A Multistep Flow Process for the Synthesis of Highly Functionalized Benzoxazoles

An efficient and scalable transformation of 3-halo-N-acyl anilines to the corresponding benzoxazoles within a continuous flow reactor is reported. This transformation proceeds via base-mediated deprotonation, ortho-lithiation, and intramolecular cyclization to provide unstable lithiated benzoxazole moieties. The subsequent in-line electrophilic quench results in the formation of substituted benzoxazoles in high yield and quality. Continuous flow technology allowed for accurate temperature control and immediate in-line quench while minimizing the hold-up time for the unstable lithiated intermediates thereby minimizing associated byproduct formation

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

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

Pharmaceutical industry perspectives on flow chemocatalysis and biocatalysis

In response to a growing demand for more sustainable and cost-effective synthetic processes, the pharmaceutical industry is increasingly relying on continuous manufacturing as a valuable alternative to conventional batch processing. Particularly, flow processing may enable process intensification of chemocatalytic and biocatalytic transformations, both being of strategic importance on the design and production of active pharmaceutical ingredients. This review outlines the current status of flow chemocatalysis and biocatalysis within the pharmaceutical landscape. Furthermore, the trends and challenges that these technologies face are highlighted, based on recently disclosed applications from industry and innovative solutions from academia

BF₃·Et₂O-Promoted Decomposition of Cyclic α-Diazo-β-Hydroxy Ketones: Novel Insights into Mechanistic Aspects

We report novel insights into the cascade rearrangement of destabilized vinyl cations deriving from the BF3·Et2O-induced decomposition of cyclic α-diazo-β-hydroxy ketones in turn prepared by aldol-type condensation of cycloalkanones with diazoacetone. Complexation of the hydroxy group of the α-diazo-β-hydroxy compound with the Lewis acid is the first event, followed by the generation of the cycloalkanylidenediazonium salt that, after nitrogen loss, produces the highly reactive vinyl cation. The subsequent ring expansion results in the formation of a cycloalkenyl vinyl cation that affords the allylic cation by 1,2-methylene shift and ring contraction. The cation can then trap the solvent, the fluoride or the hydroxide released from the [BF3OH]− to afford different reaction products. The effect of both solvent and substrate ring size on products types and ratios were analyzed and discussed from a mechanistic point of view

Reaction Calorimetry in continuous flow mode. A new approach for the thermal characterization of high energetic and fast reactions

A new method for the calorimetric characterization of high-energetic, fast reactions in flow mode has been developed. The use of an engineered flow reactor in combination with a process modelling software allowed the deconvolution of the reaction enthalpy from space-resolved temperature profiles. The new procedure was verified in a comparison with a conventional batch calorimeter and subsequently implemented for the thermal characterization of an organolithium flow process. The information collected for this reaction successfully supported a scale-up to the pilot plant. Overall, the new approach resulted to be superior when compared with established procedures, enabling the generation of precise calorimetric data in an accurate scale-down flow device

A Multistep Flow Process for the Synthesis of Highly Functionalized Benzoxazoles

An efficient and scalable transformation of 3-halo-<i>N</i>-acyl anilines to the corresponding benzoxazoles within a continuous flow reactor is reported. This transformation proceeds <i>via</i> base-mediated deprotonation, ortho-lithiation, and intramolecular cyclization to provide unstable lithiated benzoxazole moieties. The subsequent in-line electrophilic quench results in the formation of substituted benzoxazoles in high yield and quality. Continuous flow technology allowed for accurate temperature control and immediate in-line quench while minimizing the hold-up time for the unstable lithiated intermediates thereby minimizing associated byproduct formation

A simple scale-up strategy for organolithium chemistry in flow mode: From feasibility to kilogram quantities

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 flash 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 semi-batch 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

Scale-up of continuous biphasic liquid/liquid reactions under super-heating conditions: methodology and reactor design

Biphasic liquid/liquid reactions are commonplace, however their scale-up under super-heating conditions are not. An even more challenging effort has to be expected in case of a large scale continuous production process, which also includes the development in lab scale, the selection and design of the continuous reaction equipment. However, by running chemistry above the boiling point of the solvent, the solvent selection can be widened to include green solvents and continuous processing guarantee a limited and safe footprint. Herein is reported a systematic methodology for the development and scale-up of a biphasic reaction under super-heating conditions, as well as the design of a continuous reactor column suitable for handling such conditions. Taking the alkylation of benzylamine with 1,5-dibromopentane as model reaction, kinetic determination and fluid dynamic characterization of the biphasic media have been instrumental for a successful scale-up concept which was proven in a custom-made hastelloy reactor column