Development of sustainable and selective synthetic strategies in organic and pharmaceutical chemistry: a journey from lab scale to process chemistry

This Ph.D. thesis presents a multidisciplinary investigation of selective organic transformations, encompassing the reduction of nitrate esters, the development of novel synthetic methodologies for pharmaceutical intermediates, and mechanistic studies on the decomposition of organosulfur compounds harmful to humans. In the first part, the reduction chemistry of isosorbide-2,5-dinitrate (ISDN) was systematically studied to develop a regioselective, reproducible, and sustainable route to isosorbide-5-mononitrate (IS-5-MN). The process currently adopted by Dipharma Francis S.r.l is based on the principles disclosed in EP201067, relying on the selective reduction of ISDN with powdered metallic zinc in acidic conditions under carefully controlled parameters to ensure regioselectivity and high reproducibility. Through optimization of the zinc-mediated process and exploration of metallic dopants, selenium-catalyzed NaBH4/NaOH systems, and catalytic hydrogenation over Pt/C and Pd/C, the study provided mechanistic insight into factors governing conversion, selectivity, and redox equilibria. Pt/C hydrogenation emerged as a scalable, environmentally friendly, and highly selective alternative, offering potential for industrial implementation while avoiding the use of toxic reagents. NMR studies confirmed site-specific coordination effects that rationalize experimentally observed selectivity enhancements. The second part focuses on the development of an alternative synthetic route to a diol which is a key precursor in the industrial synthesis of Fesoterodine. Prins reaction conditions between styrene and formaldehyde were systematically optimized to maximize formation of the protected diol intermediate, achieving yields up to 72% and demonstrating robustness and reproducibility on a multigram scale. Subsequent translation to continuous-flow conditions further enhanced safety, minimized operator exposure, and provided a scalable, potentially automatable platform suitable for industrial application. The methodology offers a safer, cost-efficient, and high-purity alternative to classical borohydride-based reductions, supporting sustainable pharmaceutical manufacturing. Finally, the oxidative behavior of aromatic thioethers, as structural analogues of organophosphorus nerve agents, was investigated using tert-butyl hypochlorite (tBuOCl). Mechanistic studies with model compounds elucidated the electronic factors controlling selective sulfoxidation, α-chlorination, and subsequent dealkylation. These findings provide predictive insight for the safe and efficient neutralization of hazardous organosulfur compounds, supporting the rational design of continuous-flow detoxification strategies. Overall, this thesis advances fundamental and applied understanding in three areas of organic chemistry, combining mechanistic insight, process optimization, and innovative methodology development with direct relevance to pharmaceuticals, chemical safety, and sustainable chemical processes.