CS271493B2 - Method of 4-benzyloxy-3-pyrroline-2-on-1-yl-acetamide production - Google Patents

Abstract

4-benzyloxy-3-pyrroline-2-on-1-ylacetamide, is a suitable semi-product for the production of pharmaceutically efficient 4-hydroxypyrrolidine-2-on-1-ylacetamide is obtained through a reaction of 4-alkoxy-3-pyrroline-2-on, where the alkoxyl part contains 1 to 4 carbon atoms, with benzyl alcohol in the presence of a catalytic amount of acid at a temperature of 60 to 100 degrees C to 4-benzyloxy-3-pyrroline-2-on, which is alkylated by alkyl ester of a 2-bromoacetic acid, in which the alkyl part contains 1 to 4 carbon atoms, at a temperature of 0 to 40 degrees C in the presence of an alkaline metal hydride to alkyl ester of 4-benzyloxy-3-pyrroline-2-on-1-yl-acetic acid, in which the alkyl part of the alkyl ester contains 1 to 4 carbon atoms and this one is left to react with the ammoniac at a temperature of 60 to 80 degrees C of the final product.

Description

(57) 4-Benzyloxy-3-pyrrolin-2-one-1-ylacetamide, a useful intermediate for the preparation of pharmaceutically active 4-hydroxypyrrolidin-2-one-1-ylacetamide, is obtained by reacting 4-alkoxy-3. -pyrrolin-2-one in which the alkoxy moiety contains 1 to 4 carbon atoms, with benzyl alcohol in the presence of a catalytic amount of an acid at 60 to 100 ° C to 4-benzyloxy-3-pyrrolin-2-one which is alkylated with an alkyl ester of the acid 2-bromoacetic acid in which the alkyl moiety contains 1 to 4 carbon atoms, at a temperature of 0 to 40 ° C in the presence of an alkali metal hydride to the alkyl ester of 4-benzyloxy-3-pyrrolin-2-on-1-ylacetic acid in which the alkyl moiety The alkyl ester contains 1 to 4 carbon atoms and is reacted with ammonia at a temperature of 60 to 80 ° C to give the final product.

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CS 271 492 B2

The new 4-benzyloxy-3-pygolin-2-one-1-ylacetamide is a valuable intermediate for the synthesis of cerebrally active 4-hydroxypyrrolidin-2-one-1-ylacetamide (oxiracetam).

Pifferi et al., II Farmaco, Ed. Sc., 32, 602 (1977) is a known way to make an active ingredient.

however, poor yields and expensive starting material make this process unprofitable.

Therefore, the task is to find a way to overcome these disadvantages.

Remarkably, this problem can be solved simply by the novel 4-benzyloxy-3-pyrrolin-2-one-1-ylacetamide disclosed. This compound is accessible from 4-alkoxy-3-pyrrolin-2-one in which the alkoxy moiety contains 1 or 2 carbon atoms. Without further measures, compounds having longer alkoxy groups are useful as starting materials. Since these groups cleave again during the reaction, such compounds are not of interest.

The starting 4-alkoxy-3-pyrrolin-2-one in which the alkoxy moiety contains 1 or 2 carbon atoms is reacted in the first step in the presence of an acid with benzyl alcohol to give 4-benzyloxy-3-pyrrolin-2-one. Suitably the acids used for this reaction step are sulfonic acids, such as methanesulfonic acid or p-toluenesulfonic acid, in a catalytic amount which expediently amounts to 0.05 to 0.2 parts by molar. It is preferred to work directly in benzyl alcohol as a solvent. The benzyl alcohol is suitably used in an amount of 1.5 to 5 parts by mol per 1 part by mol of the starting material. The reaction temperature is preferably in the range of from 60 to 100 ° C. Since this reaction is formally a re-esterification reaction, it is preferred that the reaction be carried out under a reduced pressure of between 1 and 5 kPa to remove the elimination of the lower-boiling alcohols from the equilibrium mixture. After completion of the reaction, i.e. after about 10 to 25 hours (depending on the catalyst, eulfonic acid and amount thereof), the 4-benzyloxy-3-pyrrolin-2-one can be worked up in the usual manner, for example by azeotropic separation of excess benzyl alcohol and product.

In the second step, the product obtained is reacted with an alkyl bromoacetate in which the alkyl portion of the alkyl ester contains 1 to 4 carbon atoms, in the presence of an alkali metal hydride to the 4-benzyloxy-3-pyrrolin-2-on-1-ylacetic acid alkyl ester, in wherein the alkyl portion of the alkyl ester contains 1 to 4 carbon atoms. The preferred alkyl bromoacetate is ethyl bromoacetate, suitably in an amount of 1 to 5

1.5 parts molar to 1 part molar of 4-benzyloxy-3-pyrrolin-2-one. Preferred alkali metal hydride is sodium hydride, in an amount of 1 to 1.5 parts molar per 1 part molar of 4-benzyloxy-3-pyrrolin-2-one. Preferably, it is operated in a polar aprotic solvent

a solvent such as dimethylformamide, dimethylacetamide, acetonitrile, acetonitrile being particularly preferred as solvent, at a reaction temperature between 0 and 40 ° C.

The resulting 4-benzyloxy-3-pyrrolin-2-one-1-ylacetic acid alkyl ester in which the alkyl portion of the alkyl ester contains 1 to 4 carbon atoms can then be reacted with ammonia to form 4-benzyloxy-3-pyrroline- 2-on-1-ylacetamide. Suitably, the starting material is dissolved in an alcohol such as methanol or ethanol, the alcohol previously being Rasycen with ammonia at -10 to 0 ° C, and then the reaction mixture is stirred in an autoclave at a reaction temperature between 60 and 80 ° C. ° C for 10-15 hours.

After conventional work-up, 4-benzyloxy-3-pyrrolin-2-one-1-ylacetamide can be obtained in good yield and quality.

The new 4-benzyloxy-3-pyrrolin-2-one-1-ylacetamide is a suitable novel intermediate for the preparation of the active substance, 4-hydroxypyrrolidin-2-one-1-ylacetamide.

CS 271 492 B2

Example 1

a) A method for producing 4-benzyloxy-3-pyrrolin-2-one

To 5.7 g of 4-methoxy-3-pyrrolin-2-one and 10.8 g of benzyl alcohol, 0.4 g of methanesulfonic acid is added and the mixture is stirred for 24 hours at 80 ° C and 2 kPa. 50 ml of ice-water and 100 ml of methylene chloride are then added to the reaction solution and neutralized with 4 ml of saturated sodium bicarbonate solution. The aqueous phase is extracted twice more with 50 ml of methylene chloride each time. After drying the organic phase with sodium sulfate and distilling off the solvent, 150 ml of ice-water are added to the residue, heated to 100 DEG C. and 100 ml of water and benzyl alcohol are distilled off azeotropically. The crystals precipitated upon cooling are recrystallized hot from 50 ml of toluene. 6.7 g of white crystalline product are obtained, m.p. 147-148 ° C. NMR (300 MHz, DMSO-d6):?

7.38 (m, 5H), 6.20 (broad s, 1H), 5.16 (s, 1H), 4.98 (s, 2H), 3.98 (s, 2H), mass spectrum (70 eV):

189 (M ^& lt ^{; +} & gt ^; , 40), 172 (18), 132 (51), 91 (100).

b) A method for producing 4-benzyloxy-3-pyrrolin-2-one-1-ylacetamide from 4-benzyloxy-3-pyrrolin-2-one

8.4 g of 4-benzyloxy-3-pyrrolin-2-one and 9.8 g of ethyl bromoacetate (95%) are dissolved in 50 ml of anhydrous acetonitrile and cooled to 0 ° C. To this reaction solution was added 1.67 g of sodium hydride (80% in white oil) over 20 minutes. The mixture was allowed to stir for 2 hours, acidified to pH 6-7 with concentrated hydrochloric acid and the solvent was distilled off. The residue is taken up in water and methylene chloride. After separation of the organic phase, 14.4 g of crude product are obtained. This crude product was dissolved in 20 ml of methanol, which had previously been saturated with ammonia gas at -10 to 0 ° C. In the autoclave, the reaction solution was stirred at 60-80 ° C for 12 hours. After methanol was distilled off and the crude product was washed with carbon tetrachloride, recrystallization from water was carried out. 5.1 g of product are obtained which is pure by thin layer chromatography.

Claims (3)

SUBJECT OF THE INVENTION Process for the preparation of 4-benzyloxy-3-pyrrolin-2-one-1-ylacetamide, characterized in that 4-alkoxy-3-pyrrolin-2-one is reacted in which the alkoxy moiety contains 1 to 4 carbon atoms , with benzyl alcohol in the presence of a catalytic amount of acid at 60 to 100 ° C to 4-benzyloxy-3-pyrrolin-2-one, the resulting intermediate is alkylated with an alkyl ester of 2-bromoacetic acid in which the alkyl moiety contains 1 to 4 carbon atoms, 0 to 40 ° C in the presence of an alkali metal hydride to an alkyl ester of 4-benzyloxy-3-pyrrolin-2-one-1-ylacetic acid in which the alkyl portion of the alkyl ester contains 1 to 4 carbon atoms, optionally in the resulting reaction mixture It is reacted with ammonia at a temperature of 60-80 ° C to give the final product. 2. A process according to claim 1, wherein the acid for the reaction of 4-alkoxy-3-pyrrolin-2-one in which the alkoxy moiety contains 1 or 2 carbon atoms is sulfonic acid. 3. The process according to claim 1, wherein the reaction of the 4-alkoxy-3-pyrrolin-2-one in which the alkoxy moiety contains 1 to 4 carbon atoms is carried out under reduced pressure of 1 to 5 kPa.