New preparation method of brivaracetam

A compound and molar ratio technology, applied in a new field of preparation, can solve problems such as high cost and unsuitable for large-scale production

Active Publication Date: 2018-09-07
BEIJING ABLEPHARMTECH CO LTD
View PDF5 Cites 13 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, the method is costly and not suitable for mass production

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • New preparation method of brivaracetam
  • New preparation method of brivaracetam
  • New preparation method of brivaracetam

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0089] Embodiment 1: the synthesis (toluene as solvent) of (R)-3-bromomethylhexanoic acid

[0090]

[0091] operate:

[0092] At room temperature, dry toluene (60mL) was added to a 250mL three-necked flask, and (R)-4-n-propyl-dihydrofuran-2(3H)-one (12.8g, 0.1mol, 1eq) and no Zinc chloride hydrate (6.8g, 0.05mol, 0.5eq) was added dropwise with trimethylbromosilane (61.2g, 0.4mol, 4eq) under stirring. After the addition was completed, the temperature was raised to 70-80°C for 1 hour. As detected by TLC, (R)-4-n-propyl-dihydrofuran-2(3H)-one disappeared, the heating was stopped and the temperature was lowered. Water (100 mL) was added dropwise at 0-10°C to quench the reaction. Separate the layers, wash the organic phase with water (100 mL×2), and wash once with saturated sodium chloride (100 mL) solution, collect the organic phase, and dry over anhydrous sodium sulfate (10 g) for 2 hours. Filter and concentrate the organic phase to dryness. 18.1 g of the target compound w...

Embodiment 2

[0094] Example 2: Synthesis of (R)-3-bromomethylhexanoic acid (n-heptane as solvent)

[0095] operate:

[0096]At room temperature, dry n-heptane (60mL) was added to a 250mL three-necked flask, followed by (R)-4-n-propyl-dihydrofuran-2(3H)-one (12.8g, 0.1mol, 1eq) and anhydrous zinc chloride (6.8g, 0.05mol, 0.5eq), under stirring, trimethylbromosilane (61.2g, 0.4mol, 4eq) was added dropwise, after the addition was complete, the temperature was raised to 70-80°C for 1 hour. As detected by TLC, (R)-4-n-propyl-dihydrofuran-2(3H)-one disappeared, the heating was stopped and the temperature was lowered. Water (100 mL) was added dropwise at 0-10°C to quench the reaction. Separate the layers, wash the organic phase with water (100 mL×2), and wash once with saturated sodium chloride (100 mL) solution, collect the organic phase, and dry over anhydrous sodium sulfate (10 g) for 2 hours. Filter and concentrate the organic phase to dryness. 19.4 g of the target compound was obtained a...

Embodiment 3

[0097] Embodiment 3: the synthesis of (R)-3-bromomethylhexanoyl chloride

[0098]

[0099] operate:

[0100] At room temperature, dichloromethane (100mL) was added to a 250mL three-necked flask, (R)-3-bromomethylhexanoic acid (19.0g, 0.09mol, 1eq) was added, and under stirring, thionyl chloride ( 32.1 g, 0.27 mol, 3 eq). After addition, the reaction was stirred at room temperature. TLC detects that the starting material disappears, and the reaction is stopped. Concentrate to dryness under reduced pressure to obtain 21.4 g of the target compound as a yellow oil with a yield of 104.5%. used directly in the next step.

[0101] 1 H NMR (400MHz, Chloroform-d) δ3.58 (ddd, J = 18.6, 10.5, 3.9Hz, 1H), 3.52–3.42(m, 1H), 3.20–2.87(m, 1H), 2.73–2.36(m ,1H),2.33–2.14(m,1H),1.53–1.26(m,4H),0.98–0.89(m,3H).

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

Abstract

The invention relates to a new preparation method of brivaracetam, and belongs to the field of chemical synthesis. According to the present invention, optically pure (R)-4-n-propyl-dihydrofuran-2(3H)-one is used as a raw material, and ring opening, halogenation, condensation, ring closure and other steps are performed to obtain the high-purity brivaracetam; and the preparation method has advantages of easily available raw materials, low cost, high total yield, high optical purity of the obtained product, simple reaction conditions and simple operation process.

Description

technical field [0001] The invention belongs to the field of drug synthesis and relates to a new preparation method of buvaracetam. Background technique [0002] Brivaracetam, the structure is shown in formula (I), the chemical name is (2S)-2-((4R)-2-oxo-4-n-propyl-1-pyrrolidinyl)butanamide [0003] [0004] Brivaracetam is a novel high-affinity synaptophysin 2A ligand that inhibits neuronal voltage-dependent sodium channels and is used for the treatment of refractory epileptic partial-onset seizures. At the beginning of 2016, it was approved for marketing in the European Union and the United States. [0005] After searching the literature, it is found that there are five synthetic routes of brivaracetam reported so far. [0006] Benoit M. (J.M.C.2004,47,530-549.) reported a preparation route of buvaracetam, which uses 2(5H)-furanone as a starting material and reacts with n-propylmagnesium bromide to obtain racemic 4-n-propyl-dihydrofuran-2-one reacts with iodotrimethy...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/27
CPCC07B2200/07C07D207/27C07D207/267
Inventor 马良
Owner BEIJING ABLEPHARMTECH CO LTD
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap