HU196368B - Process for production of 1-/3-brom-/25/-methil-prophionil/-pirrolidin-/25/-carbonic acid - Google Patents

Description

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

The compound of formula (I) or its monohydrate is an intermediate for the preparation of 1- [3-mercapto- (2S) -methyl-propionyl] -pyrrolidine (2S) -carboxylic acid (captopril) with antihypertensive activity.

Several processes for preparing the compound of formula (I) have been described.

Each of the known processes produces the compound of formula (I) in two steps. No. 185,576, No. 1. According to a Hungarian patent, 3-bromo (2R, S) -methylpropionic acid is first prepared into the acid chloride and then reacted with (S) -proline under Schotten-Baumann acylation conditions. With (S) -proline, 1- [3-bromo (2S) -methyl-propionyl] -pyrrolidine (2S) -carboxylic acid and 1- [3-bromo- (2R) -methyl- are obtained in only 15% yield. propionyl] pyrrolidine (2S) -carboxylic acid (1: 1). The disadvantage of this extremely uneconomical known process is that the acid chloride from 3-bromo (2R, S) -methylpropionic acid is difficult to form because the acid chloride formed is volatile and difficult to separate from excess thionyl chloride.

No. 184,082, No. 1. The process of the Hungarian patent also requires the preparation of the acid chloride from the racemic 3-bromo-2-methylpropionic acid and coupling it with (S) -proline under the Schotten-Baumann acylation conditions. The discrepancy is found in No. 185,576, No. 1. The process according to the Hungarian patent specification is in the process of processing, whereby the product is not extracted with an organic solvent but precipitated with water under cooling, which has the great advantage that the desired diastereomer is clearly separated. This is the reason why the desired product can be obtained in this way in a yield of 40%, but it also means that the utilization of the valuable (S) -proline component is only 40%. The recovery of (S) -proline from the undesired diastereomer in the mother liquor is very laborious.

A 186 605.1. s. According to the Hungarian patent, (S) -proline is acylated in a separate step with acid chloride made from 3-bromo (2S) -methylpropionic acid in thionyl chloride.

According to Hungarian Patent Application Publication No. T / 38903 (S) -proline trimethylsilyl ester is acylated with 3-bromo (2S) -methylpropionyl chloride.

in summary, none of the known processes avoids the use of thionyl chloride and the associated environmental and technological problems.

SUMMARY OF THE INVENTION The object of the present invention is to overcome the drawbacks of the known processes and to provide an economically feasible process for the preparation of a compound of formula (I).

It has been found that the above object is achieved by the addition of (S) -proline-benzyl ester of 3-bromo (2S) -methyl-propionic acid containing up to 25% of 3-bromo-(2R) -methyl-propionic acid. with a condensing agent in an inert organic solvent to form a benzyl ester of 1- [3-bromo (2S) -methylpropionyl] -pyrrolidine (2S) -carboxylic acid of formula (II) not exceeding 25% of 1- [3-bromo The (2R) -methylpropionyl] -pyrrolidine (2S) -carboxylic acid benzyl ester is debenzylated by catalytic hydrogenation and, if desired, the resulting compound of formula (I) is recrystallized from water.

The starting compound of formula (III) of the present invention can be readily prepared by mixing 3-bromo (2S) methylpropionic acid and (S) -proline benzyl ester in an inert organic solvent. The (S) -pro'-benzyl ester in the form of its hydrochloride is commercially available and the (S) -proline benzyl ester is liberated from this acid addition salt with a base such as triethylamine.

3-Bromo (2S) -methylpropionic acid is prepared by resolution from racemic 3-bromo (2R, S) -methylpropionic acid.

This racemic compound can be obtained by methods known in the art [Cesk. Farm. 24, 112 (1975)]. For resolution, (R) -3- (E ', 4'-dimethoxyphenyl) -2-methyl-2-aminopropionitrile, which is a by-product of alpha-methyl dopa synthesis in taste, is used. The resolution is carried out in an inert organic solvent, preferably 1,2-dichloroethane, at room temperature. The resolving agent is used in a stoichiometric ratio, and the resolved product is liberated from the crystalline precipitated diastereomeric salt with dilute mineral acid to give, by extraction and evaporation of the solvent, about 40% yield of 3-bromo (2S) -methylpropionic acid contains the desired enantiomer of the (S) configuration and comprises up to about 25% of the enantiomer of the (R) configuration. Of course, the resulting 3-bromo (2S) -methyl-propionic acid may also be substantially free of the (R) -configuration enantiomer.

Suitable inert organic solvents for the reaction of the starting compound (111) with the condensing agent are, 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 ethyl acetate. A preferred organic solvent is dichloromethane.

The condensing agent used is a dehydrating compound, preferably a carbodiimide, most preferably dicyclohexylcarbodiimide, which is usually taken in a chromiotrimetric amount.

The reaction of the compound of formula (III) with the condensing agent is generally carried out at a temperature of 0 ° C to 20 ° C. Since the chemical bread of formula II! the effluent being exothermic, the reaction mixture is suitably cooled to 0 ° C at the beginning of the reaction.

Deprotection of the starting compound of formula (III) affords the benzyl ester of 1- (3-bromo (2S) -methyl-propionyl) -pyrrolidine (2S) -carboxylic acid (11), which is also up to 25% of 1- [3-bromo - Contains (2R) -methyl-propionyl-1-pyrrolidine (2S) -carboxylic acid benzyl ester.

The benzyl group of the compound of formula (II) is cleaved by catalytic hydrogenation in an inert organic solvent, preferably ethyl acetate, at about atmospheric pressure and at room temperature. The catalyst used is, for example, a metal of the platinum group, preferably palladium, in a support such as activated carbon. Catalytic hydrogenation yields essentially quantitative yields of the product of Formula (I) which can be conveniently isolated by filtration of the reaction mixture and evaporation of the filtrate. Recrystallization of the resulting compound of formula (I) from water yields the monohydrate of the product of formula (I) while remaining in a solution of 1- (3-bromo (2R) -methyl-propionyl) -pyrrolidine (2S) -carboxylic acid.

The process of the present invention provides the desired product with a yield of 70% based on (S) -prolifibenzyl ester.

196,368 products of optical purity. The process can be carried out on an operational scale without difficulty. From an environmental point of view, there is no need for acid chloride formation with thionyl chloride.

The invention is illustrated in detail by the following examples.

Preparation of 3-Bromo (2S) -methyl-propionic acid Dissolve 1 kg of racemic 3-bromo-2-methyl-propionic acid in 800 L of 1,2-dichloroethane and add 120 kg of (R) -3- (3) at 20 ° C. ', 4'-dimethoxyphenyl) -2-methyl-2-amino-propionitrile. The volume of the mixture was made up to 1350 liters. The solution was cooled from 20 ° C to 10 ° C over a period of 2 to 2.5 hours, then stirred for 1 hour and then the precipitated diastereomeric salt was filtered and washed with 30 liters of 1,2-dichloroethane at 10 ° C. . The white crystalline product is suspended in 800 L of water and acidified to pH 0.5 with concentrated hydrochloric acid. The temperature is maintained at a maximum of 20 ° C. The aqueous phase is extracted four times with 100 liters of 1,2-dichloroethane. The organic layer was combined, dried and evaporated, and the title compound was distilled under vacuum (1 Kg), boiling at 80 ° C, as a colorless liquid. Optical rotation: [α] D = -6.7 ° (c = II, 1,2-trifluoroethane). Optical purity was determined by 1 H-NMR in deuterochloroform with Eu (hfc) ₃ reagent. At a ratio of 0.616 reagents / sorbate, the methyl doublets can be readily separated and the integral exhibits a 75/25 enantiomeric ratio, i.e., the optical purity of the (S) -enantiomer corresponds to a 50% enantiomeric excess. Yield: 40%.

Example 7

A) 1- [3-Bromo (2S) -methyl-propionyl] -pyrrolidine (2S) -carboxylic acid benzyl ester

3.34 g (0.02 mol) of 3-bromo (2S) -methylpropionic acid and 4.60 g (0.02 mol) of (S) -proline-benzyl ester hydrochloride are dissolved in 50 ml of anhydrous dichloromethane and A solution of 1.9 g of triethylamine in 5 ml of anhydrous dichloromethane was added under cooling and mechanical stirring, and the resulting 3-bromo (2S) -methyl-propionic acid [(S) -proline-benzyl ester was added. ], a solution of 4.12 g (20 mmol) of dicyclohexylcarbodiimide in 20 ml of anhydrous dichloromethane was added at 0 ° C. The reaction mixture was kept at 0 ° C for an additional two hours and then stirred at room temperature for 12 hours. The reaction mixture was then filtered. The filtrate was extracted with 20 ml of 9% hydrochloric acid, 20 ml of water, 20 ml of 5% aqueous sodium bicarbonate solution and finally 20 ml of water. The organic phase is dried over anhydrous magnesium sulfate and evaporated.

6.4 g (95%) of the title compound are obtained as a light yellow oil. When run in a 3: 1 mixture of benzene glacial acetic acid, the vrk values are Rf: 0.44 and Rp: 0.48, respectively, corresponding to a 75/25 diastereomeric mixture as determined by 1 H-NMR. A value of 0 48 corresponds to the title compound. Optical rotation: [α] D = -74 ° (c = 3, dichloromethane).

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

A solution of 6.0 g (17 mmol) of the compound prepared in A above is dissolved in 60 ml of clylate, and 0.6 g of 10% palladium on carbon is added and the reaction mixture is hydrogenated at room temperature under TLC. The starting material did not react without any residue. The catalyst is filtered off, washed with ethyl acetate and evaporated to give 4.25 g (95%) of weight, which is recrystallized from 9 ml of water to give 3.2 g of the title compound. This corresponds to 95% optical purity of the starting compound used, while the utilization of the (S) -proline benzyl ester component is 70%. Melting point: 69-72 ° C; Optical rotation: -88.1 ° (c = 1, ethanol).

Example 2 1- [3-Bromo (2S) -methyl-propionyl] -pyrrolidine (2S) -carboxylic acid benzyl ester

6.68 g (40 mmol) of 3-bromo (2S) -methyl-propionic acid and 8.28 g (40 mmol) of (S) - propylene benzyl ester are dissolved in 40 ml of anhydrous dichloromethane and a solution of the salt of formula III is obtained. cooled to 0 ° C and a solution of 8.25 g (40 mmol) of N, N'-dicyclohexylcarbodiimide in 20 ml of anhydrous dichloromethane was added at this temperature. The solution was stirred at 0 ° C for 1.5 hours. The precipitated dicyclohexylurea was then filtered and the filtrate was washed with 1 N hydrochloric acid (2 x 15 mL), water (15 mL), then 15 mL (2 x 2 mL). It is extracted with 1 N sodium hydroxide solution and finally with 15 ml of water. The organic phase is dried over anhydrous magnesium sulfate and the solvent is evaporated. 14.1 g (99%) of the title compound are obtained in the form of a colorless oil having an optical rotation of [α] D = -74 ° (c = 3, dichloromethane).

In the following, the procedure of Example 1 (B) is followed.

Claims (3)

Claims A process for the preparation of 1- [3-bromo (2S) -methylpropion: l] -pyrrolidine (2S) -carboxylic acid or monohydrate of the formula I wherein 3-bromo (2S) -methyl -propionic acid, containing up to 25% of 3-bromo (2R) -methylpropionic acid, is reacted with a (S) -proline-benzyl ester (111) in a inert organic solvent to form 1- (3-) Bromo (2S) -methylpropionyl] -pyrrolidine (2S) -carboxylic acid benzyl ester - Not more than 25% 1- [3-bromo (2R) -methylpropionyl] -pyrrolidine (2S) -carboxylic acid benzyl ester - debenzylate by catalytic hydrogenation and, if desired, recrystallize the resulting compound (1) from water. 2. A process according to claim 1 wherein the condensing agent is a carbodiimide. 3. The process according to claim 2, wherein the carbodiimide is dicyclohexylcarbodiimide.