CONTINUOUS-FLOW STRATEGIES FOR THE PREPARATION OF ACTIVE PHARMACEUTICAL INGREDIENTS AND RELEVANT INTERMEDIATES

This PhD thesis explores the development and application of continuous-flow strategies for the synthesis of active pharmaceutical ingredients (APIs) and key intermediates, with the aim of improving reaction efficiency, safety, and scalability. The work focuses on the integration of modern synthetic methodologies with enabling technologies such as flow chemistry, photoredox catalysis, ultrasound, and electrochemistry. In the first part, palladium-catalyzed cross-coupling reactions involving highly reactive organolithium reagents are investigated under continuous-flow conditions, demonstrating how precise control of reaction parameters allows safer handling and improved selectivity compared to batch processes. The second part describes the use of metallaphotoredox catalysis for the synthesis of tryptamine derivatives, highlighting the potential of light-driven processes to access structurally complex motifs under mild conditions. The thesis further addresses one of the major limitations of flow chemistry, namely solid handling, through the development of ultrasound-assisted strategies that enable reliable processing of heterogeneous systems at an industrially relevant scale. Additionally, electrochemical methods are explored for the oxidative functionalization of quinoline and isoquinoline derivatives, providing sustainable and reagent-efficient alternatives to traditional oxidative protocols. Finally, the applicability of the developed methodologies to real-world pharmaceutical processes is demonstrated through a collaborative project with Suanfarma S.p.A. Overall, this work showcases continuous-flow chemistry as a powerful platform for the development of innovative, safe, and scalable synthetic processes relevant to the pharmaceutical industry.