Preparation method of (S)-oxiracetam

Abstract

A preparation method of (S)-oxiracetam comprises the steps of conducting a reaction of a glycine ethyl ester hydrochloride with (S)-4-halgen-3-hydroxy-ethyl butyrate in an alcohol solvent under an alkaline condition, wherein the glycine ethyl ester hydrochloride and the (S)-4-halgen-3-hydroxy-ethyl butyrate are adopted as raw materials, filtering, washing with an inorganic alcohol, concentrating, then extracting, conducting water-phase concentration, introducing stronger ammonia water for a reaction so as to prepare a crude product of (S)-oxiracetam, and purifying the crude product; and mixing the glycine ethyl ester hydrochloride with alkali and the alcohol solvent firstly, then dropping the (S)-4-halgen-3-hydroxy-ethyl butyrate raw material in the mixture, and adding the alkali in times so as to control the pH value in the reaction to be 8-9. Purification treatment comprises the steps that the crude product of (S)-oxiracetam is dissolved in a benign solvent, a saturated solution is prepared at the room temperature, and then the saturated solution is dispersed in a closed environment by a poor solvent. The HPLC (high-performance liquid chromatography) purity of the prepared (S)-oxiracetam reaches up to more than 99.0%, the yield is high and reaches up to 33%, the reaction condition is moderate, the operation is simple, and the industrialized scale production is facilitated.

Description

technical field [0001] The invention relates to a method for preparing oxiracetam, in particular to a method for preparing (S)-oxiracetam, which belongs to the field of chemical synthesis. 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...

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Problems solved by technology

[0003] Regarding the report on the synthesis of (S)-oxiracetam, US Patent No. 4,797,496 and WO 93 / 06826 disclose the method for preparing oxyracetam, the method disclosed in this document includes obtaining chiral alkyl from chiral β-hydroxybutyrolactone 3,4-epoxybutyrate, react the resulting product with N-protected glycinamide and make the resulting product carry out N deprotection, then obtain optically pure oxyracetam through cyclization, the steps of this method are relatively few, but due to the manual The synthetic yield of permanent alkyl 3,4-epoxybutyrate is extremely low and causes the high cost of this method

U.S. Patent No. 4,173,569 describes another (s)-oxiracetam synthesis method: (s)-γ-amino-β-hydroxybutyric acid is the starting material, the hydroxyl group is protected by a silylating agent, and the cyclization The final product is reacted with ethyl haloacetate, and the reaction product is through deprotection, ammonolysis, and finally obtains the target compound; this kind of 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 take a long time, increase the cost and reduce the total yield

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