Development of a Quality Controllable and Scalable Process for the Preparation of 7,8-Difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-ol: A Key Intermediate for Baloxavir Marboxil

A novel six-step synthesis of 7,8-difluoro-6,11-dihydrodibenzo­[b,e]­thiepin-11-ol (1) is described. Starting with 3,4-difloro-2-methylbenzoic acid and using diphenyl disulfide as an ideal sulfur source effectively solve the problems such as harsh reaction conditions, usage of smelly thiophenol, which might restrict the known process from pilot plant application. Large-scale applicability of this new route has been successfully demonstrated on kilogram-scale production to afford 1 with 98.04% purity in 75% overall yield. Meanwhile, the corresponding impurity profile was thus studied in detail and well documented.