Green Chemistry applied to industrial processes for the preparation of APIs for diagnostics and intermediates thereof

This doctoral research applies the strategies of green chemistry to the preparation of diagnostic agents and synthetic intermediates, bridging innovation and industrial relevance. Key achievements include: 1) The optimization of the synthesis of DA364, a NIR fluorescent probe targeting integrin avp3 in tumors. The combination of traditional and automated solid-phase peptide led to higher overall yield, simpler purification, allowing multigram scale preparations suitable for preclinical studies. 2) A study of a key step of the preparation of iopamidol, a iodinated CT probe, devoted to replacing the use of toxic solvents with aqueous micellar reactions and using lipophylically protected serinol derivatives to explore the feasibility of this alternative and greener approach. 3) A systematic study of the formation of crystalline salts of serinol was undertaken with the aim of replacing the energy-intensive high vacuum distillation for the purification of this industrially relevant aminodiol with an energetically favorable precipitation. Four crystalline salts (along with the crystalline free base) were obtained and studied by SC-XRD. 4) The transition from batch to flow of a key amidation step for the preparation of a synthetic intermediate of a iodinated contrast agent was explored, using a Corning flow reactor and a screening of experimental conditions by a DoE approach. The results included the enhancement of yield, purity, safety, and the reduction of the environmental footprint, compared to batch process. The integrated approaches followed in this PhD work clearly demonstrated that combining green chemistry and process intensification can be successfully achieved, leading to cleaner, safer, and economically viable pharmaceutical manufacturing.