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Preparation method of brivaracetam isomer (2S,4S)

A volume, isopropanol technology, applied in the field of preparation of buvaracetam isomers, can solve the problems of high cost and high requirements for reaction operation

Active Publication Date: 2019-04-09
SHANGHAI INST OF PHARMA IND CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] The problem to be solved by the present invention is to provide a kind of Buvaracetam isomer in order to overcome the shortcomings of chromatographic column separation and purification, high cost and high requirements for reaction operation in order to overcome the existing method for preparing the compound shown in formula 1a (2S, 4S) (compound as shown in formula 1a) preparation method

Method used

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  • Preparation method of brivaracetam isomer (2S,4S)
  • Preparation method of brivaracetam isomer (2S,4S)
  • Preparation method of brivaracetam isomer (2S,4S)

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0074] 1. Synthesis of 5-hydroxy-4-n-propyl-furan-2-one

[0075]

[0076] Add heptane (131mL) and morpholine (43mL) into a 500mL four-necked flask and stir mechanically. When t=0°C, add 50mL of glyoxylic acid and react at 20°C for 1h. 49.6 mL of n-valeraldehyde was added dropwise, followed by t=43°C for 20 h. After the reaction was completed, the reaction was quenched with 65 mL of concentrated hydrochloric acid, and stirred at room temperature for 2 h. The liquid was separated, and the aqueous phase was washed with heptane, extracted with isopropyl ether, washed with salt, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 51.8 g of brown oil with a yield of 83.1%. ESI-MS (m / z): 141 [M-H] - .

[0077] 2. Synthesis of (2S)-2-(2-oxo-4-n-propyl-5-hydroxyl-1-pyrrolidinyl)butanamide

[0078]

[0079] First dissociate an appropriate amount of 18g (S)-2-aminobutanamide hydrochloride with 100mL ammonia in iso...

Embodiment 2

[0106] 1. Synthesis of 5-hydroxy-4-n-propyl-furan-2-one

[0107]

[0108] Add heptane (65.6mL) and morpholine (21.3mL) into a 250mL four-neck flask and stir mechanically. When t=0°C, add 25mL of glyoxylic acid and react at 20°C for 1h. 24.8 mL of n-valeraldehyde was added dropwise, followed by t=43°C for 20 h. After the reaction was completed, the reaction was quenched with 33 mL of concentrated hydrochloric acid, and stirred at room temperature for 2 h. The liquid was separated, and the aqueous phase was washed with heptane, extracted with isopropyl ether, washed with salt, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 25.8 g of brown oil with a yield of 82.7%. ESI-MS (m / z): 141 [M-H] - .

[0109] 2. Synthesis of (2S)-2-(2-oxo-4-n-propyl-5-hydroxyl-1-pyrrolidinyl)butanamide

[0110]

[0111] First free an appropriate amount of (S)-2-aminobutyramide hydrochloride, and then react with 20 g of 5-hyd...

Embodiment 3

[0125] 1. Synthesis of 5-hydroxy-4-n-propyl-furan-2-one

[0126]

[0127]Add heptane (65.6mL) and morpholine (21.3mL) into a 250mL four-necked flask and stir mechanically. At t=0°C, add 25mL of glyoxylic acid and react at 20°C for 1 hour. Add 24.8mL of n-valeraldehyde dropwise, then t=0°C 43°C, 20h. After the reaction was completed, the reaction was quenched with 33 mL of concentrated hydrochloric acid, and stirred at room temperature for 2 h. The liquid was separated, and the aqueous phase was washed with heptane, extracted with isopropyl ether, washed with salt, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 25.6 g of brown oil with a yield of 82.1%. ESI-MS (m / z): 141 [M-H] - .

[0128] 2. Synthesis of (2S)-2-(2-oxo-4-n-propyl-5-hydroxyl-1-pyrrolidinyl)butanamide

[0129]

[0130] First free an appropriate amount of (S)-2-aminobutyramide hydrochloride, and then react with 20 g of 5-hydroxy-4-n-pr...

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Abstract

The invention discloses a preparation method of a brivaracetam isomer (2S,4S). The preparation method comprises the following step: in an alcohol solvent, carrying out a salt forming reaction as shownin a formula (shown in the specification) on a compound I and a resolving agent to obtain a compound as of a formula S, wherein the resolving agent is (+)-camphorsulfonic acid, D-(+)-camphanic acid,L-(-)-dibenzoyltartaric acid, D-(+)-dibenzoyltartaric acid, L-(-)-tartaric acid, L-(-)-phenylalaninol or S-(-)-phenylethylamine. The preparation method provided by the invention is low in price and easily available in raw material and mild in reaction condition. By adopting a chemical resolution method, a chromatographic column is not used, so that the preparation method is simple to operate, lowin cost and suitable for production on a large scale. The formula is as shown in the description.

Description

technical field [0001] The invention relates to a preparation method of buvaracetam isomers (2S, 4S). Background technique [0002] The chemical name of Brivaracetam (1) is (2S)-2-[(4R)-2-oxo-4-n-propylpyrrolidinyl]butyramide, which is a new type of antiepileptic drug developed by UCB in Belgium. It was approved by the FDA in February 2016 for the treatment of partial seizures in adults and adolescents over 16 years of age, with or without secondary generalized seizures. Compared with previous antiepileptic drugs, brivaracetam has a unique mechanism of action, especially the good tolerance of the central nervous system is the main reason why it is superior to other antiepileptic drugs. The compound shown in formula 1a is the most easily introduced isomer during the synthesis of brivaracetam, and its preparation will provide a reference for the study of the optical purity of 1. [0003] Brivaracetam has two chiral centers, and it has 3 stereoisomers, as shown below, which a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/27C07B57/00C07C231/20C07C231/12C07C237/12C07C59/255C07C211/27C07C215/28C07C69/78C07C309/19C07C61/06
CPCC07B57/00C07C59/255C07C61/06C07C69/78C07C211/27C07C215/28C07C231/12C07C231/20C07C309/19C07D207/27C07B2200/07C07C237/12
Inventor 张金峰郭晔堃毕增韩强钟静芬
Owner SHANGHAI INST OF PHARMA IND CO LTD
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