Synthesis, split and racemization of chirality medicament levetiracetam midbody (S)-(+)-2-amido butyramide hydrochlorate

A technology of aminobutyramide and chiral drugs, which is applied in the field of preparation of chiral drug intermediates, can solve the problem that CN1583721A does not carry out recycling, safety, three waste treatment and environmental protection, and L-2-aminobutyric acid is expensive, etc. problems, to achieve the effect of low equipment requirements, improved yield and simple operation

Active Publication Date: 2008-02-27
ABA CHEM CORP
View PDF3 Cites 41 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the route has few steps, the starting material L-2-aminobutyric acid is expensive and the cost is higher
The second is to use n-propionaldehyde as the starting material to prepare the target compound through six steps of Streck reaction, hydrolysis, resolution, esterification, ammonolysis and cyclization. The reaction steps of this method are long and the yield is only 4.7 %, CN1583721A improved this route, taking n-propionaldehyde and sodium cyanide as starting materials, and preparing the target compound through four steps of Streck reaction, hydrolysis, resolution and cyclization. With this method, the product The yield has been improved, but this method uses the highly toxic compound sodium cyanide, which has h

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
  • Synthesis, split and racemization of chirality medicament levetiracetam midbody (S)-(+)-2-amido butyramide hydrochlorate
  • Synthesis, split and racemization of chirality medicament levetiracetam midbody (S)-(+)-2-amido butyramide hydrochlorate
  • Synthesis, split and racemization of chirality medicament levetiracetam midbody (S)-(+)-2-amido butyramide hydrochlorate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] 1.1: Preparation of 2-aminobutyric acid

[0040] In a 5000ml flask, 1500ml of 28% ammonia water was added, and 500g of 2-bromobutyric acid was added dropwise at room temperature. After the addition was completed, it was heated to 40°C and reacted for 12 hours. It was concentrated to dryness under reduced pressure, and the residual solid was refined with methanol to obtain 220 g of white crystal 2-aminobutyric acid with a yield of 71% and a content of 99.45%.

[0041] 1.2: Preparation of vortexed free base (±)-2-aminobutyramide

[0042] In a 2000ml flask, add 88g (0.854mol) of 2-aminobutyric acid and 600ml of methanol, cool to below 0°C, add 142.6g (1.2mol) of thionyl chloride dropwise, after the addition is complete, reflux for 3 hours, and concentrate under reduced pressure Remove methanol, add 400ml of ammonia water, extract with 400ml of dichloromethane, dry over anhydrous magnesium sulfate, filter, concentrate under reduced pressure to remove solvent, add 660ml of ...

Embodiment 2

[0049] 2.1: Preparation of 2-aminobutyric acid

[0050] In a 5000ml flask, 2400ml of 28% ammonia water was added, and 800g of 2-bromobutyric acid was added dropwise at room temperature. After the addition was completed, it was heated to 40°C and reacted for 12 hours. It was concentrated to dryness under reduced pressure, and the residual solid was refined with methanol to obtain 340 g of white crystal 2-aminobutyric acid with a yield of 68.9% and a content of 99.3%.

[0051] 2.2: Preparation of vortexed free base (±)-2-aminobutyramide

[0052] In a 5000ml flask, add 325g 2-aminobutyric acid and 2200ml methanol, cool to below 0°C, add 527g (1.2mol) thionyl chloride dropwise, after the dropwise addition, reflux for 3 hours, concentrate under reduced pressure to remove methanol, add 1480ml Ammonia, extracted with 1500ml of dichloromethane, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure to remove the solvent, added 2440ml of anhydrous methan...

Embodiment 3

[0059] 3.1: Preparation of 2-aminobutyric acid

[0060] In a 5000ml flask, 2400ml of 28% ammonia water was added, and 800g of 2-bromobutyric acid was added dropwise at room temperature. After the addition was completed, it was heated to 40°C and reacted for 12 hours. It was concentrated to dryness under reduced pressure, and the residual solid was refined with methanol to obtain 355 g of white crystal 2-aminobutyric acid, with a yield of 71.9% and a content of 99.0%.

[0061] 3.2: Preparation of vortexed free base (±)-2-aminobutyramide

[0062] In a 5000ml flask, add 350g 2-aminobutyric acid, 2300ml methanol, cool to below 0°C, add 549g thionyl chloride dropwise, after the dropwise addition, reflux for 3 hours, concentrate under reduced pressure to remove methanol, add 1540ml strong ammonia water, and use Extract with 1540ml of dichloromethane, dry with anhydrous magnesium sulfate, filter, concentrate under reduced pressure to remove solvent, add 2540ml of anhydrous methanol,...

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 new synthesizing technique of chiral drug (S)-alpha-ethyl-2-oxo-1-pyrrolidine acetamide ( left Piracetam) intermediate (S)-(+)-2-aminobutanamide hydrochlorate, which comprises the following steps: adopting 2-brobutyrate as initial raw material; aminating; esterifying; ammonolyzing; detaching; looping; obtaining the object compound; making mixed rotary free alkaline (+-)-2-aminobutanamide; adopting half-quantum resolution method to connect chemical detaching salt to evolve salt; removing the detaching agent through alkalization; obtaining the (S)-(+)-2-aminobutanamide hydrochlorate with optical activity; using the mother liquor to make the product. The invention improves the receiving rate and saves the cost of raw material with simply technical operation and low cost, which resolves the resolved mother liquor after racemic action again to reduce the pollution of environment, therefore fitting for industrialized manufacturing.

Description

technical field [0001] The invention relates to the technical field of preparation of chiral drug intermediates. In particular, it relates to the synthesis, resolution and racemization methods of the chiral drug levetiracetam intermediate (S)-(+)-2-aminobutyramide hydrochloride. Background technique [0002] The preparation method of chiral drug levetiracetam has been reported in the literature, such as EP1566376, CN1015541B and CN1583721A have introduced the synthesis of the compound respectively, the main route has, the first is starting raw material with L-2-aminobutyric acid, through Esterification, ammonolysis, cyclization or first cyclization, esterification, and then ammonolysis, the target compound. Although this route has few steps, the starting material L-2-aminobutyric acid is expensive and the cost is higher. The second is to use n-propionaldehyde as the starting material to prepare the target compound through six steps of Streck reaction, hydrolysis, resolutio...

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): C07C231/02C07C231/20C07C237/06
Inventor 史宝珠蔡彤阙利明
Owner ABA CHEM CORP
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