Preparation method of (S)-4-hydroxy-2-oxo-1-pyrrolidineacetamide

Abstract

A preparation method of (S)-4-hydroxy-2-oxo-1-pyrrolidineacetamide comprises allowing reaction of ethyl glycinate hydrochloride and ethyl (S)-4-halo-3-hydroxybutyrate in alcohol solvent and alkaline conditions, filtering, washing, concentrating, extracting, separating, introducing ammonia water to obtain a crude product, and purifying the crude product, wherein the ethyl glycinate hydrochloride is dissociated by using diethyl ether and ammonia gas to obtain ethyl glycinate; the alcohol solvent is anhydrous methanol or anhydrous ethanol; and the alkaline condition is provided by sodium carbonate or sodium bicarbonate. The method adopts ethyl (S)-4-halo-3-hydroxybutyrate and ethyl glycinate hydrochloride as main raw materials, which has the characteristics of cheap and easily-accessible raw material, environment friendliness and no pollution; and the method firstly carries out dissociation on the ethyl glycinate hydrochloride, which effectively reduces the material consumption in reaction and lowers the cost, and simultaneously plays a positive role in the reaction yield. The method has the characteristics of low preparation cost, high yield up to 36% and mild reaction conditions, and is suitable for industrial production. The prepared (S)-oxiracetam product has high performance liquid chromatography (HPLC) purity up to above 98.5%.

Description

technical field [0001] The present invention relates to the preparation of (S)-4-hydroxyl-2-oxopyrrolidine derivatives, in particular to the preparation method of (S)-4-hydroxyl-2-oxo-1-pyrrolidineacetamide, which belongs to chemical synthesis field. 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 Alz...

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Problems solved by technology

[0003] Regarding the report on the synthesis of (S)-oxiracetam, U.S. Patent 4,797,496 and WO 93 / 06826 disclose the method for preparing (S)-oxiracetam. The method disclosed in this document includes obtaining chiral β-hydroxybutyrolactone from chiral 3,4-epoxybutyrate, reacting the resulting product with N-protected glycinamide, and carrying out N-deprotection of the resulting product, followed by cyclization to obtain optically pure oxiracetam, the method has relatively few steps, but The process is costly due to the very low yield of chiral 3,4-epoxybutyrate synthesis

U.S. Patent US4173569 describes another (s)-oxiracetam synthesis method: using (s)-γ-amino-β-hydroxybutyric acid as the starting material, protecting the hydroxyl group with a silylating agent, and after cyclization The product of the product is reacted with ethyl haloacetate, and the reaction product is deprotected, ammonolysis, and finally obtains the target compound; this preparation method is not suitable for industrial scale production, and the use of protecting groups to protect the hydroxyl group will increase the reaction steps and waste raw materials , takes a long time, increases the cost, and reduces the total yield

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