Development of a Continuous Process for Tasisulam Sodium

The development of a synthetic route to tasisulam sodium (5-bromo-thiophene-2-sulfonic acid 2, 4-dichlorobenzoylamide sodium salt, hereafter referred to as tasisulam) utilizing continuous Schotten-Baumann reaction conditions is presented.  This process was envisioned with the goal of creating a process with fewer unit operations utilizing the direct formation of the final sodium salt from a sulfonamide and acid chloride without isolation of the free acyl sulfonamide.  Very tight release specifications were in place for the tasisulam API batch process and the challenges of meeting these requirements are detailed.  Another processing goal was to minimize worker exposure to the cytotoxic API.  This was accomplished by eliminating a solid isolation and reducing the total material in the system at any one time.  Operating the Schotten-Baumann conditions in a continuous fashion gave two main advantages.  It allows for inexpensive, dedicated lab hood equipment for API production, and it enables higher yield and better impurity rejection in the extraction, solvent exchange, and crystallization for this route.  Batch development, continuous proof of concept, 50 g/day lab scale demonstration and 5 kg/day commercial scale runs will be presented.