The
focus of this study was to develop a chemical reaction sequence
toward a key benzoxazole building block, required for clinical manufacturing
of a lead candidate in the respiratory disease area. The chemistry
consisted of initial low-temperature reactions with an organometallic
reagent to generate the benzoxazole core, and was followed by noncryogenic
transformations toward a sulfonamide substituent. With particular
interest in continuous-flow manufacturing we attempted to integrate
the entire sequence on lab scale. Subsequent in-depth process research,
supported by PAT and calorimetry studies, revealed the critical parameters
of each step, leading to a more rational attribution of mode of operation:
flow, batch, or semibatch. Two bench-scale cascades of continuously
stirred tank reactors (CSTRs) were constructed to meet the challenge
of high exothermicity and solids formation and were key to smoothly
upscaling the chemistry to deliver 17 kg of benzoxazole in superior
yield, quality, and robustness.
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