Preparation method of (S)-oxiracetam

A technology of glycine ethyl ester hydrochloride and crude product, applied in the direction of organic chemistry, etc., can solve the problems of unattainable high purity, low purity, low preparation yield, etc., to reduce the amount of materials, reduce the content of impurities, and reduce pollution. Effect

Active Publication Date: 2012-07-25
CHONGQING RUNZE PHARM CO LTD
View PDF6 Cites 5 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Regarding the report on the synthesis of (S)-oxiracetam ((S)-4-hydroxy-2-oxo-N-pyrrolidineacetamide), US Patents 4,824,966, 4,843,166 and 5,276,164 disclose the preparation of oxiracetam and its intermediates method, the methods disclosed in these patents include making 4-(C 1 -C 2 )-alkoxy-3-pyrroline-2-one-1-yl-acetic acid (C 1 -C 4 )-Alkyl esters are reacted with trichloromethylsilane to protect the hydroxyl group, and the resulting product is then hydrogenated and amidated, according to which the racemic oxiracetam is obtained by reduction of the hydrogenated double bond; therefore, this method has the disadvantage of being unsuitable for the preparation of Disadvantages of optically pure oxiracetam, moreover, low yields for the preparation of 4-(C1-C2)-alkoxy-3-pyrrolin-2-one-1-yl-acet

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 (S)-oxiracetam
  • Preparation method of (S)-oxiracetam

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] A kind of preparation method of (S)-oxiracetam, carry out as follows:

[0027] 1. Preparation of crude product:

[0028] (a) Add 139.6 g of glycine ethyl ester hydrochloride into 1200 ml of anhydrous ether, ice-cool to -2°C, and pass through 25.5 g of ammonia gas to fully dissociate glycine ethyl ester hydrochloride into glycine ethyl ester, wherein the glycine ethyl ester salt Salt: ether: ammonia=1mol: 1200ml: 1.5mol;

[0029] (b) Add 100.8g of sodium bicarbonate, 705ml of absolute ethanol and 250.0g of (S)-4-chloro-3-hydroxyl-butyric acid ethyl ester dropwise to the above glycine ethyl ester, and the dropping time is 3 hours , reacted at pH 8.0 and temperature 68°C for 28 hours;

[0030] (c) filter, fully wash the filtrate with ethanol, concentrate, then add 4 times the weight of the filtrate in chloroform to extract, concentrate, and separate by column chromatography; finally add 25% concentrated ammonia water and react at 21°C for 8 hours to obtain (S) - Oxirace...

Embodiment 2

[0037] A kind of preparation method of (S)-oxiracetam, carry out as follows:

[0038] 1. Preparation of crude product:

[0039] (a) Add glycine ethyl ester hydrochloride to anhydrous ether, cool it to 0°C, and feed ammonia gas to fully dissociate glycine ethyl ester hydrochloride into glycine ethyl ester, wherein glycine ethyl ester hydrochloride: ether: ammonia Gas=1mol: 1000ml: 1mol;

[0040] (b) Add sodium carbonate, anhydrous methanol and dropwise (S)-4-bromo-3-hydroxyl-butyric acid ethyl ester in above-mentioned glycine ethyl ester, described dropping time is 2.5 hours, at pH8.0, Reaction at 70°C for 25 hours;

[0041] (c) Filtrate, fully wash the filtrate with ethanol, concentrate, then add ethyl acetate 5 times the weight of the filtrate to extract, concentrate, and separate by column chromatography; finally add concentrated ammonia water and react at 20°C for 5 hours to obtain (S) - Oxiracetam crude;

[0042] Wherein ethyl glycine: sodium carbonate: (S)-4-bromo-3-h...

Embodiment 3

[0048] A kind of preparation method of (S)-oxiracetam, carry out as follows:

[0049] 1. Preparation of crude product:

[0050] (a) ethyl glycine hydrochloride is dissociated into ethyl glycine using ether and ammonia;

[0051] (b) Add sodium carbonate, absolute ethanol and (S)-4-iodo-3-hydroxyl-butyric acid ethyl ester dropwise to the above-mentioned glycine ethyl ester, the adding time is 2.3 hours, at pH8.5, Reaction at 67°C for 28 hours;

[0052] (c) Filtrate, fully wash the filtrate with ethanol, concentrate, then add dichloromethane 7 times the weight of the filtrate to extract, concentrate, and separate by column chromatography; finally add concentrated ammonia water and react at 30°C for 8 hours to obtain (S) - Oxiracetam crude;

[0053] Wherein ethyl glycine: sodium carbonate: (S)-4-iodo-3-hydroxyl-butyric acid ethyl ester=1: 0.5: 1.0, in mol ratio, the consumption of dehydrated alcohol is 8 times of sodium carbonate weight;

[0054] 2. Purification of crude produ...

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

A preparation method of (S)-oxiracetam is characterized in that the preparation method comprises the steps of conducting a reaction of a glycine ethyl ester hydrochloride with a (S)-4-halogen-3-hydroxy-ethyl butyrate in an alcohol solvent under an alkaline condition, wherein the glycine ethyl ester hydrochloride and the (S)-4-halogen-3-hydroxy-ethyl butyrate are taken as raw materials, filtering, washing with inorganic alcohol, concentrating, then extracting, separating, and introducing ammonia water to prepare a crude product of the (S) oxiracetam, and purifying the crude product. The glycine ethyl ester hydrochloride is dissociated into glycine ethyl ester by diethyl ether and ammonia gas firstly, and the purification of the crude product comprises recrystallization treatment by use of water and acetone as solvents, wherein a weight ratio of the water to acetone is 1:(5-20). According to the (S)-oxiracetam prepared by the preparation method, the yield is high and reaches up to 36%, the HPLC (high performance liquid chromatography) purity of the (S)-oxiracetam reaches up to more than 99.4%, in addition, the reaction condition is moderate, the period is short, the operation is simple, and the industrialized scale production is facilitated.

Description

technical field [0001] The invention relates to the preparation of oxiracetam, in particular to a preparation method of (S)-oxiracetam. Background technique [0002] Oxiracetam is a nootropic drug synthesized for the first time in 1974 by the Italian Skelebechem Company. The drug was launched in Italy in 1987. Oxiracetam is composed of two isomers (S) - A racemate of oxiracetam ((S)-oxiracetam) and (R)-oxiracetam ((R)-oxiracetam). The report on oxiracetam discloses that it is a synthetic hydroxyaminobutyric acid (GABOB) cyclic derivative, which can promote ATP in the brain, promote the synthesis of acetylcholine and enhance the conduction of nerve excitation, and it can prevent retrograde neuropathy caused by hypoxia. Sexual amnesia has improvement effect, can enhance memory, improve learning ability, is one of effective drugs for treating diseases such as Alzheimer's dementia (AD), cerebrovascular dementia (VD). [0003] Regarding the report on the synthesis of (S)-oxirac...

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): C07D207/273
Inventor 叶雷陈宇瑛李坤荣祖元于媛媛平原
Owner CHONGQING RUNZE PHARM 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