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

A technology of pyrrolidine acetamide and oxo, which is applied in the fields of nervous system diseases, organic chemistry, drug combination, etc., and can solve problems such as difficult recovery, affecting the yield of oxiracetam, and large amount of solvent

Active Publication Date: 2009-02-18
CHONGQING RUNZE PHARM CO LTD
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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

Method used

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

Examples

Experimental program
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Effect test

Embodiment 1

[0076] A kind of preparation method of (S)-4-hydroxyl-2-oxo-1-pyrrolidineacetamide, its concrete steps are:

[0077] (a) Put 518.4g of glycinamide hydrochloride, 394g of sodium bicarbonate and 3.7L of absolute ethanol into a three-necked reaction flask, control the pH value to about 7.4, and heat up to reflux under stirring;

[0078] (b) After reflux for 2 hours, gradually add 781.6 g of (S)-4-chloro-3-hydroxybutyric acid ethyl ester dropwise, in the process of dropping, add the remaining sodium bicarbonate 394 g in 8 batches, and pass the pH value Check and control the amount of alkali added each time to ensure that the pH value of the reaction≤8.5;

[0079] (c) After (S)-4-halo-3-hydroxybutyrate was added dropwise, the reaction was refluxed for 24 hours, and the product (S)-4-hydroxyl-2-oxo-1-pyrrolidineacetamide was determined by HPLC When the content is 75%, the reaction is terminated, and the obtained solution is hot-filtered and concentrated to obtain the crude product ...

Embodiment 2

[0083] A kind of preparation method of (S)-4-hydroxyl-2-oxo-1-pyrrolidineacetamide, its concrete steps are:

[0084] (a) Put 28.50 g of glycinamide hydrochloride, 20.65 g of sodium bicarbonate and 200 ml of absolute ethanol into a three-necked reaction flask, control the pH value to about 7.4, and heat up to reflux under stirring;

[0085] (b) After 2 hours of reflux, 39.08 g of (S)-4-chloro-3-hydroxybutyric acid ethyl ester was gradually added dropwise. During the dropwise addition, 20.65 g of the remaining sodium bicarbonate was added in 5 batches, and the pH value was passed. Check the amount of alkali added each time to ensure that the pH value of the reaction≤8.5;

[0086](c) After (S)-4-halo-3-hydroxybutyrate was added dropwise, the reaction was refluxed for 24 hours, and the product (S)-4-hydroxyl-2-oxo-1-pyrrolidineacetamide was determined by HPLC The reaction was terminated when the content was 74%, and the obtained solution was hot filtered and concentrated to obtai...

Embodiment 3

[0090] A kind of preparation method of (S)-4-hydroxyl-2-oxo-1-pyrrolidineacetamide, its concrete steps are:

[0091] (a) Put 277.1g of glycinamide hydrochloride, 210.6g of sodium bicarbonate and 2000ml of absolute ethanol into a three-necked reaction flask, control the pH value to about 7.4, and heat up to reflux under stirring;

[0092] (b) After reflux for 2 hours, gradually add 417.8 g of (S)-4-chloro-3-hydroxybutyric acid ethyl ester dropwise. During the dropwise addition, add the remaining sodium bicarbonate 210.6 g in 8 batches, and pass the pH value Check the amount of alkali added each time to ensure that the pH value of the reaction≤8.5;

[0093] (c) After (S)-4-halo-3-hydroxybutyrate was added dropwise, the reaction was refluxed for 24 hours, and the product (S)-4-hydroxyl-2-oxo-1-pyrrolidineacetamide was determined by HPLC The reaction was terminated when the content was 72%, and the obtained solution was hot filtered and concentrated to obtain the crude product of...

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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...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/273A61P25/00
Inventor 陈宇瑛荣祖元叶雷平原于媛媛
Owner CHONGQING RUNZE PHARM CO LTD
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