Optimized Synthesis of a Key Intermediate of Nirmatrelvir

In this study, the development of a concise alternative process for synthesis of a key nirmatrelvir intermediate cyclic glutamine analog is described. The process proceedes via alpha-cyanomethylation of dimethyl N-BocGlu in the presence of NdCl3, followed by one-pot Raney nickel-catalyzed hydrogenation of the cyano group with concomitant cyclization and ammonolysis and subsequent deprotection of N-Boc to deliver the target intermediate cyclic glutamine analog in three steps with an 82% overall yield and 99.4 A% high-performance liquid chromatography (HPLC) purity. This study resulted in improved synthetic efficiency and stereoselectivity of alpha-cyanomethylation for production of a key nirmatrelvir intermediate cyclic glutamine analog.