Preparation method of high chiral purity lactam intermediate and brivaracetam

Abstract

The invention provides a preparation method of a high chiral purity lactam intermediate. The preparation method of the high chiral purity lactam intermediate specifically includes the steps of: conducting hydrogenation reduction on a formula I compound under the conditions of a catalyst and a chiral inducer to generate a formula II compound with a de value of greater than 98%. The invention also discloses a preparation method of brivaracetam, and the formula II compound can produce a brivaracetam product under an ammoniation condition. The method provided by the invention has the advantages ofsimple operation of process route, low cost, high yield, high chiral purity of product, easy industrial production and the like.

Description

technical field [0001] The invention relates to the field of organic synthesis. Specifically, the invention provides a method for preparing a lactam intermediate with high chiral purity and a method for preparing buvaracetam. Background technique [0002] Brivaracetam, the chemical name is (2S)-2-[(4R)-2-oxo-4-propyl-1-pyrrolidinyl]butanamide, and its structural formula is as follows: [0003] [0004] Brivaracetam is a third-generation antiepileptic drug developed by Belgian UCB Company, which was approved by EMEA and FDA in January and February 2016, respectively, for the treatment of partial seizures in adults and adolescents over 16 years old with epilepsy, With or without adjuvant therapy for secondary generalized seizures. [0005] At present, the preparation process of buvaracetam is mainly divided into three categories. One is the process represented by the original research UCB, which requires chiral chromatographic columns to separate isomers, which requires hi...

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Problems solved by technology

[0005] At present, the preparation process of buvaracetam is mainly divided into three categories. One is the process represented by the original research UCB, which requires chiral chromatographic columns to separate isomers, which requires high equipment and greatly increases production costs. For example, patent CN1882535A discloses a A preparation method of buvaracetam, the final obtained is a mixture of buvaracetam and its diastereoisomers, which needs to pass through (CHIRALPAK AD 20um) chiral stationary phase, n-hexane / ethanol (45 / 55, V / V) is the eluent, and the above-mentioned mixture can be separated by chromatography to obtain pure buvaracetam with a higher temperature, which cannot be produced on a large scale

One is the synthesis of chiral source method. Taking CN106432030A as an example, this kind of method has the disadvantages of long reaction route, high activity of intermediates, difficulty in purification, and easy occurrence of racemization in the reaction process, which is not conducive to quality control and cost control. For the resolution method, the lactam intermediate is resolved by enzymes, chemical reagents and other methods, but this type of method generally has many characteristics such as long routes and cumbersome steps, especially the chemical resolution method. The introduction of the resolution agent has a great impact on the quality of the product. control is particularly disadvantageous

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