CS262693B2 - Process for preparing 1-/3-brom-/2s/-methylpropionyl/pyrrolidin-/2s/-carboxylic acid - Google Patents

Description

A process for the preparation of 1- [3-bromo- (2S) -methyl-propionyl] -pyrrolidine- (2S) -carboxylic acid of formula I and its monohydrate is characterized in that the salt of formula III is reacted in an inert solvent with a condensing agent to form benzyl-1. [3-bromo- (2S) -methyl-propionyl] -pyrrolidine- (2S) -carboxylate of formula II which is debenzylated by catalytic hydrogenation to give the product of formula I, which is optionally converted to the monohydrate by recrystallization from water. The compound of formula I and its monohydrate are (useful for making a valuable antihypertensive agent known as captopril).

The present invention relates to a process for the preparation of 1- [3-bromo- (2S) -methyl-propionyl] -pyrrolidine- (2S) -carboxylic acid of the formula I

(I) and its monohydrate.

The compound of the above formula I and its monohydrate are useful as intermediates for the synthesis of 1- [3-mercapto- (2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid, a compound possessing valuable antihypertensive activity known as "captopril" .

Several methods for the preparation of a compound of formula I are known, but each of these known methods consists of two reaction steps.

Thus, according to Hungarian Patent Specification 185 576, 3-bromo- (2R, S) -methylpropionic acid is first converted to the acid chloride, which is then reacted with (S) -proline under Schotten-Baumann acylation conditions to yield the desired product in yield. only 15 ° / o. This reaction product consists of a mixture of equal parts of 1- [3-bromo- (2S) -methyl-propionyl] -pyrrolidine- (2S) -carboxylic acid with 1- [3-bromo- (2R) -methyl-propionyl] -pyrrolidine- (2S) - carboxylic acids. A further disadvantage of this highly uneconomical process lies in the difficult preparation of the acid chloride, since the chloride is volatile and can only be separated from the excess of thionyl chloride with great difficulty.

According to the process described in British Patent Specification 2,066,252, racemic 3-bromo-2-methylpropionic acid is converted to the acid chloride, which is then reacted again with (S-proline) under Schotten-Baumann acylation conditions. Hungarian Patent Specification No. 185,576 and the process described in British Patent Specification No. 2,066,252 (526) consist of a process for treating the reaction mixture, since the reaction product is not extracted into an organic solvent but precipitated under cooling with water. In this way a yield of up to 40% is achieved, but this means, however, that only 40% (Sj-proline) has been used. The remaining part (SJ-proline, by conversion to the second diastereomer can only be recovered with great difficulty.

According to the process described in Hungarian Patent Specification No. 186,605, (S) -proline is acylated with an acid chloride prepared in a separate reaction step by reacting 3-bromo- (2S) -methylpropionic acid with thionyl chloride.

According to a further process, (S) -proline trimethylsilyl ester is acylated with 3-bromo- (2S) -methylpropionyl chloride.

In summary, none of the known methods has avoided the use of thionyl chloride and the associated environmental problems.

The object of the present invention is to overcome the disadvantages of the known processes and to provide an economical industrial process for the preparation of the compound of formula I.

It has been found that the above object is achieved by implementing the method of the invention.

In accordance with the invention, the salt of formula III is used

(lil)

reacted with a condensing agent in an inert organic solvent to form the benzyl 1- (3-bromo- (2S) -methyl-propionyl) -pyrrolidine (2S) -carboxylate of formula II

on activated carbon. Catalytic hydrogenation yields the product of formula L in virtually quintine. 26693 is debenzylated by catalytic hydrogenation to produce the product of formula Ί, which is then optionally recrystallized from water to give the monohydrate.

The starting material of formula III is prepared by simply mixing 3-bromo- (2S) -methylpropionic acid and (S) -proline benzyl ester in an inert organic solvent. (S) -proline benzyl ester is commercially available as the corresponding hydrochloride from which it can be liberated by treatment with a base such as triethylamine.

3-Bromo- (2S) -methylpropionic acid can be prepared by resolution of racemic 3-bromo- (2R, S) -methylpropionic acid.

The racemic compound may be prepared according to literature procedures [Cesk. Farm., 24, 112 (1975)]. The racemic compound is resolved with a stoichiometric amount of (R :) -3- (N -dimethoxyphenyl) -2-methyl-4-aminopropionitrile, a by-product of α-methyldopa synthesis. The cleavage is carried out in an inert organic solvent, preferably 1,2-dichloroethane, at room temperature. The precipitated crystalline diastereomeric salt is reacted with dilute mineral acid to liberate the cleaved product which is isolated by extraction and evaporation of the solvent in a total yield of 40%. The 3-bromo- (2S) -methylpropionic acid thus obtained contains 0-25% (2R) -enantiomers as a possible impurity.

The reaction of the starting material of formula III with a condensing agent is carried out in an inert organic solvent, for example an aromatic hydrocarbon such as benzene or toluene, a chlorinated aromatic hydrocarbon such as chlorobenzene, a chlorinated aliphatic hydrocarbon such as dichloromethane or an ester such as in ethyl acetate. The preferred solvent is dichloromethane.

The coupling agent is a compound capable of dehydrating the starting material of formula III. Preferred condensing agents for the process of the invention are carbodiimides, preferably N, N‘-dicyclohexylcarbodiimide, which is generally used in stoichiometric amounts.

The reaction of the compound of formula III and the condensing agent is usually carried out at a temperature of 0 to 20 ° C. Since the release of water from the compound of formula III is generally an exothermic reaction, the reaction mixture is cooled to about 0 43 at the start of the reaction.

Dehydration of the starting material of formula III results in the formation of benzyl 1- [3-bromo- (2S) -methylpropionyl] -pyrrolidine (2S) -carboxylate of formula II containing 0 to 25% benzyl-1- [3-bromo- (2R) methylpropionyl] pyrrolidine (2S) -carboxylate impurity.

The compound of formula II is debenzylated by catalytic hydrogenation in an inert organic solvent, preferably ethyl acetate, usually at atmospheric pressure and at ¹ room temperature. The catalyst used is, for example, a platinum group metal, preferably palladium, in active form, i.e. on a support, as a native yield.

The reaction mixture after hydrogenation is filtered and the solvent is distilled off to isolate the compound of formula (I). When the latter product is recrystallized from water, its monohydrate is obtained, while all the possible 1- [S-bromo-R] -N-methylpropionylpyrrolidine-2S) -carboxylic acid is present in the mother's desire.

According to the process of the invention, the compound of the formula I is obtained in the desired optical purity in a yield of 70% (based on benzyl ester) of proline. The process according to the invention can also be carried out on an industrial scale without any difficulties. From an environmental point of view, it is significant that no thionyl chloride is required for the synthesis described above.

The invention is illustrated in more detail by the following non-limiting examples.

Preparation of 3-bromo-'(S) -methylpropionic acid kg of racemic Z-отгот-2-methylpropionic acid is dissolved in 0/8 m ^{3 of} 1,2-dichloroethane and 120 kg (20 ° C) are added to the solution at 20 ° C. ] -3- (3 ^4, 4 ^ς -Α1ιηβthoxyf phenyl) -2-m ethyl-2-aminopropyl OPI onttrilu. the volume was adjusted with 1,2-dichloroethane to 1.35 m ³ solution was added over 2-2, Cooled from 20 ° C to 10 ° C for 5 hours and stirred for an additional hour The precipitated diastereomeric salt was filtered off and washed at 10 ° C with 30 liters of 1,2-dichloroethane The white crystalline product was suspended in 0.8 m ^{3 of} water and adjusting the pH of the slurry * while maintaining the temperature below 20 [deg.] C. with concentrated hydrochloric acid ^to 0-5. The aqueous phase is extracted four times with T00 dm ^{3 of} 1,2-dichloroethane each, the organic phases are combined, dried and spun off. Upon distillation at a pressure of 1 bar, the title compound becomes a colorless liquid at boiling 80 ^° C / 0.1 MPa and optical rotation [α] d ²⁵ = -6.7 ^° (c-11, 1,2-dichloroethane).

The optical purity of the product was ascertained by ^X H-NMR in deuterochloroform using Eu (hfc) 3 as a reagent. At a reagent / substrate ratio of 0.616, methyl doublets can be well separated. Integration indicates a ratio of 75: 25 enantiomers so that the optical purity of the (S) -enantiomer corresponds to a 50% excess of enantiomers. Yield 40%.

He did

AND.

Benzyl 1- [3-bromo- (2S) -methyl-propionyil] -pyrrolidine (2S) -carboxylate

3.34 g (0.02 mol) of 3-bromo- (2S) -methyl-7-propionic acid and 4.6 g (0.02 mol) of (S) -propyl benzyl ester hydrochloride are dissolved in 50 ml of anhydrous dichloromethane, After cooling, a solution of 1.9 g of triethylamine in 5 ml of anhydrous dichloromethane was added thereto with stirring. In this way, a solution of [benzylpyrrolidine (2S) -carboxylate] -3-bromo- (2S) -methylpropionate is obtained, to which a solution of 4.12 g (20 mmol) of N, N'-dicyclohexylcarbodiimide is added at 0 ° C. in 20 ml of anhydrous dichloromethane. The reaction mixture is stirred at 0 ° C for 2 hours and then at room temperature for a further 12 hours, then filtered and the filtrate is extracted successively with 20 ml of 9% hydrochloric acid, 20 ml of water, 20 ml of 5% aqueous sodium bicarbonate and 20 ml water. The organic phase was dried over anhydrous magnesium sulfate and the solvent was evaporated. This afforded 6.4 g (95%) of the title compound as a pale yellow oil.

When thin-layer chromatography in the system benzene - glacial acetic acid (3: 1) gives the product of the two spots, _Rf 0.44, respectively. 0.48. The latter spot corresponds to the title compound, while the former corresponds to benzyl 1- [3-bromo- (2R) -methylpropionyl] pyrrolidine (2S) -carboxylate. By determining the ^X H-NMR, the ratio of the enantiomers of 75: 25. The product had an optical rotation [#] ²⁵ _D = -74 ° (c = 3, dichloromethane).

B.

1- [3-Bromo- (2S) -methyl-propionyl] -pyrrolidine- (2S) -carboxylic acid monohydrate

6.0 g (17 mmol) of benzyl 1- [3-bromo- (2S) -methylpropionyl] -pyrrolidine (2S) -carboxylate, prepared as described above, are dissolved in 60 ml of ethyl acetate, to which 0 ml is added. 1.6 g of 10% palladium on carbon catalyst and the mixture was treated with hydrogen at room temperature and atmospheric pressure. The completion of the reduction was monitored by thin layer chromatography. The catalyst is filtered off, washed with ethyl acetate and the organic phase is evaporated. 4.25 g (95%) of a residue is obtained, which, after recrystallization from water, gives 3.2 g of the title compound. Taking into account the optical purity of the starting material, the yield is 95%. The use of (S) -proline benzyl ester is up to 70%.

[α] _D ²⁵ = -88.1 ° (c = 1; ethanol).

Example 2

Benzyl 1- [3-bromo- (2S) -methyl-propionyl] -pyrrolidine- (2S) -carboxylate

6.68 g (40 mmol) of 3-bromo-4 (2S) -methylpropionic acid and 8.28 g (40 mmol) of (S) -proline benzyl ester are dissolved in 40 ml of anhydrous dichloromethane to give a salt solution of the above formula III . To this solution, cooled to 0 ° C, was added at 0 ° C 8.25 g (40 millimoils) of N, N'-dicyclohexylcarbodiimide in 20 ml of anhydrous dichloromethane. The resulting solution was then stirred at this temperature for ⁵ more 1.5 hours. The precipitated N, N'-dicyclohexylurea is filtered off and the filtrate is extracted successively with 2 x 15 ml of 1N hydrochloric acid, 15 ml of water, twice with 15 ml of 1N sodium hydroxide each and 15 ml of water. The organic phase was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. 14.1 g (99 percent) of the title compound are obtained as a colorless oil having an optical rotation of [.alpha.] D @ ²⁵ = -74 DEG (c = 3; dichloromethane).

The product prepared as described in Example 1 was converted to the free acid.

Claims (3)

SUBJECT OF THE INVENTION Process for the preparation of 1- [3-bromo- (2S) -methyl-propionyl] -pyrrolidine- (2S) -carboxylic acid of the formula I CrH a -CH 2 CH-CH 2 (S) (I) and its monohydrate, characterized in that the salt of formula III 262893 l 3 θ β г С о \ s) is reacted with a condensing agent in an inert organic solvent to form benzyl 1- [3-bromo- (2S) -methylpropionyl] -pyrrolidine (2S) -carboxylate of formula II which is debenzylated by catalytic hydrogenation to give the product of formula I, which is then optionally recrystallized from water to give the monohydrate. 2. The process of claim 1 wherein the condensing agent is carbodiimide. 3. The process of claim 2 wherein the carbodiimide is N, N ' -dicyclo hexylcarbodiimide.