Continuous-Flow Technology for Chemical Rearrangements: A Powerful Tool to Generate Pharmaceutically Relevant Compounds

• Antonella Ilenia Alfano^a, Sveva Pelliccia^a, Giacomo Rossino^b, Orazio Chianese^c, Vincenzo Summa^a, Simona Collina^b, and Margherita Brindisi^a

• ^aDepartment of Pharmacy (DoE 2023-2027), University of Naples Federico II, via D. Montesano 49, 80131, Naples, Italy
• ^bDepartment of Drug Sciences, University of Pavia, Via Taramelli 12, 27100 Pavia, Italy
• ^cGenetic S.p.A., Via Canfora, 64, 84084 Fisciano (Salerno), Italy

The efficacy, safety, and scale-up of several chemical rearrangements remain unsolved problems due to the associated handling of hazardous, toxic, and pollutant chemicals and high-risk intermediates. For many years batch processes have been considered the only possibility to drive these reactions, but continuous-flow technology has emerged, for both academic laboratories and pharmaceutical companies, as a powerful tool for easy, controlled, and safer chemistry protocols, helping to minimize the formation of side products and increase reaction yields. This Technology Note summarizes recently reported chemical rearrangements using continuous-flow approaches, with a focus on Curtius, Hofmann, and Schmidt reactions. Flow protocols, general advantages and safety aspects, and reaction scope for the generation of both privileged scaffolds and active pharmaceutical ingredients will be showcased.

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