CS226950B1 - Method of preparing 1-(d-3-mercapto-2-methylpropionyl)-l-proline - Google Patents

Description

The invention relates to a process for the preparation of 1- (D-3-mercapto-2-methylpropionyl) -L-proline of the formula I ch ₃

HS-CH _of CHCCh

COOH (I)

The compound of formula I is known in the literature under the generic name captopril and is used clinically in the treatment of various forms of hypertension. The mechanism of its antihypertensive action is explained by its inhibitory effect on the enzyme that converts angiotensin I into a potent vasoconstrictor angiotensin II.

The synthesis of the compound of formula I has been described by D. W. Cushman et al. in Biochemistry 16, 5484, 1977. It starts from tert-butyl L-proline ester, which is acylated with 3-acetylthio-2-methylpropionic acid in dichloromethane in the presence of N, N'-dicyclohexylcarbodiimide, and the product removes tert-butyl by reaction with anisole. and trifluoroacetic acid. Obtained mixture of diastereoisomeric 1- (DL-3-acetylthio-2-methylpropionyl) 2

The L-proline is separated by crystallization of the dicyclohexylammonium salts and the isolated desired isomer is removed by treatment with methanolic ammonia solution. The compound of formula (I) thus obtained is purified by crystallization of its dicyclohexylammonium salt from which it is liberated by treatment with potassium hydrogen sulphate in a mixture of water and ethyl acetate.

This lengthy and demanding process for the preparation of the compound of formula I is also described in German Patent Application Publication No. 2 703 828. Other possibilities for the preparation of the compound of formula I, for example the reaction of 1- (3-halo- 2-methylpropionyl) -proline with compounds containing a mercapto group substituted with various leaving groups in the molecule.

The use of 1- (3-halo-2-methylpropionyl) -L-proline for the synthesis of the compound of formula I is the essence of the Czechoslovak patent No. 219 935. This application describes the preparation of 1- (D-3-bromo-2-methylpropionyl) -L-proline by acylating L-proline with 3-bromo-2-methylpropionyl chloride and converting it to the compound of formula I by reaction with sodium thiosulfate or trithiocarbonate and acid hydrolysis of non-isolated products.

A process for the preparation of a compound of formula I according to 226950

228350 of the finding consists in the first step in the reaction of the above-mentioned 1- (D-3-bromo-2-methylpropionyl) -L-proline, respectively. its sodium salts with readily available potassium O-ethyldithiocarbonate in an aqueous medium. The reaction proceeds at room temperature and is complete in 16 h. The product, 1- (D-3-ethoxythiocarbonylthio-2-methylpropionyl) -L-proline of formula II ^C 2 H -1 _with 0. CS. 5-CH ₂ CHCO ₃

COOH (K) is obtained by acidification and aspiration or purified by dissolution in aqueous sodium carbonate solution, filtration of the activated carbon solution and acidification of the filtrate. Thus, a sufficiently pure crystalline product of formula II is obtained in a yield of up to 90% of theory. The intermediate of formula II is then converted to the compound of formula I by treatment with ammonia in aqueous methanol or ethanol at room temperature. The reaction is complete in 24 h. The compound of formula I is then isolated by acidifying the reaction mixture, shaking it into ethyl acetate and, after distilling off the solvent, by crystallization from a mixture of ethyl acetate and hexane. The pure compound of formula I is obtained in a yield of up to 80% of theory.

The advantages of the process according to the invention for the preparation of a compound of the formula I according to the invention are that it is simple to carry out and a good purity of the compound of the formula I thus produced, favorably influenced by converting the pure, crystalline intermediate of formula II .

Details of the preparation process according to the invention are given in the following examples.

Example 1

1- (D-3-Ethoxythiocarbonylthio-2-methylpropionyl) -L-proline

-bromo-2-methylpropionyl) -L'proline and 11 g of sodium carbonate in 100 ml of water are added with stirring a solution of 38 g of potassium O-ethyldithiocarbonate in 80 ml of water and the mixture is left to stand for 16 h at room temperature. It is acidified with 10% hydrochloric acid to precipitate the product in oily or crystalline form and heated at 70 ° C for 40 minutes. After cooling, the precipitated crystalline product is dissolved by alkalization to pH 8-9 by adding 10% sodium carbonate solution with stirring. The resulting yellow solution was filtered with charcoal and acidified to pH with hydrochloric acid

2. The precipitated product is filtered off with suction, washed with water and dried. There was obtained 49.2 g (86.1% of theory) of 1- (D-3-ethoxythiocarbonylthio-2-methylpropiomyl) -L-proline having a melting point of 60-64 [deg.] C. which was sufficiently pure for the next step of the synthesis. ethanol and dried under reduced pressure (13.3 Pa) for 8 h at 53 ° C changes the crystal modification and melts at 79-80 ° C, ( _a ) _{D 2} = -175.3 ° (c = 1, ethanol Example 2

1- (D-3-Mercapto-2-methylpropionyl) -L-proline 1- (D-3-ethoxythiocarbonylthio-2-methylpropionyl) -L-proline is dissolved in 50 ml of ethanol and 90 ml of 25% aq. ammonia. The mixture is allowed to stand at room temperature for 24 h, concentrated on a evaporator under reduced pressure to a volume of about 60 ml and, after dilution by addition of 60 ml of water, is shaken twice with ether. The separated aqueous solution was acidified to pH 2 with hydrochloric acid and the resulting oily product was taken up in ethyl acetate. The ethyl acetate solution was washed with saturated brine, dried over anhydrous magnesium sulfate, and ethyl acetate was distilled off under reduced pressure. The crystalline product is obtained by dissolving the residue in ethyl acetate and adding hexane. There were obtained 27.5 g (78.7% of theory) of l- (D-3-mercapto-2-methyl-propionyl) -L-proline with mp 103-105 ° C ( «) _D ²⁰ ₌ -130.7 ° ( c = 1, ethanol).

To a solution of 52.8 g of 1- (D-3-) monohydrate

Claims (1)

A process for the preparation of 1- (D-3-mercapto-2-methylpropyl) -L-proline of formula I CH ₃ HS-CH _of CHCO-N. COOH II) _S O ^C ZH »C ^S. s-ch ₂ CHCO-1 ( COOH (11) characterized in that 1- (D-3-bromo-2-methylpropionyl) -1-proline by reaction of potassium O-ethyldithiocarbonate in aqueous solution is converted to crystalline 1- (D-3-ethoxythiakartoonylthio-2-methylprapionyl) - The compound of formula II wherein the ethoxythiocarbonyl group is removed by treatment with ammonia in an aqueous C 1 -C 3 alkanol, preferably methanol or ethanol.