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

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.