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Preparation method for brivaracetam intermediate

A technology of intermediates and carboxylic acid compounds, applied in the field of preparation of brivaracetam intermediates, can solve the problem of low utilization rate of isomeric intermediates

Active Publication Date: 2018-06-26
ZHEJIANG JINGXIN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The technical problem to be solved by the present invention is that racemate is generated in the synthetic route of buvaracetam or its intermediate, the end product needs to be subjected to chiral resolution, and the utilization rate of isomer intermediate is low, etc. The preparation method of Vasitam intermediate, more specifically, provides a kind of preparation method of (R)-4-propyl group-4,5-dihydrofuran-2-one

Method used

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  • Preparation method for brivaracetam intermediate
  • Preparation method for brivaracetam intermediate
  • Preparation method for brivaracetam intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] (1) Potassium tert-butoxide (5.6 g, 0.05 mol) was dissolved in 120 mL THF. The reaction solution was cooled to 5° C. in an ice bath, and a solution of diethyl propylmalonate (10.1 g, 0.05 mol) in THF (30 mL) was quickly dropped into it. After dropping, keep the reaction at 5°C-10°C for 1h. Chloromethylbenzyl ether (7.8 g, 0.0 mol) in THF (tetrahydrofuran, 20 mL) was added dropwise, and the temperature was controlled at 5°C to 10°C. After dropping, keep the reaction at 5°C-10°C for 1h. Sampling and testing showed that the reaction was complete. Add 10 mL of water to quench the reaction, add 30 mL of 1N hydrochloric acid, and extract and separate layers with 100 mL of EA (ethyl acrylate). The organic phase was successively washed with water, saturated sodium bicarbonate and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and spin-dried to obtain intermediate A colorless liquid 16g, ESI(M+1)=323.

[0043] Intermediate A (31g, 0.0963mol) was dis...

Embodiment 2

[0064] (1) Potassium tert-butoxide (1.2 g, 0.01 mol) was dissolved in 20 mL THF. The reaction solution was cooled to 5° C. in an ice bath, and a solution of diethyl propylmalonate (2.0 g, 0.01 mol) in THF (10 mL) was quickly dropped into it. After dropping, keep the reaction at 5°C-10°C for 1h. Chloromethyl methyl ether (0.8 g, 0.01 mol) in THF (tetrahydrofuran, 10 mL) was added dropwise, and the temperature was controlled at 5°C to 10°C. After dropping, keep the reaction at 5°C-10°C for 1h. Sampling and testing showed that the reaction was complete. Add 10mL of water to quench the reaction, add 10mL of 1N hydrochloric acid, extract with 20Ml*3EA (ethyl acetate), combine the organic phases, wash with water, saturated sodium bicarbonate, and saturated sodium chloride successively, dry over anhydrous sodium sulfate, filter and spin dry , to obtain intermediate A colorless liquid 2.5g, ESI(M+1)=247.

[0065] Intermediate A (2.5g, 0.01mol) was dissolved in 20mL of ethanol, and...

Embodiment 3

[0071] (1) Methyl valerate and methyl formate are transesterified to generate a formyl compound, then reduced by sodium borohydride to obtain a hydroxyl compound, then protected by TBDMS, and the methyl ester is hydrolyzed to obtain TBDMS-protected compound C (i.e. carboxylic acid Compound C); The reaction scheme is as follows:

[0072]

[0073] (2) Carrying out chiral resolution of carboxylic acid compound C in the same method as step (2) in Example 1 to obtain R-configured carboxylic acid compound C-1 and S-configured carboxylic acid compound C-2.

[0074] (3) R configuration carboxylic acid compound C-1 is operated and reacted according to conventional reaction conditions to generate alcohol intermediate D-1, and then reacted according to the following synthetic route:

[0075]

[0076] Specifically, alcohol intermediate D-1 (2.4g, 0.01mol) was dissolved in 20mL of DCM, triphenylphosphine (4.0g, 0.015mol, 1.5eq) was added, replaced with nitrogen, cooled in an ice bath...

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Abstract

The invention discloses a preparation method for (R)-4-propyl-4,5-dihydrofuran-2-one. The preparation method comprises the following steps: subjecting a carboxylic acid compound to chiral resolution so as to obtain an R-configuration carboxylic acid compound and an S-configuration carboxylic acid compound; and separately subjecting the R-configuration carboxylic acid compound and / or the S-configuration carboxylic acid compound to a reaction so as to obtain (R)-4-propyl-4,5-dihydrofuran-2-one. According to the preparation method, a synthetic route is ingeniously designed, and the two opticallypure isomers obtained through chiral resolution of the carboxylic acid compound are separately utilized by different reaction routes, so the target compound is eventually prepared; and the method improves the utilization rate of the isomers while ensuring optical purity and eliminates the cumbersome steps of racemization and re-splitting of the other half of the isomers.

Description

technical field [0001] The present invention relates to the preparation method of Bu Waracetam intermediate. Background technique [0002] Brivaracetam is a third-generation antiepileptic drug developed by UCB in Belgium. On February 19, 2016, it was approved by the FDA for the adjuvant treatment of partial seizures in adolescents and adults aged 16 and over. [0003] (R)-4-Propyl-4,5-dihydrofuran-2-one is an important intermediate in the synthesis of brivaracetam. [0004] Benoit M. (J.Med.Chem.2004, 47, 530-549) reported the reaction of 2(5H)-furanone with propylmagnesium bromide to obtain 4-propyl-4,5-dihydrofuran-2- Ketone, and then further synthesize the reaction route of buvaracetam. However, this synthetic route generates a racemate, and the final product needs to be separated by chiral preparation, which is costly. [0005] CN105646319A discloses that lactone is obtained by reacting malonate diester with epichlorohydrin, and then reacted with ethyl metal reagent,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/33
CPCC07B2200/07C07D307/33Y02P20/55
Inventor 徐辉郭四根
Owner ZHEJIANG JINGXIN PHARMA
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