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Preparation method of brivaracetam intermediate

A technology of an intermediate and an operation method, which is applied in the field of preparation of the intermediate-3-propyl-γ-butyrolactone, can solve the problems of few reaction steps and poor stereoselectivity, and achieve high overall yield and reaction good stereoselectivity

Active Publication Date: 2021-09-03
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0018] The synthetic route of the present invention cleverly utilizes the chiral auxiliary agent (R)-4-benzyl-2-oxazolidinone, optimizes the reaction conditions, has the advantages of few reaction steps, high yield, good reaction stereoselectivity, etc., at the same time The raw materials are cheap and easy to obtain, the operation is simple and safe, and it overcomes the problems in the prior art that the reaction needs chiral resolution, chiral column separation, low yield and poor stereoselectivity, etc., and has a good industrial application prospect

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Embodiment 1: the preparation of compound III

[0059] Add compound II (0.88g, 5.00mmol) to a dry 50mL round bottom flask, add dichloromethane (10mL) and stir to dissolve, add triethylamine (0.76g, 7.50mmol) at room temperature, cool to 0°C in an ice bath , slowly added a dichloromethane solution of compound I (0.90 g, 6.00 mmol), reacted for 2 hours, and detected the reaction by TLC. After the reaction, dichloromethane (15mL) was added for dilution, washed with saturated sodium bicarbonate solution (15mL) and separated, the aqueous phase was extracted with dichloromethane (30mL×2), and the organic phase was successively washed with saturated brine. Dry over sodium sulfate, concentrate under reduced pressure, and purify by column chromatography (petroleum ether / ethyl acetate=10:1 to 2:1 gradient elution) to obtain a white solid (1.05 g), with a reaction yield of 72%.

[0060] White solid, m.p.90-91℃; R f =0.27(PE:EA=3:1); 1 H NMR (500MHz, CDCl 3 ):δ=7.21-7.36(m,5H),...

Embodiment 2

[0061] Embodiment 2: the preparation of compound III

[0062] Take a dry 50mL round bottom flask, add compound II (0.88g, 5.00mmol) and sodium hydride (60% dispersed in paraffin oil, 0.30g), add tetrahydrofuran (10mL) and stir to dissolve, cool to 0 ° C in an ice bath, Compound I (0.90 g, 6.00 mmol) was added, and the stirring reaction was continued at 0° C. for 2 h, and the reaction was detected by TLC. After the reaction was completed, the reaction was quenched with 1mol / L hydrochloric acid, extracted with dichloromethane (30mL×2), the organic phases were combined, and the mixed organic phases were successively washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purified by column chromatography (petroleum ether / ethyl acetate=10:1 to 2:1 gradient elution), a white solid compound (1.14 g) was obtained, and the reaction yield was 78%. The characterization data of the obtained white solid is consistent with that of Example...

Embodiment 3

[0063] Embodiment 3: the preparation of compound III

[0064] Add compound II (0.88g, 5.00mmol) to a dry 50mL round bottom flask, add dichloromethane (10mL) and stir to dissolve, add triethylamine (0.76g, 7.50mmol) and DMAP (0.31g, 0.25 mmol), the temperature was cooled to 0° C. in an ice bath, and a dichloromethane solution of Compound I (0.90 g, 6.00 mmol) was slowly injected, reacted for 2 hours, and the reaction was detected by TLC. After the reaction, dichloromethane (15mL) was added for dilution, washed with saturated sodium bicarbonate solution (15mL) and separated, the aqueous phase was extracted with dichloromethane (30mL×2), and the organic phase was successively washed with saturated brine. Dry over sodium sulfate, concentrate under reduced pressure, and purify by column chromatography (petroleum ether / ethyl acetate=10:1 to 2:1 gradient elution) to obtain a white solid (1.05g), with a reaction yield of 83%. The characterization data of the obtained white solid is c...

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Abstract

The invention provides a preparation method of a brivaracetam intermediate (R)-3-propyl-gamma-butyrolactone, which comprises the following steps: by taking 4-chloro-4-oxobutyric acid methyl ester as a starting raw material, connecting a chiral auxiliary group, introducing R configuration propyl, removing a ligand, reducing carboxyl, and finally esterifying to form a ring, thereby obtaining the (R)-3-propyl-gamma-butyrolactone. The synthesis route ingeniously utilizes the chiral adjuvant (R)-4-benzyl-2-oxazolidinone, optimizes the reaction conditions, has the advantages of few reaction steps, high yield, good reaction stereoselectivity and the like, meanwhile, the raw materials are cheap and easy to obtain, the operation is simple, convenient and safe, and the method has a better industrial application prospect;.

Description

technical field [0001] The invention belongs to the field of pharmaceutical chemical synthesis, and in particular relates to a preparation method of an intermediate (R)-3-propyl-γ-butyrolactone of an antiepileptic drug buvaracetam. Background technique [0002] Brivaracetam is a third-generation antiepileptic drug developed by UCB, Belgium, for the treatment of partial seizures in adults and adolescents over 16 years old with or without secondary generalized seizures adjuvant therapy. Brivaracetam was approved for marketing by the European Medicines Agency (EMA) on January 14, 2016, and was approved by the US Food and Drug Administration (FDA) on February 18, 2016. clinical stage. Compared with other anti-epileptic chemical drugs, the dosage of brivaracetam is small and well tolerated. Its performance in the Chinese market is worth looking forward to. [0003] Brivaracetam, chemical name (2S)-2-[(4R)-2-oxo-4-propyl-1-pyrrolidinyl]butanamide, trade name Briviact, molecular...

Claims

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Application Information

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IPC IPC(8): C07D307/33
CPCC07D307/33C07B2200/07
Inventor 张兴贤管悦
Owner ZHEJIANG UNIV OF TECH
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