Process Development for Continuous Manufacturing of Baloxavir Marboxil. Part 1: Step 1 Synthesis

Annually, influenza viruses have a substantial impact on global health, often resulting in severe illness and death. While influenza vaccines are accessible, antiviral medications, such as baloxavir marboxil (marketed as Xofluza), play a vital role in both postexposure prevention and treatment, specifically targeting seasonal influenza A and influenza B. The Step 1 synthesis of baloxavir marboxil is from S199AL to S-033447 and includes four unit operations (i.e., reactive crystallization to S-033447·CSA (camphorsulfonic acid), continuous rotary filtration of S-033447·CSA, neutralization and purification of S-033447·CSA to S-033447, and continuous rotary filtration of S-033447). S-033447·CSA was formed from S199AL and S199AR through a continuous reactive crystallization in a 500 mL five-stage CSTR cascade. The solid yield was 66.2% with a residence time of 28 h. The neutralization of S-033447·CSA and crystallization of S-033447 were performed in a two-stage MSMPR cascade. A pH probe was located in the first stage (i.e., neutralization stage), and a ReactIR probe was placed in the second stage (i.e., crystallization stage) to monitor the antisolvent addition. The crystallization yield was 91–93% for a 65% water volume fraction. The filtration processes of S-033447·CSA and S-033447 slurry were conducted with a continuous rotary filter, and steady state was achieved.