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Preparation method of (S)-oxiracetam

A technology of S-4- and solvents, which is applied in chemical instruments and methods, compounds of group 4/14 elements of the periodic table, organic chemistry, etc., can solve problems such as high cost, cumbersome operation, and difficult industrialization, and achieve cost Low, high purity, simple operation effect

Pending Publication Date: 2022-06-14
成都百途医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among them, (S)-4-chloro-3-hydroxybutyrate and glycinamide react under alkaline conditions to obtain the final product (S)-oxiracetam by adding alkali at one time to control the alkalinity of the reaction solution , but because the raw materials (S)-4-chloro-3-hydroxybutyrate ethyl ester and oxiracetam are easily destroyed in a strong alkali solution, various side reactions occur, so that the purity of the reaction is not high, and there are many and because (S)-oxiracetam has strong hydrophilicity, it is very difficult to purify the product, and it is difficult to separate the obtained product from the impurity salt compounds produced by various reactions, requiring column layer Analysis to remove the impurity salts produced can be further crystallized and purified
[0004] Column chromatography is not only costly, but also cumbersome to operate. For example, silica gel column chromatography is performed with dichloromethane methanol mixed solvent as the eluent, and the obtained effluent is concentrated to remove the solvent and then recrystallized with methanol to obtain the product
However, the operation of silica gel column chromatography is very cumbersome, requires a large amount of organic solvents, is costly, and is difficult to industrialize
Another example: column chromatography with strong acidic cation exchange resin, and then neutralized with 711# strong basic anion exchange resin, the effluent is collected and concentrated, and then crystallized with ethanol to obtain the product. This purification scheme uses two kinds of ions Exchange resin has various problems in cost control, quality stability, industrial scale-up, etc., making it difficult to scale up production

Method used

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

Examples

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Effect test

Embodiment 1

[0049] A preparation method of (S)-oxiracetam, comprising the following steps:

[0050] S1, the preparation of the crude product reaction solution containing product (S)-oxiracetam:

[0051] Dissolve 40 g of S-4-chloro-3-hydroxybutyric acid ethyl ester in 400 ml of ethanol, add 50 g of glycinamide hydrochloride, 50 g of anhydrous sodium carbonate, and stir at reflux for 24 hours to obtain a product containing (S)-oxiracetam The crude product reaction solution;

[0052] S2, the preparation of intermediate I:

[0053] The crude product reaction solution containing the product (S)-oxiracetam obtained in step S1 was concentrated to remove the solvent ethanol, dissolved in 500 ml of ethyl acetate, cooled to 0 ° C, added with 64 g of triethylamine, stirred for 30 minutes, and added with dimethylamine 55g of base tert-butyl chlorosilane was added dropwise and stirred at the same temperature for 5 hours, water 500ml was added, the organic phase was separated and concentrated to obta...

Embodiment 2

[0064] A preparation method of (S)-oxiracetam, comprising the following steps:

[0065] S1, the preparation of the crude product reaction solution containing product (S)-oxiracetam:

[0066] Dissolve 40 g of S-4-chloro-3-hydroxybutyric acid ethyl ester in 400 ml of isopropanol, add 50 g of glycinamide hydrochloride, 38 g of anhydrous sodium bicarbonate, and stir at reflux for 48 hours to obtain the product (S)- The crude product reaction solution of oxiracetam;

[0067] S2, the preparation of intermediate I:

[0068] The crude product reaction solution containing the product (S)-oxiracetam obtained in step S1 was concentrated to remove the solvent isopropanol, dissolved in 500 ml of DMF, cooled to 10 ° C, added with 45 g of imidazole, stirred for 30 minutes, and added with dimethyl tertiary 55g of butylchlorosilane was added and stirred at the same temperature for 5 hours, 500ml of water and 500ml of ethyl acetate were added, the organic phase was separated and concentrated ...

Embodiment 3

[0075] A preparation method of (S)-oxiracetam, comprising the following steps:

[0076] S1, the preparation of the crude product reaction solution containing product (S)-oxiracetam:

[0077] Dissolve 40 g of S-4-chloro-3-hydroxybutyric acid ethyl ester in 400 ml of n-propanol, add 50 g of glycinamide hydrochloride, 66 g of anhydrous potassium carbonate, and reflux for 48 hours to obtain a product containing (S)-O The crude product reaction solution of Piracetam;

[0078] S2, the preparation of intermediate I:

[0079] The crude product reaction solution containing the product (S)-oxiracetam obtained in step S1 was concentrated to remove the solvent n-propanol, dissolved in 500 ml of DMSO, cooled to 10 ° C, added with 52 g of pyridine, stirred for 30 minutes, and added with tertiary dimethyl dimethylamine. 55 g of butyl chlorosilane was added and stirred at the same temperature for 5 hours, 500 ml of water and 500 ml of ethyl acetate were added, the organic phase was separate...

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Abstract

The invention discloses a preparation method of (S)-oxiracetam, which comprises the following steps of: S1, condensing S-4-chloro-3-hydroxybutyric acid ethyl ester serving as an initial raw material and glycinamide under an alkaline condition to obtain a crude product reaction solution containing the product (S)-oxiracetam; s2, the crude product reaction liquid obtained in the step S1 reacts with a protective reagent, an intermediate I is obtained, and the protective reagent is methyl tert-butyl chlorosilane; s3, crystallizing and purifying the intermediate I obtained in the step S2 in a first solvent to obtain a high-purity intermediate I; s4, the high-purity intermediate I obtained in the step S3 reacts with an acid catalyst in a second solvent, and high-purity (S)-oxiracetam is obtained. The (S)-oxiracetam prepared by the preparation method disclosed by the invention is high in product purity and high in chiral purity, and does not need to be purified by column chromatography.

Description

technical field [0001] The invention relates to the technical field of preparation of (S)-oxiracetam, in particular to a preparation method of (S)-oxiracetam. Background technique [0002] Oxiracetam is a nootropic drug first synthesized by the Italian company Smith Co., Ltd. in 1974. It is composed of two isomers (S)-oxiracetam ((S)-oxiracetam) and (R)- The racemate composed of oxiracetam ((R)-oxiracetam). (S)-Oxiracetam is a single enantiomer of Oxiracetam, chemical name: (S)-4-hydroxy-2oxo-1-pyrrolidineacetamide. Nootropic Oxiracetam is a synthetic hydroxyaminobutyric acid (GABOB) derivative, which is a central nervous system drug that promotes learning, enhances memory, and protects damaged nerve cells. [0003] At present, (S)-oxiracetam is mainly produced by reacting (S)-4-chloro-3-hydroxybutyric acid ethyl ester with glycinamide to obtain the target compound, or reacting with glycine ethyl ester, and then by aminolysis to obtain the target compound. Wherein, (S)-4...

Claims

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Application Information

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IPC IPC(8): C07D207/273C07F7/18
CPCC07D207/273C07F7/188
Inventor 袁华杰彭宇蒋宁
Owner 成都百途医药科技有限公司