SU1165233A3 - Method of obtaining n-/(2s)mercapto-2-methylpropionyl/-l-proline - Google Patents

Abstract

METHOD OF IMPROVEMENT OF N-

Description

The invention relates to the production of H 28) -3-mercapto-2-methyl-propioniamine-proline, which is one of the broad-spectrum antihypertensive drugs.

The purpose of the invention is to simplify the process.

Example 1. 1 mmol of (2S)-3-acetyl trimethylpropyl ionic acid in 5 ml of anhydrous ethyl acetate is treated with 1 mmol of chlordiphenylphosinate (prepared from chlordiphenylphosinate by air oxidation) in the presence of 1 mol of N-methyl morpholine. The solution is stirred for two hours at ambient temperature, after which a solution of 1 mmol of L-proline trimethylsilyl ester and 1 mmol of N-methylmorpholine in 5 ml of anhydrous ethyl acetate is added.

The solution is maintained at ambient temperature for four hours with stirring, then treated with water and stirring is continued for half an hour. The organic layer is separated and the aqueous layer is extracted several times with ethyl acetate. The organic extracts are washed with a small amount of water saturated with sodium chloride, dried and evaporated to dryness.

The resulting N-(2S)-3-acetyl-2-methyl-propionyl-1-L-proline is hydrolyzed with an aqueous solution of acetic acid at ambient temperature. If the hydrolysis is carried out with aqueous solutions of sodium carbonate or aqueous solutions of organic bases at ambient temperature, the same result is achieved.

The resulting solution after hydrolysis is percolated through acid resin to remove cations. The fractions containing 1"aa and N-t(2S)-3-mercapto-2-methyl-propionyl-L-proline are combined and evaporated in vacuo, the residue is crystallized from a mixture of ethyl acetate and hexane. M.p. of the product is 103-104 C and -131.

Example 2.1 1 mmol of (2S)-3-methoxydithiocarbonyl-1-2-methyl propionic acid in 8 ml of anhydrous CH2Cl is treated with 1 mmol of chlorodiphenylphosphite in the presence of 2 mmol of triethylamine.

After stirring for two hours at ambient temperature, a solution of 1 mmol of L-proline trimethylsilyl ester in 10 ml is added. The proline ester is obtained directly in solution without isolation from 1 mmol of L-proline suspended in 10 ml of CH3CN and treated with 1 mmol of (CH3)3S1Cl and 1 mmol of tributylamine or from 1 mmol of L-proline and 1 mmol of hexamethylsilylamine in the same solvent.

The reaction mixture containing the diphenylphosphinite derivative of (28)-3-methoxydithiocarbonyl-2-methylpropionic acid and the trimethylsilyl ester of L-proline is maintained for four hours at ambient temperature and with stirring.

After this, the mixture is evaporated in a vacuum, the residue is dissolved in ammonium hydroxide and stirred for three hours, after which the solution is poured from above into a column with a basic resin (quaternary ammonium).

The column is washed with thiourea and then eluted with formic acid diluted with water. The fractions containing the N-(28)-3-mercapto-2-methyl-propionyl-L-proline product are combined and evaporated to dryness in vacuo.

Crystallization from an ethyl acetate-hexane mixture yields pure N-(2S)-3-mercapto-2-methylproponyl-L-proline.

Example 3. 1 mmol of (2S)-3-acetylthio-2-methylpropionic acid in 5 ml of anhydrous CH3Cl3 is treated with 1. mmol of thionyl chloride SOCl3 and then 1 mmol of N-methylpiperidine is added to the solution. The solution is stirred for 2 h at room temperature, after which a solution of 1 mmol of L-proline trimethylsilyl ester and 1 mmol of N-methylpiperidine in 5 ml of anhydrous methyl isobutyl ketone is added.

The B14 solution is left at room temperature for 4 hours with stirring. It is then treated with water; stirring is continued for 30 minutes.

The organic layer is separated and the aqueous layer is extracted several times with methyl isobutyl ketone. The organic extracts are washed with a small amount of water saturated with sodium chloride, dried and evaporated to dryness. The resulting N-(2S)-3-acetylthio-2-methylpropionyl-L-proline is hydrolyzed with aqueous ammonia at room temperature. The solution obtained after hydrolysis is filtered through acid resin to remove cations. The fractions containing N-(2S)-3-mercapto-2-methylpropionyl-L-proline are collected together and evaporated in vacuo, and then the resulting residue is crystallized from a mixture of ethyl acetate and hexane. M.p. -(«stVi)« -131. Yield 80%. Example 4. 1 mmol of (2S)-3-methoxydimethylcarbonyl p-2-methylpropionic acid in 8 ml of anhydrous CH2Cl2 is treated with 1 mmol of thionyl chloride, then 1 mmol of N-methylmorpholine is added to the solution. After stirring at room temperature for two hours, a solution of 1 mmol of the trimethylsilyl ester of L-proline and 1 mmol of N-methylmorpholine in 10 ml of CH2CN is added. The reaction mixture is kept for four hours at room temperature with stirring. The solvent mixture is then evaporated in vacuo, the residue is dissolved in ammonium hydroxide and stirring is continued for three hours, after which the solution is poured onto the top of a column of basic (quaternary ammonium) resin. The column is flushed with water, then eluted with formic acid diluted with water (containing N-)-3-mercapto-2-methylpropionyl-1-proline, collected together and evaporated to dryness in vacuo. The residue after crystallization in an ethyl acetate-hexane mixture gives pure N-(28)-3-mercapto-2-methylpropionyl-1-proline in 76% yield.

Claims (1)

A METHOD FOR PRODUCING N-[(2S)-3-MERCAPTO-2-METHYL-PROPIONYL]-L-PROLINE by reacting the ester of L-proline with 3-substituted-2-methylpropionic acid, followed by removal of the protective groups by hydrolysis, characterized in that, in order to simplify the process, the trimethylsilyl ester. L-proline is reacted with a derivative of (2S)-3-mercapto-2-methylpropionic acid of the general formula CH3 (2S) _-CH2 - CH-COX, SR where X is a halogen or diphenylphosphine group; R-r'-C or R—0—C, and a -.1 where R is methyl, ethyl, in the presence of a tertiary organic base followed by removal of protective groups by hydrolysis in an aqueous medium at ambient temperature. 0E SP ye SO so 1 1165233