Preparation method of Brivaracetam intermediate

Abstract

The invention discloses a preparation method of a Brivaracetam intermediate, wherein the reaction equation is shown as follows: diethyl malonate, bromopropane and an aprotic polar solvent are used forpreparing a compound of formula (1) under the action of an alkali; the compound of formula (1), tert-butyl bromoacetate and an aprotic polar solvent are used to prepare a compound of formula (2) under the action of an alkali; the compound of formula (2) and a polar solvent are used to prepare a compound of formula (3) under the action of an alkali; the compound of formula (3) is used to prepare acompound of formula (4) at high temperature; the compound of formula (4) and a polar solvent are used to prepare a compound of formula (5) under the action of an alkali; the compound of formula (5) and the resolving agent prepare the compound of formula (6) under the resolving solvent; the compound of formula (6) and a reducing agent are subjected to reduction reaction and hydrolysis reaction toprepare a compound of the formula (7). According to the invention, conventional raw materials are selected and can be prepared through conventional reactions, the optical purity materials are easier to purify, and the method is suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to the medical field, in particular to a preparation method of a chiral intermediate of Buvaracetam. Background technique [0002] Brivaracetam is a third-generation epilepsy drug developed by Belgian UCB company. It is a new type of synaptic vesicle protein 2 compound (SV2 compound) high-affinity ligand, and it is also effective for voltage-dependent sodium ion channels. Certain inhibitory effect. In 2005, brivaracetam was approved by the FDA and the European Union for the treatment of rare myoclonic seizures. In February 2016, the US FDA approved brivaracetam as an add-on treatment for other drugs for epilepsy patients over 16 years old partial seizures. During the chemical synthesis of Buvaracetam, the preparation of the chiral intermediate (R)-4-propyl-dihydrofuran-2-one is a key part of the synthesis of Buvaracetam. [0003] There are several methods for preparing chiral (R)-4-propyl-dihydrofuran-2-one in the prior art. Ho...

AI Technical Summary

Problems solved by technology

This method mainly has the following shortcoming: the starting material of the first step needs to use (1R, 2S, 5R)-(-)menthol (S)-p-toluene sulfinate, and this raw material can not be purchased from the market, And the synthesis is difficult, the process is difficult, and the expensive rhodium catalyst is used

This method has the following disadvantages: the starting material (1R, 2R)-(-)-N, N'-dimethyl-1,2-cyclohexanediamine in the first step is expensive, and allyl dichloride It is difficult to buy phosphine in the market, and the third step requires the use of ozone, which requires very high production equipment

This method has the following disadvantages: the price of the starting material 2(5H)-furanone of the first step reaction is expensive; the starting material allyl p-toluene sulfinate is difficult to buy on the market, and if it is prepared by itself, its synthetic difficulty large, the process is difficult and the chemical properties are unstable, and it needs to be produced and used immediately, which brings uncertainty to the production. Therefore, considering the cost of raw materials and the operability of the process, although this method can finally obtain (R)- 4-Propyl-dihydrofuran-2-one, but it is difficult to apply to industrial production

[0010] The final products of these three methods still need to be separated and purified by chiral preparative columns, the steps are cumbersome, the production cost is high, and the industrial feasibility is poor.

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