Brivaracetam chiral intermediate and preparing method thereof

Abstract

The invention relates to an antiepileptic drug brivaracetam chiral intermediate and a preparing method thereof. The preparing method of a compound, shown in a formula 1, of the brivaracetam chiral intermediate comprises the steps of with S-epichlorohydrin (a compound shown in a formula 7 being an original raw material, conducting open-loop preparing on ethyl metal reagent under the effect of Lewisacid to obtain a compound shown in a formula 6; conducting preparing on the compound shown in the formula 6 in the presence of a metal catalyst through a substitution reaction to obtain a compound shown in a formula 5; conducting cyan alcoholysis on the compound shown in the formula 5 under the effect of acid to obtain a compound shown in a formula 4; preparing the compound shown in the formula 4through the effect of hydroxyl activity reagent to obtain a compound shown in a formula 3; conducting preparing on the compound shown in the formula 3 and nitromethane through an SN2 nucleophilic substitution effect to obtain a compound shown in a formula 2; conducting cyclization preparing on the compound shown in the formula 2 through the effect of concentrated sulfuric acid and an Nef reactionto obtain a compound shown in a formula 1, namely the brivaracetam chiral intermediate. By means of the preparing method, the compound high in optical purity and shown in the formula 1 can be prepared and solve the problem that currently produced brivaracetam needs complex unit operation high in cost like a column chromatography and a chiral preparation column.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a chiral intermediate of an antiepileptic drug buvaracetam and a preparation method thereof. Background technique [0002] Brivaracetam is a third-generation epilepsy drug developed by Belgian UCB company. It has a certain inhibitory effect, significantly improves the antiepileptic activity, has good safety and pharmacokinetic properties, and is obviously superior to other antiepileptic drugs in terms of good tolerance of the central nervous system. In February 2016, the US FDA approved Brivaracetam as an add-on treatment to other drugs for partial seizures in epilepsy patients over 16 years old. [0003] According to the reported literature, there are several synthetic methods for buvaracetam: [0004] Method 1, the document Benoit M. (J.Med.Chem.2004,47,530~549) reported that 4-propyl-dihydrofuran-2-one was obtained by reacting 2(5H)-furanone with propylmagnesium bro...

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Problems solved by technology

[0012] Method 1, method 2 and method 3 all need to be separated and purified by silica gel column, and the final product needs to be separated and purified by chiral preparative column. The steps are cumbersome, the production cost is high, and the industrial feasibility is poor.

Method 4 Using (R)-epichlorohydrin as the starting material, the intermediate (R)-3-halomethylhexyl ester with high optical purity was obtained through a series of reactions, which realized the preparation without column chromatographic separation Brivaracetam, but in practical application, this method still has some limitations, so it is urgent to develop some new methods

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