A kind of preparation method of (s)-4-hydroxyl-2-oxo-1-pyrrolidineacetamide

Abstract

The invention belongs to the field of medicine synthesis, and particularly relates to an oxiracetam derivative and a method for preparing (S)-4-hydroxy-2-oxo-1-pyrrolidinyl acetamide from the derivative. The derivative is prepared from racemate oxiracetam and phthalic anhydride under the existence of pyridine and then reacts with a resolving agent of (S) type chiral amine to obtain solid, and the solid is acidified and extracted and then hydrolyzed under the alkaline condition to obtain (S)-4-hydroxy-2-oxo-1-pyrrolidinyl acetamide. The method is high in yield, good in product purity and suitable for the large-scale industrial preparation method.

Description

technical field [0001] The invention belongs to the field of pharmaceutical synthesis, in particular to an oxiracetam derivative and a method for preparing (S)-4-hydroxy-2-oxo-1-pyrrolidineacetamide using the derivative. Background technique [0002] Oxiracetam is a nootropic drug synthesized for the first time in 1974 by the Italian Shi Kebichem Company. It is composed of two isomers (S)-oxiracetam ((S)-oxiracetam) and (R)- Oxiracetam ((R)-oxiracetam) composed of racemate. According to WO93 / 06826, the two isomers of oxiracetam have different activities when used as brain function improvers, and the activity of (S)-oxiracetam is stronger than that of (R)-oxiracetam. The chemical name of (S)-oxiracetam is: (S)-4-hydroxy-2-oxo-1-pyrrolidineacetamide, and its chemical structure is as follows: [0003] [0004] The optically pure (S)-oxiracetam can be obtained by two methods: the resolution of the racemate and the asymmetric synthesis. The preparation method of (S)-oxirace...

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Problems solved by technology

The preparation method of (S)-oxiracetam in the patent WO2005 / 115978, wherein (S)-4-chloro-3-hydroxybutyrate and glycinamide react under alkaline conditions to obtain the final product oxiracetam The alkalinity of the reaction solution is controlled by one-time addition of alkali, but because oxiracetam is easily destroyed in a strong alkali solution, this directly affects the yield of oxiracetam

In this preparation method, the reaction can be carried out at a temperature of 0-100°C, but in such a wide temperature range, the efficiency of the reaction varies greatly, and it still cannot provide a reaction temperature range with the highest product yield

[0005] US4797496 and WO 93 / 06826 disclose the method for preparing (S)-oxiracetam, the method disclosed in this document comprises obtaining chiral 3,4-epoxybutyrate from chiral β-hydroxybutyrolactone, making The resulting product is reacted with N-protected glycinamide, and the resulting product is subjected to N deprotection, followed by cyclization to obtain optically pure oxiracetam. This method has relatively few steps, but due to the chiral 3,4-ring The synthesis yield of oxybutyrate is extremely low and the cost of this method is high

[0006] Literature (J Computer-Aided Molecul Design, 1991, 5 (4): 277) reported that the optical enantiomers of oxiracetam were resolved using a ChiralcelOC chiral column, and the mobile phase was n-hexane-ethanol (75: 25). The peak times are 39 and 44 minutes respectively, and the resolution is 1.15. This method takes a long time and does not achieve complete separation. It cannot meet the technical requirements of modern rapid and accurate quantitative analysis. The eluent used is an organic mixed solvent, and the amount of solvent is large and the pollution is large. And difficult to recycle, high cost

[0007] Racemate resolution to obtain optically pure isomers, usually by reacting a chiral resolution reagent with a pair of enantiomers in a racemate mixture to convert them into two diastereomeric salts, and then using The differences in the physicochemical properties of these diastereomers can be separated and then reduced, but there is no report on obtaining optically pure (S)-oxiracetam through racemate resolution.

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