Match-Making Reactors to Chemistry: A Continuous Manufacturing-Enabled Sequence to a Key Benzoxazole Pharmaceutical Intermediate

Abstract

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.

Reactor design and selection for effective continuous manufacturing of pharmaceuticals

“…Copyright 2020 American Chemical Society), ( e ) the two CSTRs-in-series system used in the synthesis of benzoxazole from N-pivaloyl 3,4-dichloro aniline (Reproduced with permission from Ref. [ 26 ]. Copyright 2017 American Chemical Society.…”

“…Susanne et al [ 26 ] reported the synthesis of benzoxazole from N-pivaloyl 3,4-dichloro aniline. In this case, two steps utilized CSTRs-in-series systems (Fig.…”

“…9 Heat profiles for the start-up phase of each vessel for the (a) first reaction step, and (b) second reaction step CSTRs-in-series (Reprinted with permission from Ref. [ 26 ]. Copyright 2020 American Chemical Society.…”

“…PFRs and CSTRs-in-series are popular continuous reactors that are widely used in the pharmaceutical industry. Figure 2 and Table 1 compare the differences between a PFR and CSTRs-in-series [24][25][26]. This article summarizes theories for the design and selection of continuous reactors, and highlights some examples of PFRs and CSTRs-in-series within the pharmaceutical industry.…”

Directed Ortho Metalation in 2021: A Tribute to Victor Snieckus (August 1, 1937–December 18, 2020)

“…The utility of the products of DoM can be very high given the ability to tolerate halogens and other reactive functional groups while increasing complexity. Such metalations are becoming commonplace in the pharmaceutical and fine chemical industries and can often be executed using continuous processing methodology as a practical means to access low temperatures at large scale …”