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Oxiracetam preparation technology

A preparation process and intermediate technology, applied in the field of oxiracetam preparation process, can solve the problems of yield and product quality impact, salt is not easy to remove, etc., to achieve excellent product quality, avoid cumbersome post-processing, and less side reactions Effect

Inactive Publication Date: 2013-04-24
FUAN PHARM (GRP) CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This route yield improves to some extent, if based on the starting material, the total yield can reach 22.5%, but the salt remaining in the target product is not easy to remove, and the accompanying hydrolysis and other side reactions also affect the yield when the reduction reaction is carried out in addition. and product quality

Method used

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  • Oxiracetam preparation technology

Examples

Experimental program
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Effect test

Embodiment 1

[0045] Get 171 grams (1mol) of 4-methoxyl-pyrroline-2-one-1-yl acetic acid (Guangan Kate Pharmaceutical Chemical Co., Ltd., the same below) and dissolve it in 1350ml of water, add 292 grams (2.8mol) of 35% hydrochloric acid , heated to 70°C and stirred for 3 hours to obtain an aqueous solution of Intermediate 1.

[0046] Cool the aqueous solution of Intermediate 1 to 0°C, slowly add 560 g of 20% sodium hydroxide solution, control the temperature at 0-5°C, and adjust the pH value to 3.0-4.0. Add 270 grams of 30% potassium borohydride solution dropwise, and control the temperature at about 5°C. After the dropwise addition, react at room temperature for 3 hours, then add 35% hydrochloric acid dropwise, adjust the pH value to 2.5-3.0, evaporate the solvent under reduced pressure, and obtain intermediate 2.

[0047] Intermediate 2 was dissolved in 1200 ml of methanol, 19.6 g (0.20 mol) of concentrated sulfuric acid was added, and refluxed for 8 hours to obtain an alcoholic solutio...

Embodiment 2

[0051] Dissolve 171 grams (1mol) of 4-methoxy-pyrrolin-2-one-1-ylacetic acid in 1300ml of water, add 189 grams (3mol) of nitric acid, heat up to 80°C, and stir for 2 hours to obtain the intermediate 1 in water.

[0052] Cool the aqueous solution of Intermediate 1 to 0°C, slowly add 600 g of 20% sodium hydroxide solution, control the temperature at 0-5°C, and adjust the pH value to 3.0-4.0. Add 288 grams of 30% potassium borohydride solution dropwise, and control the temperature at about 5°C. After the dropwise addition, react at room temperature for 3 hours, add nitric acid, adjust the pH value to 2.5-3.0, evaporate the solvent under reduced pressure, and obtain intermediate 2.

[0053]Intermediate 2 was dissolved in 1180 ml of methanol, 18.5 g (0.19 mol) of concentrated sulfuric acid was added, and refluxed for 8 hours to obtain an alcoholic solution of intermediate 3.

[0054] Pass the alcohol solution of intermediate 3 into 68 g (4 mol) of ammonia gas, react at room tempe...

Embodiment 3

[0056] Dissolve 171 grams (1mol) of 4-methoxy-pyrroline-2-one-1-ylacetic acid in 1200ml of water, add 245 grams (2.5mol) of concentrated sulfuric acid, heat up to 75°C, and stir for 3 hours. An aqueous solution of Intermediate 1 was obtained.

[0057] Cool the aqueous solution of Intermediate 1 to 0°C, slowly add 500 g of 20% sodium hydroxide solution, control the temperature at 0-5°C, and adjust the pH value to 3.0-4.0. 270 grams of 30% sodium borohydride solution was added dropwise, and the temperature was controlled at about 5°C. After the dropwise addition, react at room temperature for 2.5 hours, add sulfuric acid, adjust the pH value to 2.5-3.0, evaporate the solvent under reduced pressure, and obtain intermediate 2.

[0058] Intermediate 2 was dissolved in 1120 ml of methanol, 19.6 g (0.2 mol) of concentrated sulfuric acid was added, and refluxed for 8 hours to obtain a methanol solution of intermediate 3.

[0059] Pass the methanol solution of intermediate 3 into 63 ...

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Abstract

The invention provides an oxiracetam preparation technology, which is characterized in that 4-methoxy-pyrroline-2-ketone-1-yl-acetic acid is taken as an initial raw material, and four steps of deprotection, reduction, esterification and aminolysis are carried out to obtain the target product-oxiracetam. the steps of deprotection, reduction, esterification and aminolysis are realized by using an one-pot method, the overall yield reaches as high as 52.5%, and the yield is more than 30% compared with the documented yield. The application of the one-pot method can effectively simplify the operation step and shorten the production period, the generation of side effect can be avoided, and the three wastes discharge capacity can be greatly reduced, the environmental pollution is reduced, the route can greatly reduce the cost of the bulk drug, and the preparation technology is a production route having an industrialized prospect.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a preparation process of oxiracetam. Background technique [0002] Oxiracetam is a nootropic drug developed by Glaxo. It is clinically used for brain insufficiency and memory impairment caused by senile dementia, multi-infarct dementia, neurosis, traumatic brain injury, encephalitis, etc. Especially for the prevention and treatment of senile dementia has a significant effect. At present, there are capsules and injections on the domestic market, and the trade names include neuromet, neupan, and Jianlangxing. [0003] Oxiracetam is a synthetic cyclic derivative of hydroxyaminobutyric acid (GABOB) with the chemical name of 2-[4-hydroxypyrrolidin-2-one-1-yl]-acetamide, also known as Olamide , Hydroxypyridine, the structural formula is as follows: [0004] [0005] Oxiracetam structure [0006] According to existing literature reports, the synthetic method of oxiracetam mainly...

Claims

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Application Information

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IPC IPC(8): C07D207/273
Inventor 蒋晨郭子维许刘华丁冬
Owner FUAN PHARM (GRP) CO LTD
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