Fast and Efficient Synthesis of Racemic Baloxavir Catalyzed by Strong Solid Acid under Microwave Conditions

Abstract

The compound (±)-12aR-12-[(11S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl]-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione is the intermediate of baloxavir marboxil. In the literature, traditional heating methods and common acid catalysts are used, which result in long reaction times and a low yield. Therefore, finding an efficient and environmentally friendly synthetic route is necessary. In this study, (±)-12aR-12-[(11S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl]-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 (compound 3) was synthesized using a sulfonate resin solid acid catalyst (HND-580) under microwave conditions. The benzyl group was removed without further purification, and an intermediate, racemic baloxavir, was obtained under microwave irradiation. The total yield of the two steps was 78%. This method greatly reduces the reaction time and improves production efficiency.