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Synthetic method of oxiracetam

A synthetic method and intermediate technology, applied in the field of oxiracetam synthesis, can solve the problems of low condensation yield, many by-products, difficult industrialization, etc., and achieve the effect of cheap raw materials, easy operation and low cost

Active Publication Date: 2014-12-24
CHONGQING RUNZE PHARM CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Chinese patent CN10575309A reports a synthesis route that uses glycine and S-4-halo-3-hydroxybutyrate as raw materials for condensation and then esterification and ammonolysis, but this method also uses the method of dropping and strengthening alkali under high temperature conditions Condensation will be accompanied by various side reactions such as hydrolysis of S-4-halo-3-hydroxybutyrate, resulting in low condensation yield and more by-products, and the final product S-oxiracetam At this purity, direct crystallization is not possible, and ion-exchange resin chromatography is required to remove impurities. The cost is high, the purity is low, and it is difficult to industrialize

Method used

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  • Synthetic method of oxiracetam
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  • Synthetic method of oxiracetam

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] A kind of synthetic method of (S)-oxiracetam, it carries out as follows,

[0056] (l) Preparation of Intermediate I:

[0057] Take 50g of the raw material S-4-amino-3-hydroxybutyric acid, put it into a single-neck bottle, add 50ml of methanol, stir, cool in an ice-water bath, slowly add 150ml of concentrated hydrochloric acid, keep the temperature not exceeding 40°C, and the solid will first have a During the dissolution process, it precipitates again, and when the dripping speed is completed, the solid dissolves again, and finally forms a light yellow clear liquid. Stirring was continued for 3 hours, and the raw materials were basically completely reacted by pointing the board. The reaction was stopped, and the solvent was directly concentrated to remove a light yellow oil, which was solidified at a low temperature to obtain intermediate I. After nuclear magnetic detection, the intermediate I is: 1H-NMR (300MHz, D2O): δ2.76-2.67 (AB system, m, 2H,), 3.31-3.23 (AB syst...

Embodiment 2

[0070] 1, a kind of synthetic method of (S)-oxiracetam, follow the steps:

[0071] (1) Stir S-4-amino-3-hydroxybutyric acid and ethanol accounting for 18 times its weight, and react esterification reaction at 60 ° C for about 5 hours. The raw materials basically react completely, stop the reaction, and directly concentrate to remove the solvent. Solidify at low temperature to obtain intermediate I; at the same time, methanol, n-propanol, isopropanol, n-butanol, tert-butanol, cyclohexanol or cyclopentanol are used to prepare intermediate I as the above solvent, and finally tested by NMR , the prepared intermediate I is: 1H-NMR (300MHz, D2O): δ1.30 (m, 3H), 2.76-2.67 (AB system, m, 2H,), 3.31-3.23 (AB system, m, 2H), 4.12(m, 2H), 4.40(m, 1H), 4.70(bs, 3H).

[0072] (2) The intermediate I obtained from step (1) is stirred and cooled in ethanol that is 15 times by weight of S-4-amino-3-hydroxybutyric acid, and is added dropwise with n-butyl bromoacetate for condensation reaction ...

Embodiment 3--12

[0075] Embodiment 3--12: Compared with Embodiment 2, it is a further optimized embodiment of the present invention, according to the steps and parameters in Table 1 below, and the others are the same as Embodiment 1.

[0076] Table 1

[0077]

[0078]

[0079]

[0080] Through nuclear magnetic detection, the intermediate prepared in embodiment 3-12 and levoxiracetam are as shown in table 2:

[0081]

[0082]

[0083]

[0084]

[0085]

[0086]

[0087] The purity of the levoxiracetam obtained in the above examples 3-12 is measured by HPLC at 99.5-99.9%, and the calculated yield is 35-45%.

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Abstract

The invention discloses a synthetic method of (S)-oxiracetam. The synthetic method comprises the following steps: (1) by adopting S-4-amino-3-hydroxybutyric acid as a starting material, performing esterification reaction with alcohol to obtain an intermediate I; (2) performing condensation reaction between the intermediate I and halogenated acetic ester to obtain an intermediate II; (3) performing ring closing reaction on the intermediate II to obtain an intermediate III; and (4) performing ammonolysis reaction on the intermediate III to obtain a target product namely (S)-oxiracetam. By adopting a synthetic route of oxiracetam disclosed by the invention, at least more than 20% of an (S)-oxiracetam product with relatively ideal yield can be obtained, and a new oxiracetam synthetic route can be created.

Description

technical field [0001] The present invention relates to a synthesis method of oxiracetam, in particular to a synthesis method of (S)-oxiracetam. 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 with the chemical name: (S)-4-hydroxy-2oxo-1-pyrrolidineacetamide. The nootropic drug oxiracetam is a synthetic hydroxyaminobutyric acid (GABOB) derivative, which is a central nervous system drug that can promote learning, enhance memory, and protect damaged nerve cells. [0003] At present, there are four methods for the synthesis of (S)-oxiracetam reported in the literature: [0004] U.S. Patent No. 4,173,569 describes a synthetic method of (S)-oxiracetam: (S)-4-amino-3-hydroxybutyric acid is the starting material, the hydr...

Claims

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Application Information

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IPC IPC(8): C07D207/273
CPCC07B2200/07C07C229/22C07D207/273
Inventor 袁华杰代丽萍谢玲玲叶雷
Owner CHONGQING RUNZE PHARM CO LTD
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