Preparation method of 3R-amino substituted butyrylamide derivative

Abstract

The invention relates to a preparation method of a 3R-amino substituted butyrylamide derivative. The preparation method of the 3R-amino substituted butyrylamide derivative comprises the following steps: carrying out hydrogenation reduction on enamine II for preparing 3R,3S-amino substituted butyrylamide racemate III; carrying out resolution, and filtering, so as to obtain 3R-amino substituted butyrylamide R(-) mandelate with high ee% value, alkalifying to obtain the 3R-amino substituted butyrylamide derivative; and oxidizing the obtained mother liquor, so as to obtain enamine II in a recycling manner, and repeating oxidation-reduction cycle for multiple times until products at specified yield are obtained. The preparation method of the 3R-amino substituted butyrylamide derivative has the advantages that a cyclic method is utilized for converting 3S-amino substituted butyrylamide racemate or 3R,3S-amino substituted butyrylamide mixture in any ratio into the 3R-amino substituted butyrylamide derivative with high ee% value, so that the mother liquor is effectively utilized; meanwhile, an expensive catalyst or asymmetric reductive amination with high demand condition does not need to be adopted, thereby being beneficial to reduction of cost and clean production.

Description

technical field [0001] The invention relates to a preparation method of a 3R-amino-substituted butyramide derivative, which belongs to the field of medicine and chemical industry. Background technique [0002] 3R-amino-substituted butanamide derivatives are a class of compounds with important physiological activity and medicinal value, such as sitagliptin phosphate (SitagliptinPhosphate) and repagliptin phosphate (RetagliptinPhosphate), sitagliptin phosphate is The dipeptidyl peptidase-1V (DPP-1V) inhibitor developed by Merck in the United States was approved by the FDA in October 2006 and has now been approved for the treatment of type 2 diabetes in 95 countries including China . Retagliptin phosphate is a dipeptidyl peptidase-1V (DPP-1V) inhibitor developed by Hengrui Company. It is currently in Phase III clinical research, and clinical research results show that it has excellent dipeptidyl peptidase-1V (DPP-1V) inhibitory efficacy. [0003] [0004] The key to the s...

AI Technical Summary

Problems solved by technology

[0016] In summary, although people have made great progress in the synthesis of 3R-aminobutyramide derivatives such as sitagliptin phosphate or repagliptin phosphate, the chiral catalysts used are asymmetric reductive amination methods, transaminase The biocatalytic asymmetric reductive amination method and the method of using chiral small molecule raw materials to introduce chiral centers have their own shortcomings. So far, there is no route that can simultaneously meet the requirements of low production cost, simple operation, and high utilization of chiral configuration. Therefore seek a kind of simple and easy, low-cost method, 3S-amino substituted butyramide derivative or 3R,3S-amino substituted butyramide derivative is converted into 3R-amino substituted butanamide derivative, to preparation sitagliptin phosphate Or repagliptin phosphate has important production value and social significance

Images