HU187653B - Process for preparing 3-mercapto-2-methyl-propionic acid derivatives - Google Patents

Abstract

The present invention relates to a novel process for the preparation of 3-mercapto-2-methylpropionic acid derivatives of the formula I wherein R is hydroxy or 2-carboxylpyrrolidin-1-yl, Bunte of formula II. wherein R is as defined above, Me is a metal atom. According to the invention, the compound of formula (II) is reacted with a reducing agent. The process of the invention provides 3-mercapto-2-methylpropionic acid derivatives of formula (I) with a yield of about 85%. CH, I-HS-CHfCH-COR (1) 0 CH, ΖΛ II I M Ηθ-S-S-CHrCH-COR or) 11 0-1-

Description

The present invention relates to a novel process for the preparation of 3-mercapto-2-methylpropionic acid derivatives of formula I wherein R is hydroxy or 2-carboxylpyrrolidin-1-yl; of the salt wherein R is as defined above, Me is a metal atom.

The compounds of formula I have valuable therapeutic effects. For example, 1- (3-mercapto- (2S) -methyl-propionyl) -pyrrolidine (2S) -carboxylic acid is an active ingredient in antihypertensive drugs.

No. 3,049,273. The preparation of optically active compounds of formula (I) wherein R is 2-carboxylpyrrolidin-1-yl is acidic hydrolysis of the corresponding Bunte salt of the general formula (II) wherein the Bunte salt is known sodium thiosulfate from 1- [3-bromo (2S) -methyl-propionyl] -pyrrolidine (2S) -carboxylic acid.

However, the yield of the corresponding compound of formula (I) with respect to the latter compound cannot be increased to above 70%, since the decomposition of the Bunte salt also results in the decomposition of the acid amide.

It has been found that it is very economical to prepare the 3-mercapto-2-methylpropionic acid derivative of formula I from the Bunte salt of formula II by reacting the latter with a reducing agent.

Preferred reducing agents for the process of the invention include dextrose, sodium dithionite, sodium sulfite (in the presence of copper (II) ions), Clelandreagent (dithiothreitol) and the like.

Suitable reducing agents include hydrogen gas, hydrogenation catalysts such as palladium, platinum oxide, Raney nickel and the like. - in his presence. The Bunte salt of formula (II) can also be converted to the product of formula (I) by electrolytic reduction. All of these reduction methods known per se include the term "reacting with a reducing agent".

In a particularly preferred embodiment of the process of the invention, the reduction of the Bunte salt of formula II is carried out with an alkali metal borohydride such as sodium borohydride.

The Bunte salt used as starting material is known to be prepared by reaction of 3-halo-2-methylpropionic acid derivatives of the formula (III) wherein R is as defined above, Hal is a halogen atom such as chlorine or bromine. If desired, the compound of formula (II) thus obtained is reduced without isolation to the compound of formula (I).

In one embodiment of the process of the invention, the treatment of the Bunte salt of formula II with a reducing agent may be repeated using the same or another reducing agent. This gives an extremely high purity product of formula (I).

When the reduction of the Bunte salt of formula II is carried out in essentially two steps as described above, the final reduction is preferably carried out using zinc, for example zinc powder, in the presence of hydrochloric acid.

The compounds of formula (I) and (II) contain 1 or 2 chiral carbon atoms, depending on R. Any of the isomers of formula (II) or a mixture of isomers may be used as starting materials in the process of the invention. Depending on the starting material, of course, the corresponding isomer of formula (I) or mixture of isomers is obtained.

The process of the present invention provides 3-mercapto-2-methylpropionic acid derivatives of formula (I) in an yield of about 85% based on the compound of formula (III). The process is readily carried out in aqueous medium and the compounds having the 2-carboxylpyrrolidin-1-yl group in R do not undergo cleavage of the acid amide.

The invention is illustrated in detail by the following examples.

Example I 1- [3-Mercapto- (2S) -methyl-propionyl] -pyrrolidin-1 - (2S) -carboxylic acid -

A suspension of 14.1 g (0.050 mol) of 1- [3-bromo (2S) -methylpropionyl] pyrrolidine (2S) -carboxylic acid monohydrate in 80 ml of water was cooled to 15 ° C and 4.4 g of Sodium bicarbonate (0.052 mol) was added in 8-10 portions over 20 minutes and then

12.5 g (0.0504 mol) of sodium thiosulfate pentahydrate. The mixture was heated to reflux and refluxed for one hour. It was then cooled to 0- (+ 5) ° C and 3.8 g (<0.10 mol) of sodium borohydride was added to the colorless solution over one hour, followed by stirring for 3 hours at constant temperature. The pH was adjusted to 1-1.5 with 37% hydrochloric acid, and the precipitated solid was filtered. The aqueous phase was extracted with dichloromethane (3 x 50 mL), and the combined organic extracts were washed with brine (30 mL) and dried over anhydrous magnesium sulfate. After removal of the solvent, the residual viscous liquid was dissolved in a mixture of 80 ml of water and 10 ml of 37% hydrochloric acid solution, and 5.0 g of zinc powder was added in 4-5 portions with stirring. After stirring for 4 hours, the excess zinc powder was filtered, the aqueous solution was extracted with dichloromethane (3 x 50 mL), and the combined organic layers were dried over anhydrous magnesium sulfate. After removal of the solvent, the residual viscous oil was dissolved in ethyl acetate (30 mL) and the product precipitated by the addition of hexane (75 mL). After one hour at 0 - (+ 5) ° C, the product is filtered off, washed twice with hexane, washed twice and dried. 9.7 g (89.2%) of the title compound are obtained, m.p. 104-106 ° C,

Md ⁼ 129 (c = 0.5; ethanol).

Example 2 —I

3-Mercapto-2-methyl-propionic acid J

25.05 g (0.15 mol) of 3-bromo-2-methylpropionic acid and

The mixture is cooled to + 15'C with 200 ml of water. While stirring, 13.2 g (0.16 mol) of sodium bicarbonate was added in 8-10 portions over 20 minutes, followed by 37.2 g (0.15 mol) of sodium thiosulfate pentahyde-2. 187,653. The solution is heated and refluxed for one hour.

The reaction mixture is cooled to + 2 ° C and 1.4 g (0.30 mol) of sodium borohydride are added to the solution over one hour and the mixture is stirred for two hours. ⁵ then hydrochloric acid to 1 37% pH adjusted, and the precipitated solid was filtered. The aqueous phase was extracted with ethyl acetate (3 x 100 mL), and the combined organic extracts were dried over anhydrous magnesium sulfate. After removal of the solvent, the ¹ θ residue was fractionated in vacuo.

14.6 g (81.3%) of the title compound are obtained as a colorless liquid. Fp. 78-82 ° C /

106.6 Pa.

Example 3 _ ~

- [3-Mercapto- (2S) -methyl-propionyl] -pyrrolidine, - (2S) -carboxylic acid

A. Preparation of Bunte Salt ²⁰

A suspension of 28.2 g (0.10 mol) of 1- [3-bromo (2S) -methyl-propionyl-pyrrolidine (2S) -carboxylic acid monohydrate in 160 cm ^{3 of} distilled water was cooled to 15 ° C. 8-10 parts, was added 8.8 g (0.104 mole) of ²⁵ nátriumhidrogénkarboná- tót under flange 20, and (0.108 mol) of sodium thiosulfate pentahydrate 25.0 g was added. The mixture was heated to reflux and refluxed for 1 hour. The solvent was evaporated in vacuo and the residue was triturated with acetone. The crystalline product is filtered off, dried over anhydrous magnesium sulfate at 100 ° C under vacuum. 44.0 g of product are obtained which is a 1: 1 molar mixture of the Bunte salt of the formula (II) in which R is 2-carboxylpyrrolidin-1-yl, Me is sodium, and sodium bromide.

[? S ⁼ ~ 127.1 '(c = 2, water) (measured value)

Corrected for 100% Bunte Salt: 165.2 °.

IR (KBr; Perkin-Elmer 157 G)? _Max = 640, 1025, 1200 ^cm-1 (characteristic bands of Buntesóra).

B. Preparation of 1- [3-Mercapto- (2S) -methyl-propionyl] -pyrrolidine (2S) -carboxylic acid

The product (44.0 g) obtained in (A) above is dissolved in 160 ml of distilled water, cooled to 0 ° C and

Sodium borohydride (7.6 g, 0.20 mol) was added to the solution over 1 hour.

In the following, the procedure of Example 1 is followed. 19.2 g of the title compound are obtained, m.p. 104-106 ° C.

Claims (3)

Patent claims: A process for the preparation of the 3-mercapto-2-methylpropionic acid derivatives of formula I wherein R is hydroxy or 2-carboxylpyrrolidin-1-yl, from the Bunte salt of formula II, where R is above, Me is? a metal atom, characterized in that a compound of formula II is reacted with a reducing agent. Process according to claim 1, characterized in that the reducing agent is an alkali metal borohydride. 3. The process according to claim 2, wherein the alkali metal borohydride is sodium borohydride.