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Asymmetric catalytic preparation method of brivaracetam

A catalyst and compound technology, applied in the field of asymmetric catalysis preparation of brivaracetam, can solve the problems of high preparation difficulty, increased cost, inability to realize and the like

Active Publication Date: 2020-10-30
SOUTH UNIVERSITY OF SCIENCE AND TECHNOLOGY OF CHINA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this method must use silicon hydrogen compounds with high atom economy and cost as the hydrogen source. Due to the high boiling point of its unreacted products and by-products, separation and purification treatment is required, although it is mentioned in the specification that this method can be used instead Hydrogen can be used as a hydrogen source, but at present the Cu catalytic hydrogenation reaction using hydrogen as a hydrogen source has not yet had any successful reports, and the application does not have any embodiment records, so it cannot be realized at all. The large steric hindrance ligand DTBM-SegPhos with high price can achieve more ideal results, which further increases the cost in process application

Method used

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  • Asymmetric catalytic preparation method of brivaracetam
  • Asymmetric catalytic preparation method of brivaracetam
  • Asymmetric catalytic preparation method of brivaracetam

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preparation example Construction

[0025] The preparation method of buvaracetam provided by the invention comprises: the compound of formula (I) undergoes an asymmetric catalytic hydrogenation reaction in a hydrogen atmosphere and an organic solvent in the presence of a rhodium (I) catalyst to generate a compound shown in formula (II) ,

[0026]

[0027] Wherein, the rhodium (I) catalyst is generated after mixing a rhodium metal precursor and a ligand;

[0028] The ligand has a structure shown in the following formula (III),

[0029]

[0030] in,

[0031] R is H, D, CF 3 or C 1 -C 3 alkyl;

[0032] Ar is aryl or heteroaryl, wherein, each aryl and heteroaryl are optionally selected from one or more independently selected from D, F, Cl, Br, I, CN, NO 2 、CF 3 、C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy groups are substituted.

[0033] In some embodiments, R is H, D, CF 3 , methyl, ethyl or isopropyl;

[0034] In some embodiments, Ar is aryl or heteroaryl, wherein each aryl and heteroaryl are optionally se...

specific Embodiment approach

[0068] In order to make the present invention easy to understand, the present invention will be further described in conjunction with specific embodiments.

[0069] For the experimental methods that do not indicate the specific conditions in the examples, usually follow the conventional conditions and the conditions described in the manual, or according to the conditions suggested by the manufacturer; the materials, reagents, etc. used can be obtained from commercial sources unless otherwise specified. .

Embodiment 1

[0071]

[0072] Into the reaction vessel was added n-heptane (394 mL) and morpholine (128 mL). The mixture was cooled to 0 °C, and glyoxylic acid 1 (195 g, 150 mL, 50 w%, dissolved in water) was added. The mixture was heated at 20°C for 1 hour, then n-valeraldehyde 2 (149 mL) was added. The reaction mixture was heated at 45°C for 20 hours, and after cooling to 20°C, 37% aqueous hydrochloric acid (197 mL) was slowly added to the reaction mixture, and stirring was continued for 2 hours. After the reaction was finished, the n-heptane was removed by liquid separation, and the aqueous phase was washed three times with n-heptane. Diisopropyl ether was added to extract the organic phase, and the organic phases were combined, washed with saturated brine, and dried by azeotropic distillation. After filtering and concentrating the solvent, 165 g of 5-hydroxy-4-n-propylfuran-2-one was obtained, that is, compound 3, and the reaction yield was 88%.

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Abstract

The invention discloses a preparation method of brivaracetam, which adopts cheap and accessible hydrogen as a hydrogen source, can implement asymmetric preparation of brivaracetam in a catalytic system with rhodium (I) as a metal center, and has the advantages of mild reaction conditions, simplicity, controllability, high yield, high enantioselectivity, environment friendliness, favorable atom economy, low cost and the like. In addition, the invention also provides the brivaracetam compound prepared by the method.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis, in particular to an asymmetric catalytic preparation method of buvaracetam. Background technique [0002] Brivaracetam is the latest third-generation antiepileptic drug developed by UCB in Belgium. It was approved by EMA and FDA in January and February 2016, respectively. It is based on the second-generation antiepileptic drug levetiracetam. structural derivatives. Brivaracetam, as a new type of antiepileptic drug, can be used for the treatment of partial seizures in epileptic patients aged 16 and over, as well as adjuvant treatment with or without secondary generalized epilepsy. [0003] Brivaracetam and Levetiracetan are very similar in structure, and both belong to pyrrolidone derivatives. Compared with the chemical structure of levetiracetam, brivaracetam only has a n-propyl group connected to the 4th position of pyrrolidin, but the binding force of brivaracetam is 10 times that ...

Claims

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Application Information

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IPC IPC(8): C07D207/27C07B53/00B01J31/24
CPCC07D207/27C07B53/00B01J31/2409B01J31/2295C07B2200/07B01J2231/645B01J2531/822B01J2531/842Y02P20/584
Inventor 稂琪伟杨春艳杨泊高爽马保德欧阳凌云张绪穆
Owner SOUTH UNIVERSITY OF SCIENCE AND TECHNOLOGY OF CHINA
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