Efficient Synthesis of a Key Intermediate for Baloxavir Marboxil from a Greener Starting Material: Ethylene Glycol

In this article, a robust and scalable process to prepare the key intermediate 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 (1) for the synthesis of the influenza antiviral drug baloxavir marboxil is described. The process is based on a novel preparation of 2-(2,2-dimethoxyethoxy)ethanamine 5 employing inexpensive and readily available ethylene glycol as the starting material with more convenient manipulation and fewer environmental hazards compared with the original routes starting with ethanolamine or its derivatives. Large-scale applicability of this new route has been successfully demonstrated on kilogram-scale production to afford 700 grams of 1 with 99.3% purity in 31% yield over six steps. With such satisfactory quality, baloxavir marboxil is eventually furnished with excellent purity (>99.5%, single impurity < 0.1%). Meanwhile, the corresponding impurity profile is studied in detail.