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Preparation method of levetiracetam intermediate

A technology of ethyl and acetic acid, applied in the field of medicine and chemical industry, can solve the problems of residual raw materials, purity less than 80%, unstable yield, etc., and achieve the effect of inhibiting hydrolysis

Pending Publication Date: 2021-12-31
ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The present inventors found that after alcoholization of α-ethyl-2-oxo-1-pyrrolidineacetic acid under acid catalysis, direct concentration will lead to unstable yield, generally below 75%, and the purity is less than 80%. There are more than 15% raw material residues

Method used

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  • Preparation method of levetiracetam intermediate
  • Preparation method of levetiracetam intermediate
  • Preparation method of levetiracetam intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Preparation of α-ethyl-2-oxo-1-pyrrolidine acetate (II)

[0035] Add α-ethyl-2-oxo-1-pyrrolidineacetic acid (50g, 0.29mol) and methanol (100g) into the reaction flask, add concentrated sulfuric acid (2g) dropwise, and heat up to 65-70°C under stirring to reflux for 2 hour, add water (100g), control the temperature in the range of 40-50°C, add 10% Na dropwise under stirring 2 CO 3 Solution, until the pH of the reaction system is 7.0 to 7.5, control the temperature at 40 to 50°C and distill off the remaining methanol under reduced pressure, extract the residual solution twice with toluene (100g), combine the organic phases, and distill under reduced pressure until no liquid flows out to obtain α- Ethyl-2-oxo-1-pyrrolidine acetate, yield 49.1 g, yield 90.7%, HPLC purity 99.2%.

Embodiment 2

[0037] Preparation of α-ethyl-2-oxo-1-pyrrolidine acetate (II)

[0038] Add α-ethyl-2-oxo-1-pyrrolidineacetic acid (50g, 0.29mol) and methanol (100g) into the reaction flask, add concentrated sulfuric acid (4g) dropwise, and heat up to 65-70°C under stirring for 3 hour, add water (100g), control the temperature in the range of 40-50°C, add 10% NaHCO dropwise under stirring 3 Solution, until the pH of the reaction system is 7.0 to 7.5, the temperature is controlled at 40 to 50°C and the remaining methanol is evaporated under reduced pressure, and the residual solution is extracted twice with ethyl acetate (100g), the organic phases are combined, and distilled under reduced pressure until no liquid flows out to obtain α-Ethyl-2-oxo-1-pyrrolidine acetate, yield 49.3g, yield 91.2%, HPLC purity 99.4%.

Embodiment 3

[0040] Preparation of α-ethyl-2-oxo-1-pyrrolidine acetate (II)

[0041] Add α-ethyl-2-oxo-1-pyrrolidineacetic acid (50g, 0.29mol) and ethanol (150g) into the reaction flask, add concentrated sulfuric acid (5g) dropwise, and heat up to 78-80°C under stirring for 2 hour, add water (100g), control the temperature in the scope of 40~60 ℃, add dropwise 15%Na 2 CO 3 solution until the pH of the reaction system is 7.0 to 7.5, the remaining ethanol is evaporated under reduced pressure at 40 to 50°C under temperature control, the residual liquid is extracted 3 times with dichloromethane (100g), the organic phases are combined, and distilled under reduced pressure until no liquid flows out to obtain α-Ethyl-2-oxo-1-pyrrolidine ethyl acetate, yield 52.4g, yield 90.1%, HPLC purity 99.3%.

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Abstract

The invention relates to a preparation method of alpha-ethyl-2-oxo-1-pyrrolidine acetate. Particularly, by optimizing a post-treatment process, the reaction yield and the product purity are remarkably improved.

Description

(1) Technical field [0001] The invention relates to a synthetic method for preparing levetiracetam intermediate, which belongs to the field of medicine and chemical industry. (2) Background technology [0002] Levetiracetam is a broad-spectrum antiepileptic drug with high efficiency and low toxicity developed by UCB Company in Belgium. It is mainly used for the treatment of localized and secondary generalized epilepsy. Its chemical name is (S)-α-B Base-2-oxo-1-pyrrolidineacetamide, the structural formula is as shown in formula I. [0003] [0004] Patent WO2019028671 reported that 2-bromobutyrate and 2-pyrrolidone were used as raw materials to condense to generate α-ethyl-2-oxo-1-pyrrolidine acetate; and then obtained by resolution under the action of ester hydrolase (S )-alpha-ethyl-2-oxo-1-pyrrolidine acetate; then obtain the levetiracetam crude product by aminolysis; then refine the method to obtain levetiracetam, the synthetic route is as follows: [0005] [000...

Claims

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Application Information

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IPC IPC(8): C07D207/27
CPCC07D207/27
Inventor 郑晨光李敏勇龚玉龙朱元勋颜峰峰
Owner ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD
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