First-Generation Process Development for the Synthesis of Baloxavir Marboxil: Early-Stage Development of Synthetic Methods to Prepare Baloxavir Marboxil Intermediates

Described herein is the discovery and development of a process to prepare chiral triazinanone R-3 and diastereomeric intermediate 5, the key intermediates in the synthesis of the cap-dependent endonuclease inhibitor baloxavir marboxil (1), which can suppress the replication of influenza virus. Chiral triazinanone R-3 was obtained via optical resolution of its racemic form rac-3. Diastereomeric intermediate 5 was obtained by the condensation reaction of triazinanone R-3 and thiepin alcohol 4 using a combination of T3P and MsOH. These reactions were performed successfully on kilogram scale and were critical to the establishment of the baloxavir marboxil manufacturing process.