Preparation method of brivaracetam intermediate

A technology of intermediates and volumes, applied in the field of medicine, can solve the problems of difficult purification of isomers, achieve the effects of shortening process time, reducing process cost, obvious separation effect and cost advantage

Pending Publication Date: 2021-06-25
SHANGHAI SYNCORES TECH INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The inventors have found a cost-effective resolution method, that is, using L-phenylalanine methyl ester as a resolution agent, can obtain high-purity 2S, 4R-configuration brivaracetam intermediate cheaply and specifically, and solve the problem Solved the problem of extremely difficult purification of isomers in brivaracetam

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

[0034] Embodiment 1: the preparation of compound B-P

[0035] Add 150g of (S)-2(4-propyl-1,5-dihydropyrrol-2-one)butanoic acid (0.71mol) into a 2L hydrogen autoclave, add 1.5L of methanol, add 1.5g of Pd(OH ) 2 / C (1%), reacted at a pressure of 15-20 MPa for 20 hours, filtered, concentrated and distilled off methanol to obtain 140 g of compound B-P as a solid, RS:SS=85:15. See the attached HPLC chart figure 1 .

Embodiment 2

[0036] Embodiment 2: the preparation of L-phenylalanine methyl ester

[0037] Add 20gL of phenylalanine methyl ester hydrochloride to 100ml of methanol to dissolve, adjust the pH to 8-9 with 7N ammonia / methanol solution, filter with suction, and concentrate the mother liquor to obtain 17g of oil.

Embodiment 3

[0038] Embodiment 3: the preparation of compound B-Q

[0039] Add 18ml acetonitrile (3v) and 6g compound B-P (0.028mol, containing isomer 15%) and 5g L-phenylalanine methyl ester (1.0eq, 0.028mol) in 50ml there-necked flask, stir at 50 ℃ for 1 hour After cooling, low-temperature suction filtration, 10g of wet product was obtained, and dried to obtain 8g of compound B-Q. Yield: 73%, purity: 99.8%, diastereomers 0.2%.

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Abstract

The invention discloses a preparation method of a brivaracetam intermediate shown as B-R in the specification. The preparation method comprises the following steps: salifying B-P and L-phenylalanine methyl ester in a solvent to obtain B-Q, and conducting acidifying to obtain the chirally pure intermediate B-R. In the preparation process, a chiral chromatographic column is not needed to separate isomers, a separation process is simple, yield is high, the price of a resolution reagent is low, and the production cost of brivaracetam is greatly reduced.

Description

technical field [0001] The invention relates to a preparation method of buvaracetam and an intermediate thereof, belonging to the technical field of medicine. Background technique [0002] Brivaracetam, whose chemical name is (S)-2-(R)-3-propylpyrrolidin-1-ylbutyramide, was developed by UCB Pharma in Belgium and is an antiepileptic Drug levetiracetam (levetiracetam) The 4-carbon atom of pyrrolidine is connected to the analogue of n-propyl group. Brivaracetam is also a selective and high-affinity ligand for brain synaptophysin 2a (SV2A), an important site in the inhibition of partial seizures. The European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) approved on January 14, 2016 and February 18, 2016, respectively, for the treatment of partial-onset epilepsy patients aged 16 years and over, with or without Adjuvant therapy with secondary generalized seizures, trade name It belongs to the third generation of antiepileptic drugs. [0003] At present...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/27
CPCC07D207/27C07B2200/07
Inventor 占轶鹏樊海生尹凯季翔刘博洋郭效文黄鲁宁陶安平安建国顾虹
Owner SHANGHAI SYNCORES TECH INC
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