A platform for conducting organolithium chemistry in continuous flow mode, covering the scales from medicinal chemistry to later phase process development, is described. The use of this flow setup, which mimics the concept of f lash chemistry on scale, has been demonstrated by the exemplary, large-scale preparation of (4-fluoro-2-(trifluoromethyl)phenyl)boronic acid following a reaction sequence of halogen/lithium exchange, borylation, and semibatch workup. Furthermore, the key factors and corresponding practical assessments required for the streamlined and seamless scale-up from lab environment to higher productivity are highlighted.
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.
Continuous processing has been demonstrated to be a superior approach when applied to fast and energetic chemical transformations. Indeed, whereas classical batch or semi-batch methods require cryogenic conditions and slow addition rates of reactive species, flow technologies enable
rapid mixing of synthetic partners in a highly controlled environment. As a result, low yielding and dangerous processes in batch can be performed at scale in a cost competitive and safer continuous manner. Despite the advantages of higher quality and safety, the perennial problems of solids
build-up and pipe fouling threaten the robustness and reliability of flow processes. In this contribution, a new methodology to prevent reactor fouling is reported and discussed. The implementation of this methodology has been decisive in solving fouling issues encountered during the piloting
of an organolithium based flow process.
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