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Preparation method for (S)-oxiracetam

A synthesis method and C1-C6 technology, applied in the field of oxiracetam, can solve the problems of affecting the purity and yield of oxiracetam, difficult to recover, easy to be destroyed and the like

Inactive Publication Date: 2016-02-17
CHONGQING RUNZE PHARM CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Wherein (S)-4-chloro-3-hydroxybutyrate and glycinamide react under alkaline conditions to obtain the final product oxiracetam and control the alkalinity of the reaction solution by adding alkali at one time, but due to Ola Racetam is easily destroyed in a strong alkaline solution, which directly affects the purity and yield of oxiracetam; in addition, silica gel column chromatography is used in the purification of the final product oxiracetam, and the eluent used is an organic mixture Solvent, the amount of solvent is large, it is not easy to recycle, the cost is high, and the silica gel column chromatography method is not suitable for industrial scale-up production
[0006] 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
[0007] Chinese patent CN1513836A has reported a kind of method that takes 4-haloacetoacetic acid derivative as starting material to synthesize oxiracetam, but this method needs potassium hydride, potassium hydride, Sodium hydride, sodium amide, n-butyllithium, diethylamide lithium, or sodium alkoxide and other strong bases are used as catalysts, and there are many reaction by-products, and the operation safety is low. and Two impurities, these two impurities are difficult to remove even by column chromatography, so it is difficult to meet the requirements of medicine, which is not conducive to industrial application

Method used

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  • Preparation method for (S)-oxiracetam
  • Preparation method for (S)-oxiracetam
  • Preparation method for (S)-oxiracetam

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0069] A kind of synthetic method of (S)-oxiracetam, it carries out as follows,

[0070] (1) Preparation of Intermediate I:

[0071] Take 50g of the raw material S-methyl 4-chloro-3-hydroxybutyrate, put it into a single-neck bottle, add 50ml of DMF, stir, cool in an ice-water bath, add 50g of sodium azide, and keep the temperature not exceeding 40°C. The temperature was raised to 60°C. After 2 hours of reaction, the reaction was stopped to obtain a yellow solution. Add 100 ml of water, extract with 100 ml of ethyl acetate, concentrate to remove ethyl acetate, and obtain Intermediate I as a yellow oil. After nuclear magnetic detection, the intermediate I is: 1H-NMR (300MHz, CDCl3): δ1.42-1.73 (m, 2H) 2.76-2.67 (ABsystem, m, 2H,), 3.31-3.23 (ABsystem, m, 2H) , 3.75(s, 3H), 4.40(m, 1H), 3.70(s, 1H). Intermediate I is: R1 is methyl.

[0072] (2) Preparation of Intermediate II

[0073] The intermediate I obtained in step (2) was dissolved in 500ml of methanol, cooled to an e...

Embodiment 2

[0083] A kind of synthetic method of (S)-oxiracetam, it carries out as follows,

[0084] (1) Preparation of Intermediate I:

[0085] Weigh 50kg of methyl S-4-chloro-3-hydroxybutyrate, add it to a 500L azidation reaction kettle, add DMF50L, stir evenly, cool the jacket in an ice-water bath, add 50Kg of sodium azide, and keep the temperature constant When the temperature exceeds 40°C, the ice water in the jacket is pressed out, and the jacket is passed through hot water to raise the internal temperature to 60°C. After 2 hours of reaction, the reaction was stopped to obtain a yellow solution. Add 100 L of water to the kettle, extract with 100 L of ethyl acetate, separate and discard the water phase, concentrate the organic phase to remove ethyl acetate, and obtain Intermediate I as a yellow oil. After nuclear magnetic detection, the intermediate I is: 1H-NMR (300MHz, CDCl3): δ1.42-1.73 (m, 2H) 2.76-2.67 (ABsystem, m, 2H,), 3.31-3.23 (ABsystem, m, 2H) , 3.75(s, 3H), 4.40(m, 1H)...

Embodiment 3

[0098] 1, a kind of synthetic method of (S)-oxiracetam, follow the steps:

[0099] (1) Stir S-4-chloro-3-hydroxybutyric acid ethyl ester with 18 times the weight of DMSO and 1 times the weight of sodium azide, and react with azidation at 60°C for about 5 hours. The raw materials are basically The reaction is complete, stop the reaction, directly concentrate to remove the solvent, and solidify at low temperature to obtain intermediate I; meanwhile, the above solvents also use DMF, n-propanol, isopropanol, n-butanol, tert-butanol, toluene or cyclopentanol, etc. Preparation of intermediate I, and finally by nuclear magnetic detection, the prepared intermediate I is: 1H-NMR (300MHz, CDCl3): δ1.42-1.73 (m, 5H) 2.76-2.67 (ABsystem, m, 2H,), 3.31-3.23 (ABsystem, m, 2H), 4.40 (m, 1H), 3.70 (s, 1H).

[0100] (2) With the intermediate I obtained from step (1), in 15 weight times of ethanol of S-4-chloro-3-hydroxybutyrate ethyl ester, add 0.5 times of weight of 10% platinum carbon catal...

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Abstract

The invention provides a preparation method for (S)-oxiracetam. The preparation method comprises the following steps: (1) with S-4-chloro-3-hydroxy butyrate as an initial raw material, subjecting the initial raw material and an azido reaction agent to an azido reaction so as to obtain an intermediate I; (2) subjecting the intermediate I to a reduction reaction so as to obtain an intermediate II; (3) subjecting the intermediate II and halogenated acetate to a condensation reaction so as to obtain an intermediate III; (4) subjecting the intermediate III to a ring closure reaction so as to obtain an intermediate IV; and (4) carrying out an aminolysis reaction on the intermediate IV so as to obtain the target product (S)-oxiracetam. The preparation method can prepare the (S)-oxiracetam product with ideal yield of at least more than 38%, and a novel synthetic route is opened up for (S)-oxiracetam.

Description

technical field [0001] The present invention relates to (S)-oxiracetam, in particular to a preparation method of (S)-oxiracetam. Background technique [0002] Chinese patents CN102552248A, CN103599101A, etc. disclose that levoxiracetam has a good curative effect in the treatment of coma and cognitive dysfunction. At present, there are documents disclosing the synthesis method of levo-oxiracetam. The inventor has studied the published documents and found that when the purity meets 99.9%, the yield is difficult to break through 33%. The following is a brief introduction to the main method of synthesizing levo-oxiracetam: [0003] U.S. Patent US4173569A describes a synthetic method of (S)-oxiracetam: (S)-4-amino-3-hydroxybutyric acid is the starting material, the hydroxyl group is protected by a silylating agent, and after cyclization The product is reacted with ethyl haloacetate, and the reaction product is deprotected, ammonolysis, and finally the target compound is obtaine...

Claims

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Application Information

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