Method for preparing (S)-4-hydroxide radical-2-oxo-1-pyrrolidine acetamide

A technology of pyrrolidine acetamide and oxo, applied in directions such as organic chemistry, can solve problems such as high cost, inability to provide products, and difficulty in recovery, and achieve the effects of short reaction cycle, improved yield, and easy operation.

Inactive Publication Date: 2012-07-25
CHONGQING RUNZE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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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  • Method for preparing (S)-4-hydroxide radical-2-oxo-1-pyrrolidine acetamide
  • Method for preparing (S)-4-hydroxide radical-2-oxo-1-pyrrolidine acetamide
  • Method for preparing (S)-4-hydroxide radical-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, the remaining sodium bicarbonate 20.65 g 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 obtain...

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-hydroxybutyrate ethyl ester dropwise. During the dropping process, 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 of (S...

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Abstract

The invention relates to a method for preparing (S)-4-hydroxide radical-2-oxo-1-pyrrolidine acetamide, which comprises the following steps: using (S)-4-halogen-3-poly 3-hydroxybutyrate and glycine amide or glycine amide hydrochloride as raw materials for reaction in alcoholic solvents under the alkaline condition to obtain crude products of the (S)-4-hydroxide radical-2-oxo-1-pyrrolidine acetamide, and carrying out pure treatment on the crude products. The method provided by the invention is characterized in that in the reaction under the alkaline condition, the pH value is controlled to be lower than or equal to 8.5 in the reaction through adding inorganic base for many times in the reaction process; the reaction is carried out under the conditions from the temperature rising to the backflow; and the purification treatment is realized by adopting ion exchange resin and recrystallization. The method disclosed by the invention uses the (S)-4-halogen-3-poly 3-hydroxybutyrate and glycineamide hydrochloride as main raw materials which are all commercially available goods, the raw materials have a low price, can be easily obtained and have environment-friendly and pollution-free effects. In the method disclosed by the invention, the preparation reaction period is short, the operation is simple and convenient, and the high performance liquid chromatography (HPLC) purity of prepared(S)-oxiracetam products is as high as more than 98.5 percent.

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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