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

Preparation method of briracetam and intermediate compound

A technology for compounds and intermediates, applied in the field of compound synthesis, can solve the problems of harsh reaction conditions, explosion risks, and high industrial scale-up costs, and achieve the effect of mild reaction conditions and a simple method.

Pending Publication Date: 2022-07-15
四川奥邦古得药业有限公司
View PDF0 Cites 2 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantages of this route are: at least half of the diastereoisomers need to be discarded, the atom economy is poor, and because the chromatographic column is expensive and the injection volume is limited, the physical properties of each optical isomer are similar, so the chromatographic column is used for separation and purification The effect is poor, the batch processing capacity is small, the cost of industrial scale-up is high, and it is difficult to achieve low-cost mass production
The disadvantages of this route are: at least half of the diastereoisomers need to be discarded, the atom economy is poor, and the purity of the brivaracetam racemate obtained by synthesis is low, and recrystallization can only be carried out after rough separation on silica gel , in order to obtain the briracetam racemate with higher purity, after that, the briracetam racemate can be separated by chromatographic column chromatography
[0014] However, this route has the following disadvantages: 1) The steps are cumbersome; the use of oxazolidinone as a chiral inducing group has a higher price, and it has to go through assembly and removal steps, and the economic cost is higher; 2) The second step requires- The reaction conditions at 70°C are relatively harsh and difficult to achieve large-scale production; 3) The third step uses hydrogen peroxide, which has a risk of explosion as a peroxide; 4) The fourth step uses dimethyl sulfide borane, which has a risk of explosion. And has a pungent smell, there is a risk of safety and environmental protection
[0016] 1) After synthesizing the racemate, column chromatography separation is required: this route needs to discard at least half of the diastereoisomers, and the atom economy is poor; column chromatography separation is difficult, and the cost of industrial scale-up production is high
[0017] 2) Using oxazolidinone as a chiral inducing group: the steps are cumbersome and the reaction conditions are harsh; the price of oxazolidinone is relatively high, and it needs to go through assembly and removal steps, so the cost is relatively high
[0018] 3) Enzyme-catalyzed method: the chiral purity of the final product is too low to meet the medicinal requirements
[0019] 4) The reaction conditions are harsh and the safety is low

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 briracetam and intermediate compound
  • Preparation method of briracetam and intermediate compound
  • Preparation method of briracetam and intermediate compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0110] Preparation of compound 1

[0111]

[0112] Trichloroacetyl chloride (2.24 mL, 20 mmol) and phosphorus oxychloride (1.02 mL, 11.0 mmol) were dissolved in ether (10 mL), and the solution was slowly added dropwise to a solution containing 1-pentene (1.09 mL, 10 mmol) , diethyl ether (20 mL) and zinc-copper reagent (Zinc-Copper couple, CAS#: 53801-63-1, 1.96 g, 30.0 mmol) in a flask. The reaction was heated to 40°C and stirred for 2 hours, and then naturally cooled to room temperature and stirred for 8 hours. Then, the solution was filtered through celite, and 80 mL of n-hexane was added to the filtrate to precipitate zinc chloride salts. The clear solution was obtained by filtration, washed with water, saturated sodium bicarbonate solution and saturated brine successively, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and evaporated to remove the solvent to obtain a pale yellow oil (compound 5) (1.69 g), yield 94%, proceed directly to the ...

Embodiment 2

[0118] Preparation of compound 2

[0119]

[0120] Dissolve 0.39 g of ligand compound L2 and 0.24 g of scandium trifluoromethanesulfonate in 100 mL of ethyl acetate, and stir at 35 ° C for 1 hour to obtain a catalyst 1Sc (OTf) with a concentration of 0.005 M 3 -RaPr 3 ethyl acetate solution.

[0121] To a dry reaction vial under nitrogen protection, 112 mg (1.0 mmol) of compound 1, and 10 mL (0.05 mmol) of a solution of catalyst 1 prepared as described above were added. After adding 10 mL of ethyl acetate, the temperature was lowered to -20°C, 207 mg (1.2 mmol) of m-chloroperoxybenzoic acid was added, and the reaction was continued to stir at -20°C for 20 hours. Then, saturated potassium carbonate solution was added to quench the reaction, and the reaction solution was extracted three times with dichloromethane. The pure compound 2 was isolated by normal phase column chromatography on silica gel with a yield of 83% and a chiral purity of 99.8%.

[0122] Structural data ...

Embodiment 3

[0126] Preparation of compound 2

[0127]

[0128] Installed (PhCN) 2 PdCl 2 (10 mg, 0.025 mmol, 5.0 mol %) and Ligand Compound L7 (13 mg, 0.0275 mmol, 5.5 mol %) were added to a bottle of 2 mL of dry tetrahydrofuran, and stirred at room temperature for 1 hour. Then AgSbF6 (17 mg, 0.05 mmol, 10 mol%) was added, stirring was continued for 1 hour, and filtered to obtain a solution of catalyst 2. Compound 1 (56 mg, 0.5 mmol) was added to the filtrate, the reaction solution was cooled to -40°C with stirring, carbamide peroxide (61 mg, 0.65 mmol) was added, and the mixture was stirred at -40°C for 8 hours. Concentrated under pressure, purified compound 2 was obtained by column separation, the yield was 72%, and the chiral purity was 98.6%.

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 an intermediate compound for synthesizing briracetam, the intermediate compound is (R)-4-propyl-dihydrofuran-2-ketone, the preparation method comprises the following steps: 3-propyl cyclobutanone is subjected to asymmetric Baeyer-Villiger oxidation reaction in the presence of a catalyst and an optional oxidant, and the intermediate compound is (R)-4-propyl-dihydrofuran-2-ketone. And the (R)-4-propyl-dihydrofuran-2-one is obtained through a reaction. The invention further discloses a preparation method of the briracetam, wherein the intermediate compound (R)-4-propyl-dihydrofuran-2-ketone is prepared by the preparation method of the intermediate compound, and then the intermediate compound (R)-4-propyl-dihydrofuran-2-ketone reacts with L-2-aminobutanamide to obtain the briracetam. The method is simple in route, short in step, low in cost, safe and high in product yield and chiral purity.

Description

technical field [0001] The invention belongs to the technical field of compound synthesis, in particular to a preparation method of briracetam and an intermediate compound. Background technique [0002] Brivaracetam is a third-generation antiepileptic drug, which belongs to a new type of synaptic vesicle protein 2A (SV2A) high-affinity ligand, and has a certain inhibitory effect on voltage-dependent sodium ion channels. In 2016, briracetam was approved by the FDA for the treatment of epileptic seizures, and it has a good effect on generalized seizures. [0003] The structural formula of briracetam is as follows: [0004] [0005] The prior art discloses a variety of synthetic methods of briracetam, and its flow process is summarized as follows: [0006] 1. Technical route 1: Patent CN1882535A has announced a kind of synthetic preparation method of briracetam, and the synthetic route is as follows: [0007] [0008] In this route, after the briracetam racemate is syn...

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): C07D207/27C07D307/33B01J31/02B01J31/24B01J31/22
CPCC07D207/27C07D307/33B01J31/0244B01J31/0258B01J31/2447B01J31/2217C07B2200/07B01J2531/35B01J2531/824B01J2231/70
Inventor 金帅江张磊蔡成书王科杨仁明宛燕飞杨立开范世德刘波
Owner 四川奥邦古得药业有限公司
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