Preparation method of (S)-oxiracetam

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...

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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-acetic acid (C1-C4)-alkyl esters

Korean Patent Publication 2000-9456 discloses a method for preparing optically pure (s)-oxiracetam in which (s)-3,4-epoxybutyrolactone is first synthesized from optically pure (s)-3-hydroxybutyrolactone acid salt as an intermediate under aqueous conditions, and then amidation of this intermediate compound with glycinamide under aqueous conditions with concomitant cyclization; although this technique appears to be inferior in yield and purity Aspect has advantage in industry, but its shortcoming is because the purity of (s)-3-hydroxybutyrolactone is low and causes to produce a lot of impurity, and the (s)-3-hydroxybutyrolactone of preparation high purity can't reach yet, Therefore, this method does not yield oxiracetam with the required purity for pharmaceutical applications

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