Improved Synthesis of Key Intermediate of Baloxavir Marboxil, an Anti‐Influenza Drug

Abstract In this article, a process to prepare the key chiral intermediate ( R )‐7‐(benzyloxy)‐3,4,12,12a‐tetrahydro‐1H‐[1,4]oxazino[3,4c]pyrido[2,1‐f][1,2,4]triazine‐6,8‐dione 6‐R of influenza antiviral drug baloxavir marboxil is described. The process includes a novel preparation of 2‐(2,2‐dimethoxyethoxy) ethanamine 13 with more convenient and safer manipulation, and a method to convert the mother liquor of the chemical resolution to the racemate 7‐(benzyloxy)‐3,4,12,12a‐tetrahydro‐1H‐[1,4]oxazino[3,4‐c]pyrido[2,1‐f][1,2,4]triazine‐6,8‐dione 6‐rac . This new process has been successfully demonstrated on the 50 g scale of 13 with 66.4 % yield in 3 steps, and 10 g scale of 6‐R via 9 steps with 99.9 % purity, >99 % ee and 11.0 % overall yield. All the steps just involve simple purifications without chromatography.