Development of a Continuous
Schotten–Baumann
Route to an Acyl Sulfonamide
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Abstract
The development and scale-up 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 disclosed. A new synthetic
route for the cytotoxic API amenable to continuous processing was
envisioned that would minimize potential worker exposure by reducing
the number of unit operations and would allow commercial-scale API
production in laboratory fume hoods with inexpensive glassware. The
developed Schotten–Baumann conditions contained fewer unit
operations than the existing batch process by utilizing the direct
formation of the final sodium salt from a sulfonamide and acid chloride
without isolation of the free acyl sulfonamide. Batch development,
continuous proof of concept studies, 5.2 g/h lab-scale demonstration
and 5 kg/day commercial-scale runs will be discussed. Very stringent
release specifications were in place for the tasisulam API batch process,
and the challenges of meeting these requirements for the continuous
process are detailed. Finally, the quality of material generated during
startup and shutdown transitions will be addressed