HU187648B - Process for preparing 3,3-dithio-bis/propionic acid/derivatives - Google Patents

Abstract

The present invention relates to a novel process for the preparation of 3,3'-dithiobis (propionic acid) derivatives of the formula I wherein R is hydroxy or 2-carboxylpyrrolidin-1-yl. In accordance with the present invention, a Bunte salt of formula (II) wherein R is as defined above is reacted with an acid in the presence of a metal atom, preferably an alkali metal salt, an organic solvent and optionally a catalyst. The process of the present invention provides 3,3'-dithiobis (propionic acid) derivatives of the formula (I) with a yield of about 80. The compounds of formula (1) are intermediates of valuable therapeutic agents (e.g., antihypertensive agents). 1 R-CO-CH-CHfS-S-CHfCH-CO-R (i) 0 CH1 MeO-SS-CHrCH-CO-Rfii) II 0-1-

Description

The present invention relates to a novel process for the preparation of 3,3'-dithiobis (propionic acid) derivatives of formula I wherein R is hydroxy or 2-carboxylpyrrolidin-1-yl. The compounds of formula (I) may be used in the preparation of valuable pharmaceutical compounds, such as the 1- [3-mercapto- (2S) -methylpropionyl] -pyrrolidine (2S) -carboxylic acid (III) having antihypertensive activity.

No. 27 03 828. According to the German Federal Publication, the compounds of formula I are prepared by oxidation of the thiol of formula V, wherein R is as defined above, with iodine. Obviously, this is not a viable option if the 3,3'-dithiobis (propionic acid) derivatives of formula (I) are to be used in the preparation of thiols (V).

It has been found that the 3,3'-dithiobis (propionic acid) derivatives of formula (I) can be prepared simply and economically if a Bunte salt of formula (II) wherein R is as defined above, Me is a metal atom, preferably an alkali metal atom. , with an organic solvent and optionally in the presence of a catalyst. ₂ _

The Bunte salt of formula (II) is a halogen compound of formula (IV) wherein R is as defined above, Hal is a halogen atom, preferably chlorine or bromine, and can be prepared by reacting metal thiosulfate (German Patent No. 30 49 273). release document). In formula II, Me is particularly preferably sodium.

The acid treatment of the Bunte salt of formula II is carried out in the presence of an organic solvent. Organic solvents have found use of dimethoate ³⁵ tilszulfoxid particularly advantageous.

In our studies, it has been found that in the presence of a catalyst, the Bunte salt of formula (II) is formed in higher yields by acid treatment of the compound of formula (I). The optional catalyst is preferably an organic amino compounds ⁴⁰ used, such as tertiary amines may be used. Tertiary amines are preferably triethylamine, trimethylamine and the like. employed.

The acid treatment is generally carried out at a temperature of 0-150'C, preferably 50-120'C. The acid used is an organic or inorganic acid, preferably a mineral acid, preferably hydrochloric acid. The reaction is usually complete within 20-60 minutes.

In a preferred embodiment of the process of the invention, the starting compound of formula II is reacted with an acid in the reaction mixture. In this case, the reaction of the halogen compound (IV) with a metal thiosulfate, such as sodium thiosulfate, can be carried out in the presence of the selected organic solvent 55 and optionally an appropriate catalyst, followed by addition of an acid such as aqueous hydrochloric acid. is converted to the compound of formula (I). 60

In formula I there are 2 or 4 chiral carbon atoms, depending on R. Of course, the process of the present invention can be used to prepare both individual enantiomers and mixtures thereof. 65

The process of the present invention provides the 3,3'-dithiobis (5-propionic acid) derivatives of the formula (I) in about 80% yield with respect to the compound of formula (IV) which, if desired without isolation from the reaction mixture, milder than those used in the processes ttotokká formula (V), AME ₁₀ monographs such as the formation of higher purity, the reaction conditions can be converted by reduction. In the process of the invention, the target compounds are obtained from the Bunte salt (II) in a short reaction time with practically no by-products.

The invention will in the following Examples ₁₅ describe below in detail:

Example 1

3,3 '-Dithiobis-1- (2S) -methyl-propionyl) -pyrrolidine (2S) -carboxylic acid]

A suspension of 14.1 g (0.050 mol) of 1- [3-bromo (2S) -methyl-propionyl] -pyrrolidine (2S) -carboxylic acid monohydrate in 80 ml of water was cooled to 15 ° C. Sodium hydrogencarbonate (4.4 g, 0.052 mol) was added in 8-10 portions with stirring over a period of 20 minutes, followed by sodium thiosulfate pentahydrate (12.5 g, 0.0504 mol), dimethylsulfoxide (10 ml) and triethylamine (2 ml). The mixture is heated to reflux and refluxed for one hour. Thereafter, 22 ml of a 37% hydrochloric acid solution were added over 10 minutes and refluxed for an additional 45 minutes. The reaction mixture was cooled to + 5 ° C, the white crystals precipitated after 30 minutes, washed twice with water and dried. 8.6 g (79.9%) of 3,3'-dithiobis [1 - ((2S) -methylpropioml) -pyrrolidine (2S) -carboxylic acid are obtained, m.p. 230-233 'C.

After boiling the hydrochloric acid, the wet product isolated from the reaction mixture by filtration was suspended in a mixture of 80 ml of water and 25 ml of 37% aqueous hydrochloric acid, and 10.0 g of zinc powder was added at 20 ° C in 8-10 portions for 30-40 minutes. under. After stirring for 4 hours, the excess zinc powder was filtered. The colorless solution 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. The solvent was evaporated in vacuo and the remaining viscous liquid was dissolved in ethyl acetate (30 mL) and precipitated by the addition of hexane (60 mL). After 1 hour storage at +5 ° C, the crystals were filtered, washed twice with hexane, and dried. 8.2 g (75.5%) of 1- [3-mercapto- (2S) -methyl-propionyl] -pyrrolidine (2S) -carboxylic acid are obtained, m.p.

Example 2

3,3 '-dithiobis: (2-methylpropionic acid)

3-Bromo-2-methylpropionic acid (25.05 g, 0.15 mol) was treated with sodium thiosulfate as in Example 1. After hydrolysis with hydrochloric acid, the reaction mixture is cooled to 5 ° C, stirred for 1 hour, and the crystalline material is filtered off and suspended in water.

187,648 washed twice, dried. Recrystallization from a 1: 1 mixture of benzene and hexane gave 13.5 g of 3,3'-dithiobis (2-methylpropionic acid), m.p. 75-80 ° C.

17.3 g (79.9%) of 3,3'-dithiobis [1 - ((2S) -methylpropionyl) -pyrrolidine (2S) -methylpropionyl) -pyrrolidine (2S) -carboxylic acid] 230-233 ° C.

Example 3

3,3'-dithiobis [1- (2S-methylpropionyl) pyrrolidine (2S) -carboxylic acid],

28.2 g (0.10 mol) of 1- [3-bromo (2S) -methyl-propionyl] -pyrrolidine (2S) -carboxylic acid monohydrate

Cool a suspension of 160 cm ^{3 of} distilled water to 15 ° C. Sodium bicarbonate (8.8 g, 0.104 mol) was added in 8-10 portions over 20 minutes, and then sodium thiosulfate pentahydrate (25.0 g, 0.108 mol) 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 and 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.

Mm ~ ^_ 127.1 '(c = 2, water) (measured value).

The corrected value for 100% Bunte Salt is = = 165.2 °.

Infrared spectrum (potassium bromide; Perkin-Elmer 157G) ν _max = 640, 1025, 1200cm ^-1 (Bunteson characteristic bands).

The product (44.0 g) was dissolved in distilled water (160 ml), dimethylsulfoxide (20 ml) and triethylamine (4 ml) were added and the mixture was heated to reflux for 1 hour. 44 ml of a 37% hydrochloric acid solution are added over 10 minutes and proceeded as in Example 1 below.

Claims (8)

Patent claims A process for the preparation of a 3,3'-dithiobis (propionic acid) derivative of formula (I) wherein R is a hydroxy group or a 2-carboxylpyrrolidin-1-yl group. Bunte salt of the general formula wherein R is as defined above, Me is reacted with an acid in the presence of a metal atom, preferably an alkali metal atom, an organic solvent and, if desired, a catalyst. Process according to claim 1, characterized in that the organic solvent is dimethylsulfoxide. The process according to claim 1, wherein the catalyst is an organic amino compound. 4. A process according to claim 3 wherein the organic amino compound is a tertiary amine. 5. The process of claim 4 wherein the tertiary amine is triethylamine. 6. A process according to claim 1, wherein the Bunte salt of formula II is reacted in a reaction mixture of a halogen compound of formula IV wherein R is as defined in claim 1, with Hal being a halogen atom and a metal thiosulphate. acid. The process according to claim 1 or 6, wherein the acid is a mineral acid. 8. A process according to claim 7 wherein the mineral acid is hydrochloric acid.