Preparation method of (S)-4-hydroxy-2-oxo-1-pyrrolidine acetamide

A technology of pyrrolidine acetamide and oxo substitution, which is applied in the direction of organic chemistry, can solve the problems of high cost, failure to produce products, and difficulty in recycling, and achieve the effects of short reaction cycle, increased yield, and easy operation

Active Publication Date: 2012-08-22
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

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  • Preparation method of (S)-4-hydroxy-2-oxo-1-pyrrolidine acetamide
  • Preparation method of (S)-4-hydroxy-2-oxo-1-pyrrolidine acetamide
  • Preparation method of (S)-4-hydroxy-2-oxo-1-pyrrolidine acetamide

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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 When the content was 74%, the reaction was terminated, and the obtained solution was concentrated by hot filtration to obt...

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 When the content was 72%, the reaction was terminated, and the obtained solution was concentrated by hot filtration to obtain the crude product ...

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Abstract

The invention discloses a preparation method of (S)-4-hydroxy-2-oxo-1-pyrrolidine acetamide, comprising the following steps of: taking (S)-4-halogen-3-hydroxybutyrate and glycinamide or glycinamide hydrochloride as raw materials to react under the alkali condition through an alcohol solvent so as to obtain coarse products of the (S)-4-hydroxy-2-oxo-1-pyrrolidine acetamide; and then carrying out the purification process on the coarse products. The preparation method is characterized in that the reaction under the alkali condition is realized by adding inorganic base in the reaction process in times so as to control a pH value during the reaction to be <=8.5; the reaction is carried out under the condition of heating to flow backing; and the purification process is realized by utilizing ion-exchange resin and the recrystallization. In the invention, the main raw materials are the (S)-4-halogen-3-hydroxybutyrate and the glycinamide hydrochloride, both of which are products on sale; the raw materials are cheap, easily obtained, and environment-friendly without pollution; the preparation of the invention has short reaction period and is convenient and simple to operate; and the HPLC (High Performance Liquid Chromatography) purity of the prepared products of (S)-4-hydroxy-2-oxo-1-pyrrolidine acetamide is more than 98.5%.

Description

technical field [0001] The present invention relates to a preparation method of (S)-4-hydroxy-2-oxo-1-pyrrolidineacetamide (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)- Racemate of oxiracetam ((R)-oxiracetam). (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 fina...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D207/273
Inventor 陈宇瑛平原于媛媛叶雷荣祖元
Owner CHONGQING RUNZE PHARM CO LTD
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