FROM BATCH TO FLOW: RETHINK THE WAY OF DOING CHEMISTRY

In this thesis, the application of flow chemistry to overcome batch limitations in the process development of organic reactions was explored. Specifically, novel and challenging protocols for the synthesis of APIs were investigated, with the aim to develop alternative synthetic methodologies, and a special focus on improving the efficiency, sustainability and industrial applicability of the new synthetic strategy. The thesis is organized into four main chapters, a first introductive section to give a brief background on Flow chemistry basics, and three chapters on the research projects, organolithium chemistry, photochemistry, alkyl nitrite in α-keto nitrosation reaction. The last section of every chapter is dedicated to the discussion of the result where on water organolithium addition to imines, Pd mediated cross coupling reactions, synthesis of benzoxaboroles, photochemical synthesis of tryptamines and a scale-up and tech transfer of a continuous production and use of an alkyl nitrite are presented. In the first chapter, it is provided a general introduction to the concept of flow chemistry, explaining the main instruments and parameters, emphasizing the beneficial effects deriving from its use in organic synthesis in particular for safety aspects. A special attention is paid also to reactor modelling and design and the differences between PFR and CSTR. In the second part, organolithium chemistry is briefly introduced and explored for the synthesis of useful API or intermediates like benzoxaboroles, amines and cross-coupling products. It is provided an overview of the current state of art for the appropriate class of chemistry methodologies that were developed both from the batch and in continuo point of view. In the third chapter, it is described a deoxygenative strategy for the Csp3-Csp2 cross-coupling reaction for the preparation of novel interesting tryptamine derivatives, by the use of photochemistry. First, we examine the use of metallaphotoredox chemistry to perform cross coupling reaction, then the importance of tryptamine is discussed, pointing out current synthetic challenges and the absence of photochemical methodologies for this transformation. In the fourth chapter, the use of alkyl nitrites as useful nitrosation agents in industry is described, pointing out the current limitation on the scale up and demonstrating the successful development of an in continuo process to sustain the pilot plant production batch of an α-keto nitrosation reaction. Finally, after the Conclusion and the References, in the fifth chapter the experimental section, with all analytical data, is reported. In this thesis, new flow chemistry protocols were developed to provide scalability and applicability at industrial level and to realize more efficient and sustainable synthetic strategies for the preparation of challenging organic molecules, with broad implications in the fields of chemistry and pharmaceuticals.