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Novel method for synthesizing oxiracetam key intermediate ethyl 2-(2, 4-dioxopyrrolidine-1-yl) acetate

A technology of dioxopyrrolidine and ethyl acetate, which is applied in the direction of organic chemistry, can solve the problems of long synthetic route, cumbersome operation, and low total yield, and achieve the effects of less three wastes, high product purity, and convenient source

Active Publication Date: 2015-06-24
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The disadvantage of this method is that the synthesis route is longer, the operation is cumbersome, and during hydrolysis decarboxylation, 2-(4-hydroxyl-3-ethoxycarbonyl-2-oxo Pyrrolidin-1-yl) ethyl acetate (7) is prone to self-intermolecular condensation reaction, leading to the preparation of the key intermediate 2-(2,4-dioxopyrrolidin-1-yl) ethyl acetate (8) The yield is very low, which ultimately leads to a very low overall yield of oxiracetam produced by this route

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Embodiment 1: Synthesis of 2-(2,4-dioxopyrrolidin-1-yl) ethyl acetate

[0022] Add 400g of ethyl glycine hydrochloride, 610g of sodium carbonate and 4L of absolute ethanol in a 10L reactor, slowly add 400g of ethyl 4-chloroacetoacetate dropwise at reflux temperature, and drop it in about 0.5 hours. After dropping, the temperature was raised to reflux for about 5.5 hours, filtered, and the filtrate was concentrated and recrystallized with ethanol / water to obtain 397.7 g of ethyl 2-(2,4-dioxopyrrolidin-1-yl)acetate, with a yield of 88.2%. 1 H NMR (500 MHz, DMSO- d 6 ) δ =7.76 (s, 1H), 4.63 (d, J= 30.5 Hz, 3H), 4.15 (q, J= 7.1 Hz, 2H), 3.97 (d, J= 5.9 Hz, 2H), 1.22 (t, J= 7.1 Hz, 3H).

[0023] In this embodiment, ethyl 4-chloroacetoacetate uses other raw materials limited by the present invention such as ethyl 4-bromoacetoacetate etc., and alkali replaces sodium carbonate with any one in sodium bicarbonate, salt of wormwood or potassium bicarbonate, The organic solvent...

Embodiment 2

[0024] Example 2: Synthesis of 2-(2,4-dioxopyrrolidin-1-yl) ethyl acetate

[0025] Add 400g of glycine ethyl ester hydrochloride, 484g of sodium bicarbonate and 4L of anhydrous methanol in a 10L reactor, slowly add 510g of ethyl 4-bromoacetoacetate dropwise at reflux temperature, and dropwise complete in about 0.5 hours. After dripping, the temperature was raised to reflux for about 6 hours, filtered, and the filtrate was concentrated and recrystallized with ethanol / water to obtain 285 g of ethyl 2-(2,4-dioxopyrrolidin-1-yl)acetate, with a yield of 63.2%. 1 H NMR (500 MHz, DMSO- d 6 ) δ =7.76 (s, 1H), 4.63 (d, J= 30.5 Hz, 3H), 4.15 (q, J= 7.1 Hz, 2H), 3.97 (d, J= 5.9 Hz, 2H), 1.22 (t, J= 7.1 Hz, 3H).

Embodiment 3

[0026] Example 3: Synthesis of 2-(2,4-dioxopyrrolidin-1-yl) ethyl acetate

[0027] Add 400 g of glycine ethyl ester hydrochloride, 484 g of sodium bicarbonate and 4 L of anhydrous isopropanol in a 10 L reactor, slowly add 510 g of ethyl 4-bromoacetoacetate dropwise at reflux temperature, and drop it in about 0.5 hours. After dripping, the temperature was raised to reflux for about 8 hours, filtered, and the filtrate was concentrated and recrystallized with ethanol / water to obtain 333.7 g of ethyl 2-(2,4-dioxopyrrolidin-1-yl)acetate, with a yield of 74.0%. 1 H NMR (500 MHz, DMSO- d 6 ) δ =7.76 (s, 1H), 4.63 (d, J= 30.5 Hz, 3H), 4.15 (q, J= 7.1 Hz, 2H), 3.97 (d, J= 5.9 Hz, 2H), 1.22 (t, J= 7.1 Hz, 3H).

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Abstract

The invention relates to a novel method for synthesizing oxiracetam key intermediate ethyl 2-(2, 4-dioxopyrrolidine-1-yl) acetate. The method comprises the following step: by taking 4-halogenated acetoacetic ester and glycine ethyl ester hydrochloride as raw materials, under the effect of alkali, condensing in an organic solvent to obtain ethyl 2-(2, 4-dioxopyrrolidine-1-yl) acetate. The 4-halogenated acetoacetic ester and the glycine ethyl ester hydrochloride are taken as the raw materials and reacted in the organic solvent in the existence of the alkali in one step to obtain the target product; the 4-halogenated acetoacetic ester and the glycine ethyl ester hydrochloride are common merchant materials, convenient in source, cheap and easy to obtain, the reaction step is short, the operation is simple, the yield is high, the product purity is high, the product structure is authenticated, the after treatment is convenient, the three wastes are few and the method has good industrial application prospect.

Description

technical field [0001] The invention relates to a new preparation method for preparing oxiracetam key intermediate 2-(2,4-dioxopyrrolidin-1-yl) ethyl acetate. Background technique [0002] Oxiracetam is a synthetic cyclic derivative of hydroxyaminobutyric acid (GABOB), also known as Olamide, Oxypyramide, and its trade names are neuromet, Heupan, Jianlangxing, etc. It was synthesized for the first time in 1974 by the company and listed in Italy in 1987. It is one of the drugs approved by the US FDA for the treatment of senile dementia. The synthesis routes reported so far generally have shortcomings such as difficult purification or long synthesis routes. For example, in the Japanese patent JP62026267, a kind of glycinamide hydrochloride (1) and 3-hydroxy-4-halobutanoic acid ethyl ester (2) are used as raw materials to directly prepare Austrian Although the route of Piracetam (3) is relatively short, there are many side reactions in this method, and the components of the rea...

Claims

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Application Information

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IPC IPC(8): C07D207/38
CPCC07D207/38
Inventor 叶青高建荣顾凯张力
Owner ZHEJIANG UNIV OF TECH
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