DD263984A5 - METHOD OF PREPARING 1- [3-BROM- (2S) -METHYLPROPIONYL] -PYRROLIDIN- (2S) CARBOXYLIC ACID - Google Patents

Abstract

According to the invention, compounds of the formula I or the monohydrate of this compound are prepared by reacting the salt of the formula III with a condensing agent in an inert organic solvent, the resulting 1- & 3-bromo (2S) -methylpropionyl! -Pyrrolidine (2S) - benzyl ester of formula II debenzylated by catalytic hydrogenation, and if desired, the product is recrystallized from water. Formulas I, II and III

Description

CH-

Br-CH ₂ -CH-COO (S)

H ₂ N

-CH -

with a condensing agent in an inert organic solvent, the resulting 1- [3-bromo (2S) -methylpropionyl] -pyrrolidine (2S) -carboxylic acid benzyl ester of the formula

COO-CH

Br-CH2

-CH C-N

(S)

ddbenzylated by catalytic hydrogenation and, if desired, the product recrystallized from water.

2. The method according to claim 1, characterized in that the condensing agent is a carbodiimide.

3. The method according to claim 2, characterized in that the carbodiimide is Ν, Ν'-dicyclohexylcarbodiimide.

Field of application of the invention

The invention relates to a process for the preparation of 1- [3-bromo (2S) -methylpropionyl] -pyrrolidine (2S! -Carboxylic acid of the formula

CH ₃ O

He-CH,

-CH - C-N

- ^cooh

or the monohydrate of this compound. The above compounds are intermediates in the preparation of 1- [3-mercapto (2S) -methyl-propionyl] -pyrrolitiine (2S) -carboxylic acid (captopril), which has a valuable hypotensive effect.

Characteristic of the known state of the art

Various methods are known for preparing the compound of formula I, but each known method contains two reaction steps.

According to HU-PS No. 185576, 3-bromo (2R, S) -methylpropionic acid is first converted into the corresponding acid chloride, which is reacted with (S) -proline according to Schotten-Baumannscher acylation. The reaction product obtained with a yield of 15% consists of a mixture of 1 part of 1-! 3-bromo (2S) -methylpropionyl] -pyrrolidine (2S) -carboxylic acid and 1 part of 1- [3-bromo (2R) -methyl-propionyl] pyrrole-jdin- (2S) -carboxylic acid. The further disadvantage of this rather uneconomical

Process is associated with the preparation of the acid chloride, because the latter compound is volatile, and difficult to separate from the excess of thionyl chloride.

According to U.K. Patent No. 2066252, the azemic 3-bromo-2-methylpropionic acid is likewise converted into the corresponding acid chloride, which in turn is reacted with (S) -proline in accordance with Schotten-Baumann's acylation. The difference between the method according to HU-PS No. 185576 and the method according to UK Patent No. 2066252 is in the work-up of the reaction mixture, because in the latter method, the reaction product is not extracted with an organic solvent, but is precipitated with water with cooling. Thus, the desired diastereoisomer is separated in the pure state. Although a yield of 40% is achieved in this way, only this 40% portion of the (o) -proline used is utilized. The remainder of the (S) -proline converted to the other diastereoisomer is difficult to regenerate.

According to HU-PS No. 186605, (S) -Proiine is reacted with an acid chloride prepared in an oeparatane stage from 3-'- (2S) -methylpropionic acid with thionyl chloride.

According to Hungarian Patent Application No. 3901/84, the trimethylsilyl ester of (S) -proline is acylated with 3-bromo (2S) 'methylpropionyl chloride.

In summary, it can be said that the known processes can not avoid the use of thionyl chloride and thus the associated technological difficulties and environmental problems.

Object of the invention

Zisl of the invention is to provide an improved process for the preparation of 1- [3-bromo (2S) -methylpropionyl] pyrrolidine (2S) -carboxylic acid, with which the compound in a simple and economical manner in good yield and high purity Avoiding the disadvantages of the known methods can be produced.

Explanation of the essence of the invention

It is an object of the present invention to provide readily available starting compounds and suitable reaction steps for the preparation of 1- [3-drom- (2-S) -methylpropioriyl] -pyrrolidine (2S) -carboxylic acid.

It has been found that the disadvantages of the known processes can be eliminated and the compound of the formula I can be produced economically, if the salt of the formula

CH,

Br-CH ₂ -CH-COO

(5)

Θ (S)

H ₀ N

with a Kondensierunysmittel in an inert organic solvent, the obtained 1- [3-bromo (2S) -methylpropionylj-pyrrolidine (2S) -carbunic acid benzyl ester of the formula

CH ₃ 0

Br-CH ₂ -CH CN

(S)

J ₁ COO-CH ₂ -

debenzylated by catalytic hydrogenation and, if desired, the product recrystallized from water. The starting compound of formula III is prepared by simply mixing the 3-bromo (2S) -methylpropionic acid and the benzyl ester of (S) -proline in an inert solvent. The benzyl ester of (S) -proline is commercially available in the form of its hydrochloride from which the desired compound is reacted with a base, e.g. For example, triethylamine is released. The 3-bromo (2S) -methylpropionic acid is prepared by resolving racemic 3-bromo (2R, S) -methylpropionic acid, which itself can be obtained by a method known in the literature (Cesk. 1975]). The racemic compound is resolved with a stoichiometric amount of (R) -3- (3 ', 4'-dimethoxyphenyl) -2-methyl-2-aminopropionitrile, which is a by-product in the synthesis of alpha-methyldopa. The resolving is carried out in an inert organic solvent, for example 1,2-dichloroethane, at room temperature. The precipitated crystalline diastereomer salt is treated with a dilute mineral acid, extracting the vacated, ^r esolvierte product, and the solvent removed. The total yield of the resolving is 40% of theory. The 3-bromo (2S) -methylpropionic acid thus obtained contains 0 to 25% (2R) -enantiomer as a possible impurity.

The reaction of the starting compound of formula III with the condensing agent is carried out in an inert solvent, e.g. an aromatic hydrocarbon such as chlorobenzene; a chlorinated aliphatic hydrocarbon oils

Oichlormethan; or an ester such as ethyl acetate. Dichloromethane is the preferred solvent for the above reaction.

The condensing agent is a compound suitable for dehydration of the starting compound of the formula III. Preferred condensing agents are carbodiimides, advantageously N, N'-dicyclohexylcarbodiimide, which is generally used in a stoichiometric amount.

The reaction of the compound of formula III with the condensing agent is generally carried out at 0 to 2O ⁰ C.

Because the dehydration of the compound of formula III proceeds in an exothermic reaction, it is convenient to cool the reaction mixture to about 0 ° C at the beginning of the reaction.

The dehydration of the compound of formula III produces benzyl 1- [3-bromo (2S) -methyl-propionyl] -pyrrolidine (2S) -carboxylate containing from 0 to 25% of 1- [3-bromo (2R) -methyl-propionyl-1-pyrrolidine - (2S) -carboxylic acid benzyl ester may contain as an impurity.

The resulting compound of formula II is debenzylated by catalytic hydrogenation in an inert organic solvent, preferably ethyl acetate, usually at room temperature and under atmospheric pressure. The catalyst used is, for example, a metal from the platinum group, advantageously palladium, in active form, that is to say applied to a support such as active carbon. Catalytic hydrogenation provides the desired product of formula I in virtually theoretical yield.

The hydrogenation mixture is filtered and the solvent evaporated. If the residual Formet I product is recrystallized from water, the monohydrate of this compound is contained and any 1- [3-bromo (2R) -methyl-propionyl] -pyrrolidine (2S) -carboxylic acid remains in the mother liquor in a dissolved state ,

According to the invention, the compound of formula I is prepared in the desired optical purity with a yield of 70% of theory (calculated on the benzyl ester of [SJ-proline). The process according to the invention can also be carried out without difficulty on an industrial scale. For environmental protection it is important that the process requires animal application of small thionyl chloride.

embodiments

The invention is further illustrated by the following examples, but is not limited to these examples.

Preparation of 3-bromo (2S) imethylpropionic acid

91 kg of racemic 3-bromo-2-methylpropionic acid are dissolved in 0.8 m ^{3 of} 1,2-dichloroethane, and the resulting solution 120 kg of (R) -3- (3 ', 4'-dimethoxyphenyl) -2-methyl 2-amino-propionitrile added at 20 ° C. The volume of the mixture is supplemented with 1,2-dichloroethane to 1.35 m ^3, the solution was cooled from 20 ^c C to 10 ⁰ C in 2 to 2.5 hours, and then stirred for a further hour. Dor precipitated diastereomer salt is filtered and with 30dm ^{3 of} 1,2-dichloroethane at 10 ° C, jowyschen. The crystalline product is suspended in 0.8 m ^{3 of} water and the pH is adjusted to 0.5 with concentrated hydrochloric acid. During the addition of hydrochloric acid, the temperature is kept below 20 ° C. The aqueous phase is extracted four times with 100dm ^{3 of} 1,2-dichloroethane, the organic solutions are combined, dried and evaporated under reduced pressure.

The title compound is distilled under a pressure of 1 bar as a colorless liquid. Boiling point: 80 ° C / 1 bar.

[α] έ ⁵ = -6.7 ° (c - 11, 1,2-dichloroethane).

The optical purity was determined by H-NMR in CDCl ₃ . The reagent used was Eu (hfe ' _3. At a reagent / substrate ratio of 0.616, the doublets can be separated well and the integral shows an enantiomeric ratio of 75/25 (75 parts [S] enantiomer and 25 parts (R)). Enantiomer), ie the optical purity of the [S] -enantiomer corresponds to an enantiomeric excess of 50% The yield is 40% of theory.

example 1

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

3.34 g (0. C2 mol) of 3-bromo (2S) -methylpropionic acid and 4.60 g (0.02 mol) (Sl-proline benzyl ester hydrochloride are dissolved in 50 ml of anhydrous dichloromethane stirred solution, the mixture of 1.9 g of triethylamine and 5 ml of anhydrous dichloromethane is added at 0 ⁰ C. In this way, a solution of 3-bromo (2S) -methylpropionic acid [pyrrolidine (2S) -carboxylic acid benzyl ester | 4.12 g are obtained salt. This final solution (0.02 moles) of N, N'-dicyclohexyl-carbodiimide in 20 ml of anhydrous Dichlorr iethan added at 0 ° C. The reaction mixture is stirred at O ⁰ C a further 2 hours., then ^be! Stirred for a further 12 hours, then filtered The filtrate is extracted with 20ml 9% hydrochloric acid, 20ml water, 20ml 5% aqueous sodium hydrogen carbonate solution and 20ml water The organic phase is dried over anhydrous magnesium sulfate, then evaporated 6.4g title compound in the form of pale yellow oil with a Yield of 95% of theory.

Thin Layer Chromatography (3 parts benzene, 1 part glacial acetic acid):

Rf = 0.44 and 0.48 respectively. The latter R _r value corresponds to the title compound, and the first R _r value corresponds to the 1- [3-bromo (2R) -methyl-propionyl] -pyrrolidine (2S) -carboxylic acid benzyl ester. According to the 'H-NMR determination, the enantiomer ratio

[α] "= -74 ° (c = 3, dichloromethane)

B. 1- [3-bromo (2S) -methyl-propionyl-pyrrolidine (2S) -carboxylic acid monohydrate

6.0 g (0.17 mol) of 1- [3-bromo (2S) -methyl-propionyl-pyrrolidinyl (2S) -carboxylic acid benzyl ester are dissolved in 1 ml of ethyl acetate. After adding 0.6 g of 10% palladium / carbon catalyst, the reaction mixture is hydrogenated at room temperature and under atmospheric pressure. If the benzyl compound can no longer be detected by thin layer chromatography, the catalyst is filtered, washed with ethyl acetate, and the organic solvent evaporated. 4.25g (95%) of the title compound remains, which is recrystallized from 9ml of water. Thus, 3.2g title compound are obtained. Due to the optical purity of the starting compound, the yield is 95% of theory. The utilization of the benzyl ester of (S) -proline corresponds to 70%. The product obtained melts r di 69-72 ° C.

Example 2

1- [3-Brüm- (2S) -methylpropionyll-pyrrolidine- (2S) -carboxylic acid benzyl ester

6.68 g (0.04 mol) of 3-bromo (2S) -methylpropionic acid and 8.28 g (0.04 mol) of (S) -proline-benzyl ester are dissolved in 40 ml of anhydrous

Dissolved dichloromethane, and the resulting solution of the salt of formula III is cooled to ⁰ ° C. This solution becomes a solution

of 8.25 g (0.04 mol) of N, N'-dicyclohexylcarbodiimide in 20 ml of anhydrous dichloromethane at ⁰ ° C. The

Reaction mixtures are stirred at this temperature for 1.5 hours. The precipitated dicyclohexylurea becomes

filtered, and the filtrate is washed twice with 15 ml of 1N hydrochloric acid, then with 15 ml of water, twice with 15 ml of 1N Nairiumhydroxid-

Solution and finally extracted with 15ml of water. The organic solution is dried over anhydrous magnesium sulfate,

and the solvent evaporated. Su are 14.1 g of the title compound in the form of colorless oil with a yield of 99% of

Received theory.

[al "= -74 '(c = 3, dichloromethane).

The resulting product is converted into the free carboxylic acid in the example 1.8. described way transferred.

Claims (1)

claims: 1. A process for the preparation of 1- [3-bromo (2S) -methylpropionyl] -pyrrolidine (2S) -carboxylic acid of the formula ? ^H 3 0 (S) Br-CH ₂ -CH CN (S) COOH or the monohydrate of this compound, characterized in that the salt of the formula