation method of D-3-bromine-2-methyl propionyl-L-proline. According to the preparation method, 3-bromine-2-methyl propionyl chloride and L-proline react in water or organic solvents of ethanol, acetone and tetrahydrofuran, with a condensing agent of an alkaline substance like sodium hydroxide, to direct obtain D-3-bromine-2-methyl propionyl-L-proline. No separation of optical isomers by any reagent is needed, and dicyclohexylamine and isopropanol in a prior art are omitted, so as to substantially simplify production technology, shorten production period and reduce production cost.

Description

technical field [0001] The invention relates to a preparation method for D-3-bromo-2-methylpropionyl-L-proline. Background technique [0002] D-3-bromo-2-methylpropionyl-L-proline, which is an intermediate for the preparation of captopril, has the following structural formula: [0003] [0004] Captopril, also known as captopril, has a chemical name of (2S)-1-(3-mercapto-2-methyl-1-oxo-propyl)-L-proline, and its structural formula as follows: [0005] [0006] Captopril is mainly used to treat various essential hypertension. It has the advantages of rapid onset, stable blood pressure reduction, and outstanding long-term efficacy. It also has good therapeutic effects on heart failure, diabetes, and kidney disease. Approved by the US FDA in 1981, it has achieved significant curative effect through extensive clinical verification, and it still plays an important role in the clinical treatment of hypertension. [0007] Since captopril has the characteristics of wide cli...

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/16
Inventor 王勇付林徐勇覃文玲李林飞
Owner HUAZHONG PHARMA