HU209820B - Process for producing of 1-/2-methyl-1-oxo-3-rhodanidopropyl/-proline - Google Patents

Abstract

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

Description

The present invention relates to a process for the preparation of 1- (2-methyl-1-oxo-3-rhodanido-propyl) -proline of formula (I). 1- (2-Methyl-1-oxo-3-rhodanido-propyl) -proline is a novel compound and useful as an intermediate in lowering blood pressure, such as 1- [3-mercapto- (2S) -methyl-1-oxo of formula (V). propyl] -L-proline (captopril), which is disclosed, inter alia, in U.S. Pat. is known from the German patent specification.

The compound of formula (I) contains two chiral centers and may therefore exist in the form of optically active isomers and various mixtures thereof. The present invention relates to the preparation of each optically active isomer or mixture thereof in any proportion.

According to the present invention, the compound of formula (I) is prepared by acylating the proline with an active acylating derivative of rhodanidoisobutyric acid of formula (II), e.g.

In a preferred embodiment of the process of the invention, the proline is acylated with a mixed anhydride of formula (IV) wherein R is a C 1 -C 5 alkyl group or a benzyl group. When R is C 1 -C 5 alkyl, it is suitably methyl, ethyl, isobutyl or benzyl.

The acylation of proline is conveniently carried out in a solvent which is inert to the reaction components and at least slightly solubilizes the proline. For this purpose, alkanols such as ethanol, halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform, ketones such as acetone, ethers such as tetrahydrofuran, esters such as ethyl, acetate etc.

The active acylating derivative of rhodanido-isobutyric acid of formula (II) is generally used in an excess of 10-20% relative to the stoichiometric amount.

The acylation of proline is generally carried out at a temperature of from 0 ° C to -40 ° C, preferably from -5 ° C to -10 ° C.

In a preferred embodiment of the process of the invention described above, the proline is optionally reacted with a compound of formula IV in the presence of an acid scavenger. The organic acid bases used are organic bases, preferably pyridine, methylpyridine or dimethylpyridine.

The mixed anhydride of formula (IV) is prepared by reaction of rhodanido isobutyric acid (II) with a chloroformate of formula (III) wherein R is in the presence of an acid acceptor in an inert organic solvent. Preferred inert organic solvents are the organic solvents listed above, and organic bases such as pyridine, methylpyridine or dimethylpyridine are used as the acid scavenger. The reaction is carried out at a temperature of from -40 ° C to -40 ° C, preferably from -5 ° C to -10 ° C. Preferably the chloroformate ester of formula (III) is methyl chloroformate, ethyl chloroformate, isobutyl ester of chloroformate or benzyl ester of chloroformate.

In a particularly preferred embodiment of the process according to the invention, the reaction mixture obtained in the above preparation of the mixed anhydride of formula IV is carried out by acylation of proline.

The compound of formula (I) obtained by proline acylation is isolated by conventional methods of preparative organic chemistry. Preferably, the acylation reaction mixture is acidified and the compound of formula (I) is isolated or extracted with a water immiscible organic solvent and the product crystallized.

Both rhodanido-isobutyric acid of formula II and its active acylating derivatives, such as mixed anhydrides of formula IV, are new compounds.

The rhodanido isobutyric acid of formula (II) may be prepared by reacting an isobutyric acid derivative of formula (VI) with a rhodanide of formula (VII). In the formulas, X represents a halogen atom or a group of the formula R * -SO 2 -O-, wherein R ¹ represents a C 1 -C 4 alkyl group or a phenyl group optionally substituted by a methyl group, A represents an alkali metal atom, an alkaline earth metal atom or a group wherein R ² , R ³ , R ⁴ and R ⁵ are each independently hydrogen, C 1-4 alkyl or benzyl.

The chloroformic acid esters of formula (III) are commercially available or can be prepared in a known manner.

Preferably, the process of the invention is based on L-proline. When racemic (II) rhodanido-isobutyric acid is used, a mixture of two diastereomers is obtained. The diastereomers may be separated in a manner known per se.

If the compound of formula (I) is to be used for the preparation of captopril of formula (V), it is convenient to start from the corresponding enantiomer of formula (II), i.e. (2S) methyl-3-rhodanido-propionic acid and L-proline. In this case, the process of the present invention provides 1 - [(2S) -methyl-1-oxo-3-rhodanido-propyl] -L-proline directly.

The (2S) -methyl-3-rhodanido-propionic acid is conveniently prepared by resolution from the racemic compound.

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

The invention is illustrated in detail by the following examples.

Example 1

- [(2S) -Methyl-1-oxo-3-rhodanido-propyl] -L-proline

Dissolve 29.4 g of (2S) -methyl-3-rhodanido-propionic acid in 400 ml of dichloromethane. The resulting solution was cooled to -10 ° C and 17.38 g of pyridine was added dropwise followed by 30.05 g of isobutyl chloroformate over 10 minutes. The resulting suspension is maintained at -5 ° C to 10 ° C for 10 minutes, 23.06 g of L-proline and 15.8 g of pyridine are added over 5 minutes. The suspension is kept at -5 ° C for 1 hour and then allowed to return to room temperature. Water (300 mL) was added to the reaction mixture, cooled to 0 ° C and adjusted to pH 1 with 10% sulfuric acid.

HU 209,820 Β

The organic layer was separated and the aqueous layer was extracted with water (400 mL). The organic layer was dried over anhydrous magnesium sulfate, concentrated in vacuo and ether (50 mL) was added to the residue. The resulting crystalline suspension was kept at 0 ° C for several hours. The resulting crystals were filtered and washed with chilled benzene. 29.13 g (60.1%) of the title product are obtained.

M.p .: 135-136 'C. [d] - 266.4 °) c = 1 chloroform)

Infrared (potassium bromide) v value, cm ^-1 : 2153 (NCS), 1727 (CO, acid).

Example 2

1 - [(2S) -Methyl-1-oxo-3-rhodanido-propyl] -L-proline

The procedure of Example 1 was followed except that racemic 2-methyl-3-rhodanido-propionic acid was used. 13.7 g (28.2%) of the title compound are obtained.

Mp: 101-103 'C.

[α] 578 = -1θθ ° (c = 1, chloroform)

Preparation of the starting compound

2-Methyl-3-rhodanido-propionic acid

16.7 g of 3-bromo-2-methylpropionic acid are dissolved in 50 ml of toluene, cooled to 0 ° C and added.

19.42 g of potassium rhodanide and 5 ml of water. The reaction mixture was added dropwise with 10 N sodium hydroxide solution to bring 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

X is extracted with 20 ml of toluene, and the combined organic phases are extracted with 10 ml of water. The resultant solution was dried over anhydrous magnesium sulfate and evaporated in vacuo.

11.13 g (76.7%) of the title product are obtained. M.p. 24-25 'C.

Content by gas chromatography: 9899%.

IR (film): Y = NCS 2157 cm ^1st

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

14.52 g of racemic 2-methyl-3-rhodanido-propionic acid are dissolved in 20 ml of toluene and a solution of 8.48 g of (aS) -methylbenzomethanamine in 16.5 ml of toluene is added dropwise with stirring over a period of 5 minutes. the temperature rises from 26 ° C to 46 ° C. The resulting light yellow solution is kept at 50 'C for 1 hour, then cooled to 25' C and 1.33 g of the title product is added. 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.

[α] D = -54.8 ° (c = 1; water)

Optical purity: 93%.

Repeating the resolution procedure gives a product of 99% optical purity, m.p. 92-94 ° C.

B) (2S) -Methyl-3-mdanido-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 7 S = -68 ° (c = l; CHCl3) The above a) and b) above residue, extracted aqueous layers were combined and basified with 20% aqueous sodium hydroxide solution, extracted with 3 x 200 ml of benzene, and the combined the organic solutions were dried over anhydrous magnesium sulfate and evaporated. In this way, about 90% of the amount of (aS) -methylbenzomethanamine used is recovered.

Example 3 1 - [(2S) -Methyl-1-oxo-3-rhodanido-propyl] -L-proline

The procedure described in Example 1 was followed except that pyridine was not added to the reaction mixture after the addition of L-proline. 30.05 g (62%) of the title compound are obtained, m.p. 135-136 ° C.

Example 4 1 - [(2S) -Methyl-1-oxo-3-rhodanido-propyl] -D-proline

The procedure described in Example 1 was followed except that D-proline was used instead of L-proline. 29 g (60%) of the title compound are obtained, m.p. 134-135 ° C.

[[alpha]] d = +265,4 'C (c = 1; chloroform)

Example 5 1 - [(2S) -Methyl-oxo-3-rhodanido-propyl] -L-proline

The procedure of Example 1 was followed except that the isobutyl ester of chloroformate was replaced by

Ethyl chloroformate (23.9 g) was used. The product obtained is identical to that described in Example 1.

Claims (4)

A process for the preparation of 1- (2-methyl-1-oxo-3-rhodanidopropyl) -proline of formula (I), characterized in that the proline is acylated with an active acylating derivative of rhodanido-isobutyric acid (II). Process according to claim 1, characterized in that the active acylating derivative of the rhodanido-isobutyric acid of the formula (II) is a mixed anhydride of the formula (IV), wherein R is a C 1 -C 5 -alkyl or a benzyl. HU 209,820 Β 3. A process according to claim 1 or 2, wherein the acylation of proline is carried out by reaction of rhodanido-butyric acid (II) with a chloroformate ester (III), wherein R is as defined in claim 2. The anhydride of formula IV is carried out in the reaction mixture. 4. A process according to any one of claims 1 to 3, wherein L-proline is used instead of racemic proline.