CS257300B2 - Production method of 4-hydroxy-2-oxo-pyrrolidin-1-yl-acetamide - Google Patents

Abstract

A new method of producing cerebrally effective 4-Hydroxy-2-oxopyrrolidin-1-yl-acetamide, starting from 4-alkoxy-3-pyrrolin-2-on-1-yl-acetic alkyl esters acid.

Description

The present invention relates to a novel process for the preparation of an orally active 4-hydroxy-2-oxo-pyrrolidin-1-yl-acetamide. From Pfifferi et al., II Farmaco, Ed. Sc., 1977, 32, 602, a five-step preparation of 4-hydroxy-2-oxo-pyrrolidin-1-yl-acetamide is known. However, due to expensive starting materials and an overall yield of about 33.8%, this process is not profitable. Therefore, the task was to find another way that would not have the shortcomings mentioned.

The object was solved by the process according to the invention. 4- (C1-C4) -alkoxy-3-pyrrolin-2-one-1-yl-acetic acid in the form of (C1-C4) alkyl ester, preferably 4-methoxy-3-pyrrolin-2-one-1-ethyl ester -yl acetic acid is treated with an acidic anhydrous medium, the product is hydrogenated and then amidated with ammonia.

Preferably, the following procedure is performed:

The acidic medium is preferably prepared by introducing hydrogen chloride or hydrogen bromide gas into a C 1 -C 4 -carboxylic acid, which is optionally anhydrous.

A preferred C 1 -C 4 -carboxylic acid is acetic acid. Hydrogen chloride gas in acetic acid is particularly preferably used. The reaction temperature is chosen between 0 and 50 ° C.

After a reaction time of from 5 to 10 hours, the reaction mixture may be worked up in the usual manner, for example by evaporation of the solvent and optionally crystallization.

Conversion of 2,4-dioxo-pyrrolidin-1-yl-acetic acid (C 1 -C 4) -alkyl ester, especially ethyl ester, to the final product 4-hydroxy-2-oxo-pyrrolidin-1-yl-acetamide by reduction with sodium borohydride and following amidation with ammonia is described in the literature (G. Pifferi, M. Pinza, 11 Farmaco, Ed. Sc., 1977, 32, 602). Thus, 4-hydroxy-2-oxo-pyrrolidin-1-yl-acetamide is obtained as a pure white product in good yield.

Example

(a) Preparation of 2,4-dioxo-pyrrolidin-1-yl-acetic acid ethyl ester

Dissolve 10.0 g of 4-methoxy-3-pyrrolidin-2-one-1-yl-acetic acid ethyl ester (content by gas chromatography: 80%) in 50.0 ml of acetic acid and it is saturated with hydrogen chloride gas while stirring. Finally, the acetic acid is evaporated on a rotary evaporator under vacuum at a bath temperature of 60 ° C. The residue is taken up in 50.0 ml of toluene and evaporated again. 12.4 g of crude product are obtained, which crystallizes in a refrigerator.

b) Preparation of 4-hydroxy-2-oxo-pyrrolidin-1-yl-acetic acid ethyl ester

12.2 g of the crude product obtained above are dissolved in 50.0 ml of acetonitrile and added at room temperature to a suspension of 1.6 g of sodium borohydride in 50.0 ml of acetonitrile. The reaction temperature rises to 35 to 40 ° C. The reaction solution was stirred at this temperature for one hour. It is then acidified with concentrated hydrochloric acid to a pH of about 5. The solvent is removed by rotary evaporation, the residue is diluted with 25 ml of ice-water and extracted with methylene chloride. After drying the methylene chloride solution with sodium sulfate and evaporating the solvent, it remains

9.5 g of crude product which, according to HPLC, contained 51.5% of the compound to be prepared, corresponding to a yield of 66.1% based on 4-methoxy-3-pyrrolin-2-on-1-yl-acetic acid starting ethyl ester.

Chromatography on silica gel using acetic acid as the eluent gave a product which contained more than 96% of the title compound as determined by HPLC.

c) Preparation of 4-hydroxy-2-oxo-pyrrolidin-1-yl-acetamide

13.7 g (73 mmol) of 4-hydroxy-2-oxo-pyrrolidin-1-yl-acetic acid ethyl ester are dissolved in 500 ml of methanol and saturated at 0 ° C with ammonia. It is then maintained at room temperature for one hour. Evaporation of the solvent under vacuum gave a solid residue which was crystallized from methanol.

7.17 g (62%) of the product are obtained in the form of a white powder. Mp 165-168 ° C. XR (nujol) 3400 cm ^-1 , 3300 cm ^-1 , 3250 cm ^-1 (OH and NH), 1660 cm ^-1 (C = O).

SUBJECT OF THE INVENTION

Claims (4)

Process for the preparation of 4-hydroxy-2-oxo-pyrrolidin-1-yl-acetamide, characterized in that 4- (C 1 -C 4) -alkoxy-3-pyrroline-2- (C 1 -C 4) -alkyl ester is produced. on-1-yl-acetic acids of the general formula wherein R 1 is C 1 -C 2 alkyl and R 1 is C 1 -C 4 alkyl, in an anhydrous acid medium converts to (C 1 -C 4) -alkyl ester 2,4 -dioxo-pyrrolidin-1-yl-acetic acid, which is optionally isolated and then hydrogenated with sodium borohydride to give 4-hydroxy-2-oxo-pyrrolidin-1-yl-acetic acid C 1 -C 4 -alkyl ester and finally amidation treatment with ammonia converts the 4-hydroxy-2-oxo-pyrrolidin-1-yl-oenoic acid C 1 -C 4 -alkyl ester to the desired end product. 2. The process of claim 1, wherein the anhydrous medium is prepared by introducing hydrogen chloride or hydrogen bromide gas into the anhydrous C1-C4-carboxylic acid. 3. The process according to claim 1, wherein acetic acid is used as the anhydrous C1-C4-carboxylic acid. 4. The process of claim 1, wherein hydrogen chloride gas in anhydrous acetic acid is used.