Preparation method of high chiral purity lactam intermediate and brivaracetam

Abstract

The invention discloses a preparation method of a high chiral purity lactam intermediate and brivaracetam. The preparation method of the lactam intermediate structural formula compound D includes thesteps of: in a solvent, by means of a heavy metal catalyst and a chiral inducer, conducting hydrogenation reduction on a compound C into the lactam intermediate D. The lactam intermediate structural formula compound D provided by the invention can be made into brivaracetam by only one step, the synthesis route is short, the reaction conditions are mild, the post-treatment is simple, the reaction yield is high, the chiral selectivity is good, and the production cost is low. In the reaction process, the conversion rate of the compound C reaches 81%, and the de value of the compound D reaches 99%or more, therefore the method is suitable for industrial production.

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 the higher purity of Buvaracetam, which cannot be produced on a large scale

One is chiral source method synthesis. Taking CN106432030A as an example, this kind of method has the disadvantages of long reaction route, high activity of intermediates, difficulty in purification, easy occurrence of racemization in the reaction process, etc., which is not conducive to quality control and cost control. For the resolution method, the lactam intermediate is resolved by enzymes, chemical reagents, etc., but this type of method generally has many shortcomings 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, therefore, there is a need for a simple and cost-effective process for the preparation of high-purity brivaracetam to obtain brivaracetam of high optical purity

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