A kind of preparation method of high chiral purity lactam compound

Abstract

The invention discloses a method for preparing lactam compounds with high chiral purity. The method for preparing the lactam compounds with the high chiral purity includes steps of adding reactive solvents and heavy metal catalysts into a reaction vessel, and stirring the reactive solvents and the heavy metal catalysts for 10-30 minutes; adding reaction raw materials A into the reaction vessel, then adding hydrogen sources into the reaction vessel and carrying out constant-temperature reaction at the temperature ranging from -30 DEG C to 0 DEG C for 20-40 hours; terminating the reaction, filtering reaction products, and rotationally removing organic solvents from the reaction products; adding water and isopropyl acetate into the reaction products and carrying out extraction; carrying out drying, suction filtration and concentration on organic phase to obtain crude products; re-crystallizing the crude products to obtain lactam products B with high chiral purity. The reduction chiral selectivity can be effectively improved without optional added chiral auxiliaries. The method has the advantages of low production cost, convenience in production and operation, safety, atom economy, easiness in industrial production and the like.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to a preparation method for greatly improving the chiral purity of lactam compounds. 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] The existing synthesis method of 2-oxo-1-pyrrolidine chiral derivatives has problems such as difficulty in realizing industrialized mass production and high production cost. For example, patent CN1882535A discloses a preparation method of buvaracetam, and the final The obtained mixt...

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Problems solved by technology

[0005] The existing synthesis method of 2-oxo-1-pyrrolidine chiral derivatives has problems such as difficulty in realizing industrialized mass production and high production cost. For example, patent CN1882535A discloses a preparation method of buvaracetam, and the final The obtained mixture of buvaracetam and its diastereoisomers needs to pass through (CHIRALPAK AD 20um) chiral stationary phase, n-hexane / ethanol (45 / 55, V / V) as eluent, through chromatography Only by separating the above-mentioned mixture can the high-purity Buvaracetam be obtained, which cannot be produced on a large scale, and the atom economy is poor. Only half of the raw material is transformed into a product, resulting in a large number of diastereoisomers, and this diastereoisomer cannot be transformed for the product

Patent WO2017 / 076738A1 and patent WO2017 / 076737 A1 disclose methods that can effectively improve the selectivity of the reduction reaction, but in the purification process, column separation technology still needs to be used, which brings inconvenience to the process enlargement, and in the reaction The hydrogen pressure used is relatively high, which is not conducive to scale-up production

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