Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Preparation method of (R)-3-propyl-gamma-butyrolactone

A technology of butyrolactone and propyl group is applied in the field of preparation of antiepileptic drug brivaracetam intermediate-3-propyl-γ-butyrolactone, and can solve the problems of chiral column separation, low yield and chemical selection. problems such as poor performance, to achieve the effects of simple operation, high yield, good application value and economic benefits

Active Publication Date: 2018-09-14
ZHEJIANG UNIV OF TECH
View PDF9 Cites 5 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0020] The invention provides a preparation method of (R)-3-propyl-γ-butyrolactone, which has the advantages of simple process route, cheap and easy-to-obtain raw materials, short synthesis path, mild reaction conditions, simple and convenient operation, high yield and stereoselective The advantages of good properties overcome the problems of chiral resolution, chiral column separation, low yield, and poor chemical selectivity in the prior art.

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
  • Preparation method of (R)-3-propyl-gamma-butyrolactone
  • Preparation method of (R)-3-propyl-gamma-butyrolactone
  • Preparation method of (R)-3-propyl-gamma-butyrolactone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] (a) Preparation of (S)-3-p-toluenesulfonyl-γ-butyrolactone

[0045] In a 250mL single-necked flask, the raw material (S)-3-hydroxy-γ-butyrolactone (10.0g, 98mmol) was dissolved in 20.0mL of dichloromethane, the temperature was controlled at -30°C, and triethylamine (20.0g, 198mmol), and stirred evenly. p-Toluenesulfonyl chloride (30.0 g, 157 mmol) was dissolved in 40.0 mL of dichloromethane, slowly added dropwise to the above reaction system, stirred overnight at room temperature (12 hours of reaction), and TLC detected that the reaction of the raw materials was complete. The pH was adjusted to 5 with 3 mol / L hydrochloric acid, the liquid was separated, the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 20.3 g of a white solid with a yield of 81%.

[0046] 1 H NMR (DMSO, 400MHz) δ: 7.72-7.81(d,2H), 7.44-7.53(d,2H), 5.32-5.48(m,1H), 4.33-4...

Embodiment 2

[0054] (a) Preparation of (S)-3-p-toluenesulfonyl-γ-butyrolactone

[0055] In a 250mL single-necked flask, take the raw material (S)-3-hydroxy-γ-butyrolactone (13.0g, 127mmol), dissolve it in 26.0mL toluene, put it in an ice bath, and add N-methylmorpholine (25.8g, 255mmol) , stir well. Dissolve p-toluenesulfonyl chloride (48.5g, 254mmol) in 70.0mL toluene, and slowly add it dropwise to the above reaction system, the reaction produces a large amount of solid triethylamine hydrochloride, and the enlarged reaction requires mechanical stirring, and the reaction is stirred for 12 hours. TLC detects that the reaction of raw materials is complete.

[0056] Suction filtration, wash the filter cake with 13mL toluene, adjust the pH of the filtrate to 5 with 3mol / L hydrochloric acid, neutralize the excess triethylamine, continue suction filtration, separate the filtrate, and extract the water layer with toluene (26.0mL) for 1 ~2 times, combine the organic phases. Washed with water, w...

Embodiment 3

[0061] (a) Preparation of (S)-3-p-toluenesulfonyl-γ-butyrolactone

[0062] In a 250mL single-necked flask, take the raw material (S)-3-hydroxy-γ-butyrolactone (13.0g, 127mmol), dissolve it in 26.0mL of tetrahydrofuran, put it in an ice bath, add pyridine (20.2g, 255mmol), and stir well. Dissolve p-toluenesulfonyl chloride (24.3g, 127mmol) in 70.0mL tetrahydrofuran, and slowly add it dropwise to the above reaction system, the reaction produces a large amount of solid triethylamine hydrochloride, and the enlarged reaction requires mechanical stirring, and the reaction is stirred for 15 hours. TLC detects that the reaction of raw materials is complete.

[0063] Suction filtration, wash the filter cake with 13mL tetrahydrofuran, adjust the pH of the filtrate to 5 with 3mol / L hydrochloric acid, neutralize the excess triethylamine, continue suction filtration, separate the filtrate, and extract the water layer with tetrahydrofuran (26.0mL) for 1 ~2 times, combine the organic phases...

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

PropertyMeasurementUnit
melting pointaaaaaaaaaa
Login to View More

Abstract

The invention discloses a preparation method of (R)-3-propyl-gamma-butyrolactone. The method comprises the following steps: with (S)-3-hydroxyl-gamma-butyrolactone as an initial raw material, activating hydroxyl by using sulfonate, reacting the hydroxyl-activated compound with a Grignard reagent in the presence of a copper catalyst, a cocatalyst and a nitrogen-containing compound to generate (R)-3-propyl-gamma-butyrolactone. The preparation method has the advantages that the process route is simple, the raw materials are cheap and easy to obtain, the synthesis route is short, the reaction conditions are mild, the operation is simple and convenient, the yield is high, and the stereoselectivity is good, the problems of the prior art that chiral separation and chiral column separation are needed in reaction, the yield is low and the chemical selectivity is poor are solved, and an important value is provided for the process research of brivaracetam.

Description

technical field [0001] The invention belongs to the field of pharmaceutical chemical synthesis, and in particular relates to a preparation method of an antiepileptic drug buvaracetam intermediate (R)-3-propyl-γ-butyrolactone. Background technique [0002] Brivaracetam is the third-generation antiepileptic drug developed by UCB in Belgium. It was approved by EMEA and FDA in January and February 2016, respectively, for the treatment of epilepsy in adults and adolescents over 16 years old. Adjunctive treatment of partial seizures, with or without secondary generalized seizures. Brivaracetam is a structural derivative of levetiracetam, which is a highly selective and high-affinity synaptic vesicle protein 2A ligand. ) combine to affect synaptic function, and at the same time as a high-affinity sodium channel inhibitor, significantly improve antiepileptic activity. Ibuvaracetam has better safety and pharmacokinetic properties, especially the good tolerance of the central nervou...

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): C07D307/33
CPCC07D307/33
Inventor 刘惠俊张兴贤
Owner ZHEJIANG UNIV OF TECH
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

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

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com