HU206198B - Process for producing rhodanidoisobutyric acid - Google Patents

Abstract

2-(methyl)-3-(rhodanido)-propionic acid of formula (I) is new. USE/ADVANTAGE - (i) (Esp. the S-enantiomer) is an intermediate in the prepn. of 1-(3'-(mercapto)-(2's)- (methyl)-propionyl)pyrrolidine-(2s)-carboxylic acid (captopril) which can be used to reduce blood pressure. The prepn. of captopril from L-proline using (I) gives yields of more than 50% (based on L-proline) compared to e.g. a previous process using 3-(ethanoylthio)-2-(methyl)propionic acid as acylating agent, which gave yields of only 10% (based on L-proline) other processes were little better, giving yields of 30% or 34-35%. The prepn. using (I) is simple. (I) is itself produced by a simple and economical process.

Description

The present invention relates to a process for the preparation of 2-methyl-3-rhodanido-propionic acid of formula (I). 2-Methyl-3-rhodanidopropionic acid is a novel compound and is useful as an intermediate in the preparation of antihypertensive agents, such as 1- [3-mercapto- (2S) -methyl-loxopropyl] -L-proline (captopril) of formula (III). , which, inter alia, is incorporated herein by reference in its entirety under No. 2703 828. is known from the German patent specification.

The compound of formula (I) contains a chiral carbon atom and may therefore exist in the form of optically active isomers and mixtures thereof. The present invention relates to the preparation of both optically active isomers and mixtures thereof in any proportion.

According to the invention, the 2-methyl-3-rhodanido-propionic acid of formula (I) is prepared by reacting an isobutyric acid derivative of formula (II) wherein X is a halogen atom or a group of the formula R-SO ₂ -O-, wherein R is C 1-4 alkyl, phenyl or methyl substituted with a rhodanide of formula (IV) wherein A is an alkali metal ion, an alkaline earth metal ion or a quaternary ammonium ion of formula (a) wherein R ¹ , R ² , R ³ and R ⁴ is independently hydrogen, (C 1 -C 4) alkyl or benzyl.

In formula II, X is preferably bromine or chlorine or methanesulfonyloxy, benzenesulfonyloxy or p-toluenesulfonyloxy.

In the formula (IV), A is an alkali metal ion, preferably sodium or potassium, an alkaline earth metal, preferably a calcium ion, or a quaternary ammonium ion of the formula (a), preferably ammonium, tetramethylammonium tetrabutylammonium or trimethylbenzylammonium . Accordingly, the compound of formula (IV) is preferably sodium rhodanide, potassium rhodanide, calcium rhodanide, ammonium rhodanide, tetramethylammonium rhodanide, tetrabutylammonium rhodanide or trimethylbenzylammonium rhodanide.

Particularly preferred is potassium rhodanide as a compound of formula IV.

The rhodanide of formula (IV) is generally taken in excess of the compound of formula (II). One mole of the latter is conveniently reacted with 1.2 to 3.0 moles, preferably about 2 moles, of the compound of formula IV.

The reaction of the compounds of the formulas II and IV is carried out in a homogeneous or heterogeneous system. In order to provide a homogeneous phase reaction mixture, the reaction medium is an inert organic solvent, preferably a polar aprotic organic solvent such as dimethylformamide, dimethylsulfoxide, acetonitrile, acetone, methyl ethyl ketone, ethyl acetate and the like. The heterogeneous system is provided by a combination of water and a water immiscible organic solvent such as an aromatic hydrocarbon such as benzene, toluene or xylene, a halogenated aliphatic or aromatic hydrocarbon such as dichloromethane, dichloroethane or chlorobenzene, preferably toluene.

The reaction is generally carried out at a temperature of 0 ° C to 100 ° C. The homogeneous phase is preferably carried out at 41 ° C to 60 ° C, and the heterogeneous phase preferably at 0 ° C to 25 ° C.

The reaction of the compounds of the formulas II and IV is generally carried out at a pH of 2 to 9. The reaction is preferably carried out at pH 6-7 by addition of an inorganic or organic base, preferably sodium hydroxide, and after completion of the reaction, the reaction mixture is acidified to pH 2-3 with 2-methyl-3-rhodanido-propionic acid. release.

The compound of formula I is isolated by conventional methods of preparative organic chemistry, preferably organic solvent extraction and evaporation of the organic solvent solution. For the extraction, an organic solvent immiscible with water, such as an aromatic hydrocarbon such as benzene or toluene, a halogenated aliphatic or aromatic hydrocarbon such as dichloromethane, dichloroethane or chlorobenzene, an ester such as ethyl acetate, ether such as diethyl ether, and the like. used.

Most of the starting compounds of formulas II and IV are commercially available or can be prepared in a known manner. Compounds of formula (II) wherein X is R-SO ₂ -General can be prepared from 3-hydroxy-2-methylpropionic acid by esterification with the appropriate alkyl or arylsulfonyl chloride.

Starting from the racemic compound of formula (II) in the process of the invention yields a racemic compound of formula (I) which can be resolved into its antipodes in a manner known per se. When the optically active isomer of formula (II) is used as starting material in the process of the invention, the corresponding optically active enantiomer of formula (I) is obtained in advance. Separation of the enantiomers of the racemic compound of formula (I) may be accomplished by physical resolution, by resolution of the enantiomers other than the racemic compound, or by resolution with an optically active organic base.

The resolution is carried out in a manner known per se.

Optically active organic bases have been found to be (-) (aS) -methyl-benzomethanamine.

Suitable media for salt formation and crystallization are inert organic solvents such as aromatic hydrocarbons such as benzene or toluene, esters such as ethyl acetate, ethers such as diethyl ether and the like. employed.

Preferably, the process of the invention provides (2S) -methyl-3-rhodanido-propionic acid.

The process of the invention can be carried out simply and economically.

The invention is illustrated in detail by the following examples.

Example 1

2-Methyl-3-rhodanidopropionic acid

Bromo-2-methylpropionic acid (16.7 g) was dissolved in toluene (50 ml), cooled to 0 ° C, and potassium rhodanide (19.42 g) and water (5 ml) were added. The reaction1

Add 10N sodium hydroxide solution dropwise to 198 Β to adjust the pH to 6.5.

The resulting light yellow biphasic solution was stirred at 25 ° C for 48 hours while maintaining the pH at 6.4-6.6 with additional sodium hydroxide solution. The reaction mixture was cooled to 0 ° C and adjusted to pH 2.7 with 10 N sulfuric acid, filtered, and the organic phase separated. The aqueous phase was extracted with toluene (5 x 20 mL) and the combined organic layers were extracted with water (10 mL). The resulting pale yellow toluene solution was dried over anhydrous magnesium sulfate and concentrated in vacuo.

11.13 g (76.7%) of the title compound are obtained. op .:

24-25 ° C.

Content by gas chromatography: 9899%.

Infrared (film): vNCS = 2157 cm ^-1 .

Example 2

2-Methyl-3-rhodanidopropionic acid

The procedure described in Example 1 was followed except that diethyl ether was used instead of toluene in both the dissolution of the 3-bromo-2-methylpropionic acid and the extraction of the resulting product.

13.79 g (95%) of the title compound are obtained. M.p. 24-25 ° C.

Example 3

2-Methyl-3-rhodanido-propionic acid

All were prepared as in Example 1, but using 3-methanesulfonyloxy-2-methylpropionic acid instead of 3-bromo-2-methylpropionic acid. Yield: 82%.

Preparation of 3-methanesulfonyloxy-2-methylpropionic acid 10.6 g of 3-hydroxy-2-methylpropionic acid are dissolved in 80 ml of pyridine. The resulting solution was cooled to -20 ° C and 13.2 ml of methanesulfonic acid chloride was added dropwise at this temperature over 2 hours. After 3 hours at -10 ° C, the reaction mixture was allowed to return to room temperature and added to 500 ml of ice water and adjusted to pH 1 with 10% sulfuric acid.

The reaction mixture was extracted with ethyl acetate (4 x 100 mL). The organic layer was dried over MgSO ₄ and concentrated in vacuo. The residue was crystallized from hexane.

13.2 g (72.5%) of the title compound are obtained. M.p. 93-95 ° C.

Example 4

2-Methyl-3-rhodanidopropionic acid

In all cases, the procedure was as in Example 1, but 3-bromo. 3-Chloro-2-methyl-propionic acid is used instead of 2-methyl-propionic acid.

Yield: 64%.

Example 5

A) (2S) -Methyl-3-rhodanido-propionic acid - [(aS) -methyl-benzomethanamine] salt

14.52 g of the racemic 2-methyl-3-rhodanido-propionic acid prepared in Example 1 are dissolved in 20 ml of toluene and 8.48 g of (aS) -methyl-benzomethanamine in 16.5 ml of toluene are added dropwise with stirring. solution for 5 minutes while the temperature rises from 26 ° C to 46 ° C. The resulting light yellow solution was heated at 50 ° C for 1 hour, then cooled to 25 ° C and added 1 _; 33 products of the title. The resulting crystalline suspension was stirred at 0 ° C for 1 hour and then filtered. The resulting crystals were washed with chilled toluene (3 x 10 mL) and dried.

10.91 g (72%) of the title salt are obtained. 90.291.8 ° C.

[A] D: -54.8 ° (c = l, water)

Optical purity: 93%.

Repeating the resolution procedure yields 99% optical purity. M.p. 92-94 ° C.

B) (aS) -Methyl-3-rhodanido-propionic acid

26.63 g of the twice-resolved product of part A above are dissolved in 100 ml of water and 100 ml of ethyl acetate are added. The biphasic mixture was cooled to 0 ° C and 10% sulfuric acid was added dropwise until the pH of the aqueous phase was 2.5. The organic layer was separated, the aqueous layer was extracted with ethyl acetate (4 x 20 mL), and the combined organic layers were extracted with water (30 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo.

13.9 g (95.8%) of (2S) -methyl-3-rhodanido-propionic acid are obtained.

[a] ² ₅ 7 ⁵ 8: -68 ° (c = 1, CHC1 ₃₎

The extracted aqueous phases from A and B above are combined, basified with 20% aqueous sodium hydroxide solution, extracted with 3 x 200 ml benzene, and the combined organic solutions are dried over anhydrous magnesium sulfate and concentrated. In this way, about 90% of the amount of (aS) -methylbenzomethanamine used is recovered.

Example 6

2-Methyl-3-rhodan ido-propionic acid

The l. The procedure is the same as described in Example 1, except that 15.23 g of ammonium 40 µmodium rhodanide are used instead of potassium rhodanide. The yield of Example 1 gives the title compound.

Claims (5)

A process for the preparation of 2-methyl-3-rhodanido-propionic acid, its optical isomers and its salts, characterized in that an isobutyric acid derivative of the formula (II) wherein X is a halogen atom or a A group R 50 -SO ₂ -O- wherein R is C 1-4 alkyl, phenyl or methyl substituted with a rhodanide of formula IV wherein A is an alkali metal ion, an alkaline earth metal ion or a compound of formula (a); quaternary ammonium ion wherein R ¹ , R ² , R ³ and R ⁴ are independently hydrogen, C 1 -C 4 alkyl or benzyl, and then optionally converting the compound of formula (I) to a salt and / or resolving it into an optical isomer we separate it. HU 206 198 Β 2. A process according to claim 1 wherein the compound of formula II is 2-methyl-3-bromopropionic acid. 3. A process according to claim 1 wherein the compound of formula II is 2-methyl-3-chloropropionic acid. employed. 4. The process of claim 1 wherein the compound of formula II is 2-methyl-3- (methanesulfonyloxy) propionic acid. 5. A process according to claim 1 wherein the compound of formula IV is potassium rhodanide.