Preparation method of oxiracetam isomer

A technology of isomers and acid lactones, applied in the field of drug synthesis, can solve the problems such as no, inability to distinguish oxiracetam, and limited utilization, and achieve the effects of simple operation, high product yield and mild reaction conditions

Active Publication Date: 2018-10-16
福安药业集团重庆博圣制药有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The preparation process of oxiracetam in this invention is relatively simple, but the obtained oxiracetam cannot distinguish between (S)-oxiracetam and (R)-oxiracetam
Bring restrictions to subsequent use
[0010] There is no report on the process of preparing (S)-oxiracetam or (R)-oxiracetam with oxiracetam acid as raw material

Method used

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  • Preparation method of oxiracetam isomer
  • Preparation method of oxiracetam isomer
  • Preparation method of oxiracetam isomer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] Embodiment 1 comprises the preparation of the reaction system of oxiracetam acid lactone salt isomer

[0065] 1. Preparation of Oxiracetam Lactone

[0066] Add 100 g of oxiracetam acid and 2 g of concentrated sulfuric acid into 200 g of acetone, raise the temperature to 50° C., stir and react for 3 hours, then concentrate under reduced pressure to dryness to obtain oxiracetam acid lactone, and the yield of this step is calculated as 100%. .

[0067] 2. The reaction system for preparing (1R,5R), (1S,5R) and (1R,5S), (1S,5S) type oxiracetam lactone salt

[0068] Add 400 g of acetone and 144 g of D(+)-10-camphorsulfonic acid to the oxiracetam lactone obtained in step 1, raise the temperature to 50° C. and keep stirring for 1 hour, then cool down to 0° C. and grow the crystal for 2 hours.

[0069] At this time, (1R, 5R), (1S, 5R) type oxiracetam acid lactone salt crystallized out in the reaction system, and (1R, 5S), (1S, 5S) type oxiracetam acid lactone salt remained in...

Embodiment 2

[0070] Example 2 The separation of isomers in the reaction system comprising oxiracetam lactone salt isomers

[0071] 1) Take the reaction system of Example 1, filter, wash the filter cake with 40 g of acetone, collect the filter cake, control the temperature at 50° C. and dry under reduced pressure for 6 hours to obtain (1R, 5R), (1S, 5R) type oxiracetam acid lactone salt;

[0072] 3) Collect the filtrate, control the temperature and dry under reduced pressure at 50°C to dryness to obtain (1R, 5S), (1S, 5S) oxiracetam lactone salts.

Embodiment 3

[0073] The preparation of embodiment 3 (R) type oxiracetam

[0074] 1) Add 160 g of methanol to the (1R, 5R) and (1S, 5R) type oxiracetam acid lactone salt obtained in Example 2, lower the temperature to below 10°C, add 2 ml of water, and feed 24 g of ammonia gas to complete The temperature of the ammonia gas was raised to 25°C, and the reaction was carried out under heat preservation and stirring for 15 hours. The sampling was controlled in the center. The purity of the main peak was about 97%, and the remaining raw materials were 2%;

[0075] 2) After the reaction, the temperature was lowered to 0°C and the crystal was incubated for 2 hours, filtered, and the filter cake was washed with 20 g of methanol to obtain the crude product of (R) oxiracetam;

[0076] 3) Add 40g of water and 0.1g of glacial acetic acid and heat up to 60°C to dissolve, filter while hot after dissolving, slowly cool the filtrate to 40-45°C for crystallization for 30 minutes, then cool down to 5°C for 2 ...

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Abstract

The invention belongs to the field of drug synthesis, and particularly relates to a preparation method of oxiracetam isomer. (S)-oxiracetam and (R)-oxiracetam are prepared by the following steps: 1) dehydrating in an oxiracetam acid molecule to generate oxiracetam lactone; 2) enabling lactone to react with D(+)-10-camphorsulfonic acid to generate (1R, 5R), (1S, 5R), (1R, 5S) and (1S, 5S) types ofoxiracetam acid lactone salt; 3) enabling (1R, 5R) and (1S, 5R) types of oxiracetam acid lactone salt to react with ammonia to geneate (R)-oxiracetam, and enabling (1R, 5S) and (1S, 5S) types of oxiracetam acid lactone salt to react with ammonia water to generate (S)-oxiracetam. The method provided by the invention can be used for preparing (S)-oxiracetam and (R)-oxiracetam. The method provided bythe invention can be used for preparing (S)-oxiracetam and (R)-oxiracetam, does not waste materials, has the advantages of simple operation, high product yield (up to 60%) and high product purity (99.8% or higher), and is suitable for industrialized large-scale production.

Description

technical field [0001] The invention belongs to the field of medicine synthesis, and in particular relates to a preparation method of oxiracetam isomers (S)-oxiracetam and (R)-oxiracetam. Background technique [0002] The invention relates to the synthesis of 4-hydroxy-2-oxo-1-pyrrolidineacetamide (ie oxiracetam). The molecular formula of oxiracetam is C 6 h 10 N 2 o 3 , is a synthetic cyclic derivative of hydroxyaminobutyric acid, the structural formula is as follows: [0003] [0004] Oxiracetam is a nootropic drug acting on the cholinergic reticular structure of the brainstem. It is used for the treatment of brain injury and the resulting neurological function loss, memory and intellectual impairment, and has a broad market prospect. [0005] Studies have shown that (S)-oxiracetam, the isomer of oxiracetam, can play a greater role than (R)-oxiracetam. [0006] Invention patent CN 106146379 B discloses a synthesis method of (S)-oxiracetam, which includes the follo...

Claims

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Application Information

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IPC IPC(8): C07D498/08C07C309/19C07D207/273
CPCC07D207/273C07D498/08
Inventor 李隆骄洪荣川袁明华张闯丁东牟超毅
Owner 福安药业集团重庆博圣制药有限公司
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