HU201008B - Process for producing 3,3'-dithio-bis (propionic acid) derivatives - Google Patents

Abstract

Novel prepn. of 3,3'-di:thio-bis(propionic acid) derivs. of general formula (I) from cpds. of formula (III) being acylated by carboxylic acids of formula (II) or their derivs. R in all formulae = hydrogen atom, benzyl- or tri:methyl-silyl gps.

Description

The present invention relates to a process for the preparation of the 3,3'-dithiobis (propionic acid) dehydrogenase of formula (I) having the structure S, S, S, S, wherein R is benzyl or trimethylsilyl. The compounds of formula (I) may be used in the preparation of 1- [3-mercapto (2S) -methyl-propionyl] -pyrrolidine (2S) -carboxylic acid with valuable antihypertensive activity.

A 27.03.828. s. According to the German patent application, the compound of formula (I) wherein R is hydrogen is prepared by oxidation of 1- [3-mercapto- (2S) -methyl-propionyl] -pyrrolidine (2S) -carboxylic acid with iodine. This process is obviously not suitable for economical industrial synthesis.

Λ 187,648. Pat. According to the Hungarian patent, a compound of the formula (I) wherein R is hydrogen is a so-called. It is made from Bunte salt by mineral acid treatment. The 3,3'-dithiobis (propionic acid) derivatives of formula (I) wherein R is benzyl or trimethylsilyl are novel compounds.

No. 378,955. s. According to the Austrian patent, the p-nitrobenzyl ester of L-proline is reacted with racemic dithiobis (alkylcarboxylic acid) in the presence of dicyclohexylcarbodiimide. This gives about 90% yield of the compound of formula I wherein R is p-nitrobenzyl as a mixture of 3 different isomers. The S, S, S, S configuration isomer that can be used in the preparation of the pharmaceutically valuable 1- [3mcrcapto- (2S) -methyl-propionyl] -pyrrolidine (2S) -bromonic acid can theoretically be formed in only 25% yield, but in practice only a fraction of this production can be achieved by separation of the isomers.

SUMMARY OF THE INVENTION It is an object of the present invention to provide a simple, economical process for the preparation of the

S, S, S, S.

It has now been found that the above object is achieved by acylation of the L-proline ester of formula (III), wherein R is as defined above, with a carboxylic acid or reactive derivative of formula (II) in S, S configuration.

The acylation reaction is carried out in an organic medium in the presence of a base, generally at a temperature between 0 ° C and 50 ° C. Suitable bases are preferably inorganic bases such as sodium hydroxide, sodium carbonate and the like. employed. After completion of the acylation reaction, the reaction mixture is acidified to give the product of formula I in the S, S, S, S configuration. The acidification is usually carried out with a mineral acid such as aqueous hydrochloric acid.

Among the compounds of formula (III), L-proline is commercially available. Its benzyl ester or trimethylsilyl ester may be prepared in a known manner, for example by esterification with benzyl chloride or trimethylsilyl chloride.

For example, the carboxylic acid of formula II in the S, S configuration is 187,648. Pat. is prepared from 3-bromo- (2S) -methylpropionic acid. The acylation reaction of the present invention may also be carried out using any of the known activated derivatives of the carboxylic acid of formula II, such as the corresponding acid chloride, acid anhydride, active ester, mixed anhydride, and the like.

The process of the present invention provides the product of formula (I) in a yield of 70-90% for both the compound (II) and the compound (III). The acylation reaction can be carried out very simply in an organic medium. The resulting pure compound of formula (I) can be used to prepare highly pure 1- [3-mercapto- (2S) -methyl-propionyl] -pyrrolidine (2S) -carboxylic acid.

The invention is illustrated in detail by the following examples.

Preparation of starting compounds:

3,3'-dithio-bis [(2S) -methyl-propionic acid]

A mixture of 16.7 g (0.10 mol) of 3-bromo (2S) -methylpropionic acid and 80 cin of water was cooled to 15 ° C. Sodium bicarbonate (8.6 g, 0.10 mol) was added in 810 portions over 20 minutes, and then sodium thiosulfate pentahydrate (24.8 g, 0.10 mol) was added. The mixture is heated to reflux and refluxed for one hour. Then, 20 cm ^{3 of} dimethyl sulfoxide and 44 cm ^{3 of} 37% hydrochloric acid solution were added over 10 minutes and the mixture was refluxed for another 15 minutes. The reaction mixture was cooled to + 5 ° C, and after 1 hour, the precipitated crystals were filtered and washed twice with ice-water. Recrystallization from water gave 9.6 g (81%) of the title compound as a white solid, m.p. 122-124 ° C.

3,3'-dithio-bis [(2S) -methyl-propionic acid chloride]

23.8 g (0.10 mol) of 3,3'-dithiobis [(2S) -methylpropionic acid], 71.4 g (13.3 cm ³ , 0.60 mol) of thionyl chloride and 100 cm ^{3 of} anhydrous the benzene mixture was refluxed for 3.5 hours. The solvent and excess thionyl chloride were removed. 61.8 g of the title compound are obtained in the form of a yellow liquid with an acid chloride content of 98.7%.

Example I

3,3'-Dithio-bis {1 - [(2S) -methyl-propionyl] -pyrrolidine (2S) -carboxylic acid benzyl ester}

A suspension of 4.85 g (0.02 mol) of L-proline benzyl ester hydrochloride in 50 cm ^{3 of} anhydrous diethyl ether was cooled to 0 ° C and 4.05 g (0.04 mol) of triethylamine followed by 2.75 g (0) (01 mol) of a solution of 3,3'-bis [(2S) -methylpropionic acid chloride in 20 cm ^{3 of} anhydrous diethyl ether was added with stirring so that the temperature of the reaction mixture did not exceed + 10 ° C. The reaction mixture was stirred for 3 hours at 20 ° C, filtered, and the solvent was removed from the filtrate. 5.6 g (91%) of the title compound are obtained as a yellow viscous liquid [a] ²⁰ D = -198.5 (c = 0.5; ethanol).

Example 3

3,3'-Dithio-bis {1 - [(2S) -methyl-propionyl] -pyrrolidine (2S) -carboxylic acid (trimethylsilyl) ester}

II To a suspension of L-proline (50 g, 0.10 mol) in toluene (100 mL) was added triethylamine (15.0 g, 0.15 mol) followed by trimethylchloride (16.3 g, 0.15 mol). silane is added dropwise to the reaction mixture.

After stirring at room temperature for 1 minute, triethylamine (20 ml, 0.2 mol) was added with cooling to 0 ° C.

While stirring, 11.9 g (0.05 mol) of 3,3'-dithiobis [(2S) -methyl-propionic acid chloride] was added dropwise to the bis-compounds of the formula 2, where R is benzyl or trimethylsilyl, characterized in that the L-proline ester of formula (III), wherein R is as defined above, is acylated with a carboxylic acid or reactive derivative of S, S configuration of formula (II).

2. A process according to claim 1 wherein the compound of formula III is L-proline (trimethylsilyl) -6-ester.

3. The process according to claim 1, wherein the reactive derivative of the carboxylic acid of formula S, S of formula (II) is the acid chloride.

was added to the reaction mixture so that the temperature remained below 10 ° C. After the addition, the mixture was stirred for one hour at a temperature below 100 ° C and for three hours at room temperature. The precipitated triethylamine hydrochloride was filtered off, washed with toluene and the filtrate evaporated in vacuo. Normal workup gave the title compound (25.3 g, 88%) was obtained as a liquid [a] p ^M = -179.3 ° (c = 5; dichloromethane).

Claims (1)

1. Procedure for the preparation of the formula S, S, S, S, confi-3EN 201008 Β Int Ct ⁵ : C 07 D 207/08, C07 F 7/10 _CH3 (-S-CH _Z -CH-CN -J -COOR) ₂ Δ ch ₃ (-S-CH ₂ -CH-CO 3 OH) HN ^ COOR