Preparation method for (S)-4-hydroxyl-2-oxo-1-pyrrolidine ethanamide

Abstract

The present invention provides a preparation method of (S)-4-hydroxyl-2-oxo-1-pyrrolidine acetamide. The preparation method comprises: (S)-4-halogen-3-hydroxyl butyric ester as a raw material reacts under the conditions with polar solvent and alkalinity to prepare the crude product of (S)-4-hydroxyl-2-oxo-1-pyrrolidine acetamide; and the crude product is purified. The preparation method is characterized in that inorganic alkali is added for a plurality of times in the reaction process under the condition with alkalinity so as to control the pH value in the reaction to be less than or equal to 8.5. A large quantity of repeated tests are completed to determine that the optimum pH value of the reaction under the condition with alkalinity is less than or equal to 8.5, and the alkali is added in batches to strictly control the pH value of the whole reaction process, so that the alkali conditions required in the reaction can be satisfied and the reaction can be performed completely, and the target product (S)-oxiracetam is prevented from being damaged in the alkaline solution, thereby improving the yield rate of the target product (S)-oxiracetam and reducing the cost.

Description

technical field [0001] The invention relates to a preparation method of (S)-4-hydroxy-2-oxo-1-pyrrolidineacetamide (the commercial name is (S)-oxiracetam, the same below). Background technique [0002] Oxiracetam is a nootropic drug synthesized for the first time in 1974 by the Italian Shi Kebichem Company. It is composed of two isomers (S)-oxiracetam ((S)-oxiracetam) and (R)- Oxiracetam ((R)-oxiracetam) composed of racemate. (S)-Oxiracetam is a single enantiomer of Oxiracetam, the chemical name is: (S)-4-hydroxy-2-oxo-1-pyrrolidineacetamide, and its chemical structure is as follows: [0003] [0004] According to WO93 / 06826, the two isomers of oxiracetam have different activities when used as brain function improvers, and the activity of (S)-oxiracetam is stronger than that of (R)-oxiracetam. [0005] The preparation method of (S)-oxiracetam in the patent WO2005 / 115978, wherein (S)-4-chloro-3-hydroxybutyrate and glycinamide react under alkaline conditions to obtain the...

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Problems solved by technology

[0005] The preparation method of (S)-oxiracetam in the patent WO2005 / 115978, wherein (S)-4-chloro-3-hydroxybutyrate and glycinamide react under alkaline conditions to obtain the final product oxiracetam The alkalinity of the reaction solution is controlled by one-time addition of alkali, but because oxiracetam is easily destroyed in a strong alkaline solution, this directly affects the yield of oxiracetam

[0006] In addition, in the preparation method of (S)-oxiracetam in the patent WO2005 / 115978, the reaction can be carried out at a temperature of 0-100°C, but in such a wide temperature range, the reaction efficiency varies greatly. Large, it still can not give a reaction temperature range with the highest product yield

[0007] In addition, silica gel column chromatography is used in the purification of the final product oxiracetam, and the eluent used is an organic mixed solvent. The amount of solvent is large, the pollution is large and difficult to recycle, the cost is high, and the silica gel column chromatography is not suitable Industrial production

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