Sustainable Synthesis of Active Pharmaceutical Ingredients

During the three years of my Ph.D. I focused my research on the development and the exploration of efficient and sustainable organic synthetic processes for Bioindustria L.I.M. company, an Italian company leader at an international level in the synthesis of APIs (Active Pharmaceutical Ingredients). Several synthetic processes have been carried out for long times in the production site of Fresonara (AL), however, the current challenges associated with the limited availability of raw materials and energy resources underscore the necessity for the development of new and more environmentally-friendly synthetic routes. The structures of the compounds synthesized in this plant are extremely varied as well as the types of multi-step reactions used to obtain them. In Chapter 2 the work done for Bioindustria company in the investigation of the production processes of different APIs, as well as the synthesis of impurities, standards and intermediates is described. This was done both at the University of Genova and at Bioindustria R&D laboratory at Fresonara plant, in a close collaboration with the production plant and with the Bioindustria Quality Control lab, with the aim to implement the quality of the APIs and to reduce the formation of impurities during the synthetical steps. The study of a reductive amination reaction performed at Bioindustria L.I.M. was performed and descripted in Chapter 3. An investigation of the optimal reaction conditions was realized exploiting the Design of Experiments (DoE). Many different designs were employed to screen different parameters, both in a small batch laboratory system and in a scale-up process. As continuous processes have been identified as one of the most important area of research in green chemistry and engineering for the pharmaceutical industry, the reductive amination reaction was also tested in a continuous-flow system. An evaluation of the PMI (Process Mass Intensity) green metric of the process was also done. One of the crucial aims for an important company as Bioindustria L.I.M is to limit the importation of starting materials for their APIs, trying to produce them in the plant. The study developed to synthesize the Indapamide’s starting material 1-amino-2-methylindoline (AMMI) is reported in Chapter 4. The attention was focused on hydroxylamine-O-sulphonic acid as N-aminating agent to perform the N-aminating reaction, but also other methodologies were tested.