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

Preparation method of brivaracetam intermediate

An intermediate, n-propyl technology, applied in the field of drug synthesis, can solve the problems of high price of chiral starting raw materials, increase of production cost, low yield, etc., and achieve important industrial application value, simple operation and high reaction efficiency Effect

Inactive Publication Date: 2018-01-19
重庆迪维斯生物科技有限公司 +3
View PDF7 Cites 12 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] Among the above-mentioned routes, routes 1 and 2 use chiral columns or enzymatic resolution during the synthesis process to obtain products with a single configuration. This method has long routes and low yields; routes 3, 4 and 5 use manual The synthesis of (R)-4-n-propyldihydrofuran-2-one by directly constructing a chiral center with a chiral starting material can avoid the problem of low yield caused by chiral resolution, but the price of the chiral starting material More expensive, increasing production costs

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Preparation of recombinant ene reductase:

[0035] Ligate the double-digested expression vector pET-30a and the synthetic target gene with T4 ligase overnight, add 10uL of the ligated product to 100uL of Rosetta (DE3) competent cells, place on ice for 30min, and heat shock at 42°C 60sec. Place on ice for 2 minutes. Add preheated 0.45mL LB medium at 220rpm and incubate at 37°C for 1h. Add 200 uL of the bacterial solution to an LB plate containing 100 μg / mL kanamycin, and culture overnight at 37°C for 12-16 to obtain recombinant bacteria E.coli Rosseta.

[0036] A single colony of recombinant Escherichia coli containing the ene reductase gene was inoculated from the plate into 15 mL of liquid LB medium containing ampicillin resistance and activated overnight (37° C., 200 rpm). From the overnight culture, transfer 150mL liquid LB medium containing ampicillin resistance at 1 / 100 inoculum, culture at 37°C with shaking at 200rpm until the OD600 value reaches 0.6-0.8, then ...

Embodiment 2

[0038] Preparation of gram-level (R)-4-n-propyldihydrofuran-2-one:

[0039] Add 55ml of phosphate buffer (0.1M, pH6.0) to a 250mL round bottom flask, add 20mL of isopropanol, weigh 10g of 4-n-propyl-2(5H)-furanone and add it; then add 20g recombinant ene reductase, 5g ketoreductase and 30mg NAD + ; Use magnetic stirring at a temperature of 25°C, add dropwise 2mol / L sodium hydroxide solution to maintain the pH of the system, take a sample after 20 hours for GC analysis; the conversion rate> 99%, terminate the reaction, filter with diatomaceous earth, and use Rinse the filter residue with ethyl acetate, extract the filtrate with ethyl acetate, and combine the organic phases; dry with anhydrous sodium sulfate, and concentrate to obtain 9.37g with a yield of 92.2%, a GC purity of 98.2%, and an ee value of 99.4%.

Embodiment 3

[0041] Preparation of gram-level (R)-4-n-propyldihydrofuran-2-one:

[0042] Add 55ml of phosphate buffer (0.1M, pH7.0) to a 250mL round bottom flask, add 20mL of isopropanol, weigh 10g of 4-n-propyl-2(5H)-furanone and 18.9g of a Glucose water was added; then 20g recombinant ene reductase, 5g ketoreductase and 30mg NADP were added + ; Use magnetic stirring at a temperature of 30°C, add dropwise 2mol / L sodium hydroxide solution to maintain the pH of the system, take a sample after 24 hours for GC analysis; the conversion rate> 99%, terminate the reaction, filter with diatomaceous earth, and use Rinse the filter residue with ethyl acetate, extract the filtrate with ethyl acetate, and combine the organic phases; dry with anhydrous sodium sulfate, and concentrate to obtain 9.37g with a yield of 92.2%, a GC purity of 98.2%, and an ee value of 99.4%.

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 discloses a preparation method of a brivaracetam intermediate. The preparation method comprises the following steps: performing reaction on 4-n-propyl-2(5H)-furanone as a substrate in anaqueous buffer solution of which temperature is 25 to 30 DEG C and a pH value is 6.0 to 9.0 under effects of recombinant alkene reductase and coenzyme as well as a coenzyme regeneration system to generate an intermediate (R)-4-n-propyl-dihydrofuran-2-one. According to the preparation method disclosed by the invention, by adopting specific alkene reductase, the problems of long synthetic route, low yield and high cost of an existing brivaracetam intermediate (R)-4-n-propyl-dihydrofuran-2-one and large environment protection pressure caused by adopting a toxic and dangerous reagent are solved,and the brivaracetam intermediate in the prior art has important industrial application value.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a preparation method of a buvaracetam intermediate. Background technique [0002] Brivaracetam (brivaracetam), the chemical name is (2S)-2-[(4R)-2-oxo-4-propyl-1-pyrrolidinyl]butanamide, and its structural formula is as follows: [0003] [0004] Brivaracetam is the latest 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 partial seizures, concomitant With or without adjuvant therapy for secondary generalized seizures. [0005] As a new type of high-affinity ligand for SV2A, brivaracetam exerts an anti-epileptic effect by affecting synaptic function, and also has a certain inhibitory effect on voltage-dependent Na ion channels. By interacting with sodium ion channels, it inhibits The release of excitatory neurotransmitters reduces the duration and frequenc...

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
IPC IPC(8): C12P17/10C12N9/02C12N15/70
Inventor 唐圆圆艾忠良刘朝
Owner 重庆迪维斯生物科技有限公司
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