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Preparation method of (R)-oxiracetam

A technology of glycine ethyl ester hydrochloride and crude products, which is applied in the direction of organic chemistry, can solve the problems of low production yield, expensive raw materials, low yield, etc., and achieve the effect of simple operation, short cycle and low pollution

Active Publication Date: 2014-06-11
CHONGQING RUNZE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although this method provides optically pure oxyracetam, its disadvantages are: expensive raw materials, many steps, low yield, and high cost
Therefore, this method has the disadvantage that it is not suitable for the preparation of optically pure oxyracetam
In addition, 4-(C1-C2)-alkoxy-3-pyrrolin-2-one-1-yl-acetic acid (C1-C4)-alkyl esters were prepared in low yields
But do not see the preparation method of (R)-oxiracetam reported in relevant literature so far

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] The preparation method of (R)-oxiracetam, carries out as follows:

[0026] 1. Preparation of crude product:

[0027] (a) Add 139.6 g of ethyl glycine hydrochloride into 1250 ml of anhydrous ether, cool it to -4°C and blow in 25.5 g of ammonia gas to dissociate ethyl glycine hydrochloride into ethyl glycine, wherein ethyl glycine hydrochloride Salt: anhydrous ether: ammonia gas is 1mol: 1250ml: 1.5mol;

[0028] (b) Add absolute ethanol 470ml, sodium bicarbonate 117.6g, dropwise (R)-4-chloro-3-hydroxyl-butyric acid ethyl ester 266.6g in the above-mentioned product, and described dropping time is 3 hours, in React at pH 8.5 and temperature 75°C for 28 hours;

[0029](c) filter, fully wash the filtrate with ethanol, concentrate, dissolve the concentrate in water, then add 4.5 times the weight of the filtrate in chloroform for extraction, concentrate the water phase, and separate by column chromatography; finally add ammonia water with a mass percentage concentration of 28...

Embodiment 2

[0036] The preparation method of (R)-oxiracetam, carries out as follows:

[0037] 1. Preparation of crude product:

[0038] (a) Add glycine ethyl ester hydrochloride to anhydrous ether, cool to -4°C and pass through ammonia gas to dissociate glycine ethyl ester hydrochloride into glycine ethyl ester, wherein glycine ethyl ester hydrochloride: anhydrous ether : Ammonia is 1mol: 1300ml: 1.2mol;

[0039] (b) Add anhydrous methanol, sodium carbonate, (R)-4-iodo-3-hydroxy-butyric acid ethyl ester to the above product, and react for 20 hours at a pH of 8 and a temperature of 65°C;

[0040] (c) Filtrate, fully wash the filtrate with ethanol, concentrate, dissolve the concentrate in water, then add ethyl acetate 5 times the weight of the filtrate for extraction, concentrate the water phase, and separate by column chromatography; finally add a mass percent concentration of 27% Aqueous ammonia was reacted at 25°C for 7 hours to obtain the crude product of (R)-4-hydroxyl-2-oxo-1-pyrrol...

Embodiment 3

[0046] The preparation method of (R)-oxiracetam, carries out as follows:

[0047] 1. Preparation of crude product:

[0048] (a) ethyl glycine hydrochloride is suspended in chemically pure ether, then feed ammonia to make ethyl glycine hydrochloride free into ethyl glycine;

[0049] (b) Add absolute ethanol, sodium bicarbonate, dropwise (R)-4-bromo-3-hydroxyl-butyric acid ethyl ester to the above product, the time for the addition is 3.5 hours, at a pH of 9 and a temperature of 70 Reaction at ℃ for 20-26 hours;

[0050] (c) then filter, fully wash the filtrate with ethanol, concentrate, and the concentrate is dissolved in water, then add 4 times the weight of the filtrate in chloroform for extraction, and concentrate the water phase; finally add the ammonia water with a mass percentage concentration of 26%, at 28 ° C Down reaction 6 hours makes (R)-oxiracetam crude product;

[0051] Wherein ethyl glycine: sodium bicarbonate: (R)-4-bromo--3-hydroxyl-butyric acid ethyl ester=1...

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Abstract

A preparation method of (R)-oxiracetam comprises the following steps: taking glycine ethyl ester hydrochloride and (R)-4-halo-3-hydroxyl-ethyl butyrate as raw materials to react in an alcohol solvent under an alkali condition, washing with inorganic alcohol, concentrating, extracting and separating, introducing ammonia water to prepare a crude product of oxiracetam, and purifying the crude product, wherein glycine ethyl ester hydrochloride is firstly dissociated by diethyl ether and ammonia into glycine ethyl ester. According to the invention, the main raw materials are (R)-4-halo-3-hydroxyl-ethyl butyrate and glycine ethyl ester hydrochloride, and are cheap, easily accessible, environment-friendly and pollution-free; and the glycine ethyl ester hydrochloride is firstly dissociated, so that the use amount of the materials in the reaction is effectively reduced, the cost is reduced and the yield of the reaction is improved. The prepared (R)-oxiracetam is low in cost, high in yield which can reach 33%, and mild in reaction condition which is beneficial for industrial production in large scale. The HPLC (high performance liquid chromatography) purity of the prepared (R)-oxiracetam product reaches more than 98.5%.

Description

technical field [0001] The invention relates to the preparation of oxiracetam, in particular to a preparation method of (R)-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). (R)-Oxiracetam is a single enantiomer of oxiracetam with the chemical name: (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide. The nootropic drug oxiracetam is a synthetic hydroxyaminobutyric acid (GABOB) derivative, which is a central nervous system drug that can promote learning, enhance memory, and protect damaged nerve cells. [0003] U.S. Patents 4,124,594, 4,173,569 and 4,629,797 to I.S.F. Spa disclose a process for preparing optically pure oxyracetam. The methods disclosed in these patents include reacting optically pure (s)-gamma amino-beta-hyd...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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