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Preparation method of Oxiracetam

A technique called ammonolysis reaction, applied in the direction of organic chemistry, etc., can solve the problems of affecting the quality of oxiracetam, high price of sodium azide, and explosiveness.

Active Publication Date: 2011-07-27
CHONGQING SHENGHUAXI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The raw material sodium azide used in this synthesis method is expensive and explosive; when the intermediate 4-hydroxy-2-pyrrolidone is condensed with ethyl chloroacetate without protecting the hydroxyl group, it will inevitably produce O-alkylated by-products , the impurities produced by the subsequent ammonolysis reaction will enter the final product and affect the quality of oxiracetam

Method used

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  • Preparation method of Oxiracetam
  • Preparation method of Oxiracetam
  • Preparation method of Oxiracetam

Examples

Experimental program
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Embodiment 1

[0028] Embodiment 1: the preparation of 4-chloroacetoacetamide (II)

[0029] Method 1: Add methyl 4-chloroacetoacetate dropwise to 100L of concentrated ammonia water with a concentration of 25-28w% cooled to 0-5°C

[0030] (I) 20kg, continue to stir and react for 2 hours after dropping, filter, wash the filter cake with cold water lower than 10°C, and dry to obtain 13.6kg of 4-chloroacetoacetamide (II), with a yield of 75.6%.

[0031] Method 2: Add dropwise ethyl 4-chloroacetoacetate to 100L of concentrated ammonia water with a concentration of 25-28w% cooled to 0-5°C

[0032] (I) 20kg, continue to stir and react for 2 hours after dropping, filter, wash the filter cake with cold water below 10°C, and dry to obtain 11.9kg of 4-chloroacetoacetamide (II), with a yield of 72.1%.

Embodiment 2

[0033] Embodiment 2: the preparation of pyrrolidine-2,4-dione (III)

[0034] Method 1: Mix 13kg of 4-chloroacetoacetamide (II) with 104L of methanol and 19.9kg of potassium carbonate, pH9-10, and heat up and reflux for 12 hours. Filtrate while hot, and cool the filtrate to 0-5°C for crystallization for 4 hours. Filter, wash with methanol, and dry to obtain 5.9 kg of pyrrolidine-2,4-dione (III), with a yield of 62.1% and a melting point of 120-122°C.

[0035] Method 2: Mix 13kg of 4-chloroacetoacetamide (II) with 104L of ethanol and 19.9kg of potassium carbonate, pH9-10, heat up and reflux for 8 hours and filter while hot, and cool the filtrate to 0-5°C for crystallization for 4 hours. Filter, wash with ethanol, and dry to obtain 6.1 kg of pyrrolidine-2,4-dione (III), with a yield of 64.2% and a melting point of 120.5-122°C.

[0036]Method 3: Mix 13kg of 4-chloroacetoacetamide (II) with 130L of acetone and 19.9kg of potassium carbonate, pH 9-10, heat up and reflux for 12 hour...

Embodiment 3

[0041] Example 3: Preparation of 2-(2,4-dioxopyrrolidin-1-yl) acetate (IV)

[0042] Method 1: Suspend 60% 2.5kg of sodium hydride in 60L of toluene, slowly add 6kg of pyrrolidine-2,4-dione (III), stir and react at room temperature for 1 hour, then add 8.2kg of ethyl chloroacetate dropwise at room temperature, drop After heating up to 50-60°C for 8 hours, cool to room temperature, add 20 L of water to wash the toluene layer, repeat once, separate the toluene layer, dry, filter, and concentrate to obtain 2-(2,4-dioxopyrrolidine- 1-yl) ethyl acetate (IV) 8.9kg, yield 79.5%, melting point 88-91°C.

[0043] Method 2: Suspend 60% 2.5 kg of sodium hydride in 60 L of toluene, slowly add 6 kg of pyrrolidine-2,4-dione (III), stir and react at room temperature for 1 hour, then add 7.2 kg of methyl chloroacetate dropwise at room temperature, drop After heating up to 50-60°C for 8 hours, cool to room temperature, add 20 L of water to wash the toluene layer, repeat once, separate the tolue...

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Abstract

The invention relates to a preparation method of Oxiracetam, which takes 4-chlorine acetoacetic ester (1) as raw material, and prepared by the following synthetic route. The preparation method is simple and convenient, and has short route, low raw material, higher product yield, low cost and good purity.

Description

technical field [0001] The invention relates to a preparation method of oxiracetam. Background technique [0002] Oxiracetam, the chemical name is 4-hydroxyl-2-oxo-1-pyrrolidineacetamide, and its structure is shown in formula (VI). It is a nootropic drug and can be used clinically for senile dementia and multi-infarct dementia And brain insufficiency and memory impairment caused by neurosis, traumatic brain injury, encephalitis and other diseases, especially for the prevention and treatment of senile dementia. The compound was first synthesized in 1974 by the Italian Skeleton Bichem Company. The synthetic methods reported so far include: JP62026267, EP223328, JP3181458 and other synthetic methods reported in the literature. Diketene is used as the starting material and reacted with chlorine to obtain After 4-chloroacetoacetyl chloride, it is esterified with ethanol to obtain ethyl 4-chloroacetoacetate, then reduced with sodium borohydride to obtain ethyl 4-chloro-3-hydroxyb...

Claims

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Application Information

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IPC IPC(8): C07D207/273
Inventor 姜维平何亮苏家宏
Owner CHONGQING SHENGHUAXI PHARMA CO LTD
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