CS276394B6 - Process for preparing 1-/3-mercapto-(2s)-methylpropionyl/-pyrrolidine-(2s)-carboxylic acid - Google Patents

Description

Process for the preparation of 1- (3-mercapto- (2S) -methylpropionyl) -pyrrolidine- (2S) -carboxylic acid

The present invention relates to a process for the preparation of 1- (3-mercapto- (2S) methylpropionyl) -pyrrolidine- (2S) -carboxylic acid of the formula I

(I) or a pharmaceutically acceptable salt thereof.

The compound of formula I is known under the international designation captopril and exhibits valuable antihypertensive activity.

BACKGROUND OF THE INVENTION

According to British Patent No. 1,576,161, the haloacylproline halogen atom can be replaced by a mercapto group using various reagents. The reaction is carried out using the anion R5 - wherein E is hydrogen, C1 -C4 alkyl, C1 -C4 phenylalkyl, C1 -C2 triphenyl alkyl or R @ 1. -C ¹ ~ wherein R ¹ represents an alkyl group having 1 to 4 ato0 atoms or phenyl.

Of the various anions of RS ', only those in which the sulfur atom substituent of the compound formed by the halogen atom substitution reaction, i.e. as a protective group, can be removed are suitable for the preparation of captopril. This category includes the following meanings of R: hydrogen, tertiary butyl, benzyl, triphenylmethyl (trityl) and R ¹ -C-, wherein R ¹ is as defined above.

⁰

The simplest case where R is hydrogen is not mentioned.

When R is tertiary butyl, benzyl or trityl, the reagent used will be tertiary butyl mercaptan, benzyl mercaptan, or trityl mercaptan, all of which are hazardous, carcinogenic and toxic compounds. In order to substitute a halogen atom, the carboxyl group of the proline must be temporarily protected. What's more, the yield of such a reaction is unacceptably low. For example, K. Hoannann and coworkers describe a close analogous case to benzyl mercaptan (J. Am. Chem. Soc., 71, 1253 (1949)): The 4-chlorobutyl derivative is reacted with benzyl mercaptan sodium to give S-benzyl The -4-mercaptobutyl derivative in a yield of 66 was deprotected with hydrogen at birth as produced by the action of sodium on ethanol. This results in an overall yield of 34%. Even worse results can be expected with tertiary butyl mercaptan and trityl mercaptan, since in both cases the steric hindrance is much greater. In general, such protecting groups are introduced into the molecules in the reverse fashion: the existing mercapto compounds are reacted with isobutylene or thionyl chloride (T. Greene: Protective Groups in Organic Synthesis, p. 193, 1981).

When R is a group of formula R ¹ -C-, captopril can only be prepared in very low yields.

According to one of the examples given in British Patent Specification No. 1,576,161, the analogous 1- (2-mercaptoacetyl) -proline is prepared using thiobenzoic acid in a yield of only 15% based on proline.

British Patent Specification No. 2,065,643 discloses a case where R is hydrogen: N- (3-halo- (2S) -methylpropionyl) - (S) -proline is reacted with sodium hydrogen sulfide in aqueous solution. The reaction product is formed by prolonged heating; but at the same time it arises

L.

CS 276 394 B6 2 in a molar amount of 5% of the respective disulfide. This by-product must be reduced by zinc in a separate step in the presence of an acid. Yield 71%. When sodium hydrogen sulfide is dissolved in Ν, Ν-dimethylformamide, the above yield is reduced to 65%. Practically the best result is obtained by using an aqueous solution of ammonium hydrogen sulphide, but the reaction product can only be separated from the by-products formed by column chromatography. This gives a mixture of 92% captopril, 6% disulfide and 0.5% symmetrical sulfide. This latter polluting product is irreversibly formed ie it cannot be converted to captopril. In addition, the solubility of this sulfide is close to that of captopril; therefore, they cannot be separated by a simple preparative route. These facts are confirmed in the Salt by M. Shimazaki et al. (Chem. Pharm. Bull., 30, p. 3129 (1982)). It is clear from this that the latter process is not suitable for industrial scale production.

According to U.S. Patent No. 4,332,725, a halogen atom is converted to a mercapto group by treatment with sodium thiosulfate. In this case, the so-called Bunte salt is formed first, which is heated with concentrated hydrochloric acid to give captopril in a yield of 70%.

According to German Patent Application Publication No. 35 26 023, N- (3-halo- (2S) -methyl propionyl) - (S) -proline is reacted with thiourea in water, alkanol or aqueous alkanol at a temperature of 60 to 100 ° C, to give a compound of formula IV ai®

GH (S)

WHAT

COOH (IV)

X ”in which

X represents a halogen atom.

This compound is hydrolyzed in the reaction mixture without isolation by treatment with an alkali metal hydroxide or carbonate.

However, it has proved practically impossible to reproduce this known method.

It has now been found that a compound of formula I can be prepared in an economical manner from an omega-haloacylproline of formula III

CH ₂

CH

AND

CH (S)

(III) in which:

X is a halogen atom, by reaction with thiourea in a solvent to form an isothiuronium compound of formula II

COOH (L) (li)

Or a hydrogen halide salt thereof, which is hydrolyzed, optionally after isolation, and the resulting product of formula I is optionally converted into a salt or released from the salt. According to the invention, the reaction of the compound of formula III with thiourea is carried out in an organic dipolar aprotic solvent, preferably in N, N-dimethylformamide, Ν, Ν-dimethylacetamide or dimethylsulfoxide, and the resulting isothiuronium compound of formula II or its hydrogen halide addition salt. in the presence of hydrazine.

The free carboxyl group of the compound of formula (I) may be converted into a salt with an inorganic or organic base. When the salt of the compound of formula I is obtained in the process of the invention, the free carboxylic acid can be liberated in a manner known per se.

In formula III, X is a halogen atom, preferably a bromine atom.

The reaction of a compound of formula III or a salt thereof with thiourea takes place only in an organic dipolar aprotic solvent such as Ν, Ν-dimethylformamide, N, N-dimethylacetamide or dimethylsulfoxide. Generally, the reaction is carried out at a temperature of 20 to 80 ° C, preferably 50 to 70 ° C, at atmospheric pressure. The reaction time is usually 15 to 25 hours. When acid binding agents such as an organic base are also used, the compound of formula II is obtained as a solid. In the absence of an acid binding agent, the corresponding hydrogen halide addition salt is formed. Optionally, the compound of formula (II) may be isolated prior to the next reaction step, i.e., prior to hydrolysis. As a rule, the hydrogen halide addition salt of the compound of formula II remains in solution, therefore it is usually hydrolyzed without isolation.

The isothiuronium compound of formula II or its hydrogen halide addition salt is preferably hydrolyzed in the presence of a base such as hydrazine at 0 to 30 ° C, suitably at 10 to 15 ° C, at atmospheric pressure. The resulting compound of formula (I) is isolated from the reaction mixture by a known method, for example, extraction and evaporation.

The isothiuronium compound of formula II is also obtained by hydrolysis to captopril in an almost quantitative yield. Although the latter product recrystallizes, the overall yield remains above 80%. The captopril formed is not contaminated with either the corresponding disulfide or symmetrical sulfide, so it has at least 99.5% purity (determined by iodometry).

The process according to the invention is illustrated by the following examples, but is not limited thereto.

Examples

Preparation of the starting compound, i.e. 1- (3-bromo- (2S) -methylpropionyl) -pyrrolidine- (2S) -carboxylic acid monohydrate

3.34 g (0.02 mol) of 3-bromo-2-methylpropionic acid and 4.60 g (0.02 mol) of pyrrolidine- (2S) -carboxylic acid benzyl ester hydrochloride are dissolved in 50 ml of anhydrous

J methylene chloride. At 0 ° C, with stirring and cooling, 1.9 g of triethylamine in 5 ml of anhydrous methylene chloride are added, followed by the addition of 3.92 g (0.019 mol) of N, N-dicyclohexylcarbodiimide in 20 ml of methylene chloride at the same temperature. The reaction mixture was then stirred at 0 ° C for 2 hours, then at room temperature for a further 12 hours. After filtering the reaction. The mixture is extracted with 20 ml of 9% hydrochloric acid, 20 ml of water, 20 ml of 5% aqueous sodium bicarbonate solution and then 20 ml of water. The resulting organic solution was dried (MgSO 4) and evaporated. 6.40 g (95% yield) of 1- (3-bromo-2-methylpropionyl) -pyrrolidine- (2S) -carboxylic acid benzyl ester are obtained as a pale yellow oil.

TLC on silica gel (eluent = benzene / glacial acetic acid 3 L): two spots _Q R R = 0.44 and 0.48, corresponding to a 1: 1 diastereomer ratio. ·

The oil obtained is dissolved in 60 ml of ethyl acetate, 0.6 g of catalyst (10% palladium on charcoal) is added and the reaction mixture is hydrogenated at atmospheric pressure until the ester is no longer present, as determined by chromatographic analysis.

C3 276 394 Ββ on thin film. Then, the catalyst is filtered off, washed with ethyl acetate, the organic solvent is distilled off and the residue is recrystallized from water. This afforded 2.00 g (42.5% yield) of the title compound, m.p. 69-72 ° C.

-88.1 ⁰ (c = 1, ethanol)

Example 1

1- (3-mercapto- (2S) -methylpropionyl) -pyx ^, rolidine- (2S) -carboxylic acid

10.56 g (0.0374 mol) of 1- [3-bromo- (2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid and 3.04 g (0.040 mol) of thiourea were dissolved in 30 ml of KN-dimethyl acetamide and the reaction mixture was stirred at 60 ° C under nitrogen for 5 to 20 hours. The organic solvent was distilled off under reduced pressure, and the residue was dissolved in 50 ml of distilled water. 6.00 g (0.12 mol) of hydrazine hydrate was added to the resulting solution under nitrogen atmosphere while cooling the flask contents with ice water. The reaction mixture was then stirred with cooling for 30 minutes and then for an additional 30 minutes at room temperature. 100 ml of 5% sulfuric acid are then added, the white precipitate formed is filtered off and washed first with water, then with methylene chloride. The filtrate is extracted four times with 30 ml of methylene chloride each time, the organic solutions are combined, washed twice with 20 ml of water each time, and the aqueous phase is extracted twice with 15 ml of methylene chloride each time, the organic phases are combined, dried with magnesium sulphate, filtered and evaporated under reduced pressure. 7.54 g (99% yield) of an oil remained, which was recrystallized from 25 ml of trichlorethylene. 6.10 g (yield 80%) of the title compound of melting point 104 DEG-106 DEG C. are obtained.

/ OC / ²⁵ = -129.5 ⁰ (c = 2, ethanol)

Example 2

1- (3-mercapto- (2S) -methylpropxonyl) -pyrrolidine- (2S) -carboxylic acid

2.64 g (0.010 mol) of 1- [3-bromo- (2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid and 0.76 g (0.010 mol) of thiourea were dissolved in 10 ml of dimethylsulfoxide. The resulting solution was stirred at 60-70 ° C for 24 hours, then 30 mL of 10% aqueous sodium hydroxide solution was added and the resulting mixture was stirred for an additional hour. The reaction mixture is then acidified with 20% hydrochloric acid under cooling to pH 1, then extracted four times with 20 ml of methylene chloride each time. The organic solutions were combined, dried (MgSO4) and evaporated under reduced pressure. The oily residue was crystallized from trichlorethylene.

1.64 g (81% yield) of the title compound of melting point 104 DEG-106 DEG C. are obtained. [α] ²⁵ = -129.5 ⁰ (c = 2, ethanol)

Example 3

1- (3-mercapto- (2S) -methylpropionyl) -pyrrolidine- (2S) -carboxylic acid

5.28 g of 1- (3-bromo- (2S) -methylpropionyl) -pyrrolidine- (2S) -carboxylic acid (0.02 mol) and 1.67 g (0.022 mol) of thiourea are dissolved in 15 ml of N, Of N-dimethylformamide and the resulting mixture was stirred at 60 ° C for 24 hours. Then the solvent was distilled off under reduced pressure and the residue was dissolved in 30 ml of distilled water. 6.0 g of 50% hydrazine were added to the resulting solution under ice-water cooling, and the reaction mixture was stirred under ice-water cooling for 1 hour. 50 ml of 5% sulfuric acid are then added, and the precipitate formed is filtered off, washed with water and methylene chloride. 10 g of sodium chloride are added to the aqueous phase and the aqueous phase is extracted four times with 30 ml of methylene chloride each time. The organic solutions were combined, dried over magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure. The oily residue was crystallized from 20 ml of trichlorethylene to give 3.33 g (yield 82%) of the title compound, m.p. 104-106 ° C.

[.Alpha.] D @ 25 = -129.5 DEG (c = 2, ethanol)

Example 4

A. 1 - [(2S) -methyl-3-isothiuroniumpropionyl] -pyrrolidine (2S) -carboxylate

OS 276,394 B6

5.64 g (0.02 mole) of 1- (3-bromo- (2S) -methylpropionyl) -pyrrolidine- (2S) -carboxylic acid monohydrate are dissolved in 50 ml of methylene chloride and the resulting solution is stirred with 5 g for 1 hour. magnesium sulfate. After the magnesium sulfate was filtered off, washed with 10 ml of methylene chloride, the organic solutions were combined and evaporated under reduced pressure. The residue was dissolved in 15 ml of anhydrous Ν, Ν-dimethylacetamide, 1.52 g (0.02 mol) of thiourea were added thereto, and the mixture was stirred in a 70 ° C oil bath for 24 hours under nitrogen. The reaction mixture was then cooled with ice water and diluted with 150 ml of acetonitrile. A solution of 2.8 ml (0.02 mole) of triethylamine in 20 ml of acetonitrile was added dropwise to the mixture under vigorous stirring over 30-40 minutes. The reaction mixture is stirred for a further two hours, the precipitate formed is filtered off, suspended in 20 ml of acetonitrile, filtered, resuspended in 20 ml of acetonitrile, filtered and dried. 4.2 g (yield 81%) of the title compound of melting point 187-189 ° C are obtained.

/ ix / p ³ = -107 to -111 ⁰ (c = 1, acetic acid)

Chromatographic analysis by thin layer chromatography (eluent = mixture of 6 parts of pyridine: water: glacial acetic acid 20: 11: 6 and 4 parts of ethyl acetate): K _f = 0,41j (eluent = mixture of butanol, glacial acetic acid and water 7: 1: 3):

E _f = 0.2.

B. 1- (3-Mercapto- (2S) -methyl-propionyl) -pyrrolidine- (2S) -carboxylic acid (0.02 mol) 50% hydrazine was added dropwise to a solution of 2.59 under cooling with ice water and stirring. g (0.01 mol) of 1- [(2S) -methyl-3-isothiuroniumpropionyl] -pyrrolidine (2S) -carboxylate in 25 ml of water. The reaction mixture was stirred with cooling for an additional 30 minutes, then the cooling bath was removed and stirring continued for another 30 minutes. The reaction mixture was recooled to below 10 ° C and a mixture of 2 mL of concentrated hydrochloric acid with 2 mL of water was added. The reaction mixture is stirred for 30 minutes, then 6-10 g of sodium chloride are added and the product is extracted three times with 20 ml of methylene chloride each time. The organic solutions were combined, washed with 15 ml of water, and the aqueous phase was extracted with 5 ml of methylene chloride. The organic phases were combined, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue, 2.03 g of an oily liquid, was crystallized from 10 ml of trichlorethylene. This gives 1.62 g (yield 80%) of the title compound, m.p. 103-104 ° C.

/ c £ / ⁹ = -129 to -130 ° (c = 2, ethanol)

Claims (1)

A process for the preparation of 1- (3-mercapto- (2S) -methylpropionyl) -pyrrolidine- (2S) -carboxylic acid of formula I (I) or a pharmaceutically acceptable salt thereof by reacting an omega-haloacylproline of formula III CS 276 394-6 (III), CHI ο CH ₂ CH-CO (S) COOH N (S) in which X is halogen, with thiourea in a solvent and hydrolysis of the obtained isothiuronium compound of formula II H ₉ N COOH HN (1D) characterized in that the reaction of the compound of formula III with thiourea is carried out in an organic dipolar aprotic solvent, preferably in Ν, Ν-dimethyl formamide, N, N-dimethylacetamide or dimethylsulfoxide, and the resulting isothiuronium compound of formula II or its addition the hydrogen halide salt is hydrolyzed in the presence of hydrazine.