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Preparation method of brivaracetam intermediate

A technology of intermediates and compounds, applied in the field of preparation of buvaracetam intermediate-4-propylpyrrolidin-2-one, which can solve the problems of difficult industrial production and low chiral purity of products

Pending Publication Date: 2021-06-29
SHANGYU JINGXIN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

According to the enzyme and experimental method reported in the literature, the ee value of the product is only about 92%, and the chiral purity of the product is low. This route is difficult for industrial production

Method used

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  • Preparation method of brivaracetam intermediate
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  • Preparation method of brivaracetam intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] The preparation of embodiment 1 formula 4 compound

[0056] Add 4.5kg of chloroform to a 5L reactor, add 264g (1.524mol) of the compound of formula 3, heat to 45°C, add 153g (1.263mol) of S-phenylethylamine dropwise, and stir at 45°C for 10min, 5h after the dropwise addition Gradually lower the temperature to 25-30°C, keep stirring for 2 hours, filter, and rinse the filter cake with 1L chloroform once; transfer the filter cake to the reaction kettle, add a mixed solution of 4.5kg chloroform and 13g isopropanol, and stir at 25-30°C for 3h , filtered, the filter cake was rinsed once with 1 L of chloroform, and the filter cake was dried at 45°C. The two filter cakes are salts formed by the compound of formula 4 and S-phenethylamine, and a small amount of isomers, and the isomers in the first filter cake are less than the first filter cake.

[0057] Transfer the dried solid to a 500mL reaction flask, add 320g of water, cool down to -5-5°C, add 71.6g of concentrated hydroch...

Embodiment 2

[0059] The preparation of embodiment 2 formula 4 compounds

[0060] Add 4.5kg of chloroform to a 5L reaction kettle, add 264g (1.524mol) of the compound of formula 3, heat to 45°C, add 92.2g (0.762mol) of S-phenylethylamine dropwise, and stir at 45°C for 10min after the dropwise addition. Gradually lower the temperature to 25-30°C within 5 hours, keep stirring for 2 hours, filter, and rinse the filter cake with 1L chloroform once; transfer the filter cake to the reaction kettle, add a mixed solution of 4.5kg chloroform and 13g isopropanol, and stir at 25-30°C After 3 hours, filter, rinse the filter cake once with 1 L of chloroform, and dry the filter cake at 45°C.

[0061] Transfer the dried solid to a 500mL reaction flask, add 320g of water, cool down to -5-5°C, add 43.1g of concentrated hydrochloric acid dropwise while keeping warm, stir at -5-0°C for 1 hour, filter, and rinse the filter cake with 50mL of ice water , and dried the filter cake to obtain 111.1 g of white soli...

Embodiment 3

[0062] The preparation of embodiment 3 formula 4 compounds

[0063] Add 4.5kg of chloroform to a 5L reaction kettle, add 264g (1.524mol) of the compound of formula 3, heat to 45°C, add 184.4g (1.524mol) of S-phenylethylamine dropwise, and stir at 45°C for 10min after the dropwise addition. Gradually lower the temperature to 25-30°C within 5 hours, keep stirring for 2 hours, filter, and rinse the filter cake with 1L chloroform once; transfer the filter cake to the reaction kettle, add a mixed solution of 4.5kg chloroform and 13g isopropanol, and stir at 25-30°C After 3 hours, filter, rinse the filter cake once with 1 L of chloroform, and dry the filter cake at 45°C.

[0064] Transfer the above solid to a 500mL reaction flask, add 320g of water, cool down to -5-5°C, add 86.2g of concentrated hydrochloric acid dropwise while keeping warm, stir at -5-0°C for 1h, filter, rinse the filter cake with 50mL of ice water, and dry The filter cake was dried to obtain 110.1 g of white soli...

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Abstract

The invention relates to a preparation method of abrivaracetam intermediate. The preparation method comprises: 1) carrying out organic alkali resolution on a compound represented by formula 3 to obtain a compound represented by formula 4; 2) performing Hofmann degradation reaction on the compound of the formula 4 to obtain a compound represented by formula 5; and 3) performing cyclization reaction on the compound of the formula 5 to generate a compound represented by formula 2. According to the method, the high-purity compound of the formula 2 can be prepared at a high yield, a precious catalyst is not needed, meanwhile, another configuration compound left after resolution in the step 1) can be recycled, and the atom economy is improved.

Description

technical field [0001] The invention belongs to the field of chemical medicines, and relates to a preparation method of a brivaracetam intermediate, in particular to a preparation method of a brivaracetam intermediate (R)-4-propylpyrrolidin-2-one. Background technique [0002] Brivaracetam (English name: brivaracetam), chemical name: (S)-2-((R)-2-oxo-4-propylpyrrolidin-1-yl)butyramide, was developed by UCB Company in Belgium The third-generation antiepileptic drugs are clinically mainly used for the treatment of partial-onset epilepsy patients aged 16 and above, with or without adjuvant treatment for secondary generalized seizures. The structural formula of Brivaracetam is shown in Formula 1 below: [0003] [0004] In the preparation process of buvaracetam, the compound of formula 2 as an intermediate compound is a key intermediate in the synthetic route. The compound of formula 2 can undergo nucleophilic substitution reaction with 2-bromobutyric acid methyl ester, and...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/267
CPCC07D207/267C07B2200/07
Inventor 孟天卓和波王胜国王远越宋继国李国智许刘华朱志斌
Owner SHANGYU JINGXIN PHARMA
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