Multi-kg Manufacture of AZD5462 Part 1: The Fragments, Featuring C−H Borylation, Organocatalytic Desymmetrization and Curtius Rearrangement

The complex small molecule AZD5462 is currently in development as an agonist of the relaxin family peptide receptor 1 (RXFP1) with an indication for the treatment of heart failure. A previous medicinal chemistry campaign had delivered an impressive 720 g through 22 total steps, with a longest linear sequence of 13. To support GLP pre-clinal toxicology studies and a FIH phase-1 safety study, AstraZeneca Early Chemical Development (ECD) were tasked to deliver the first large scale process campaign, requiring multi kg quantities of API. Here, in part 1, we report the development of scalable processes and multi kg manufacture to deliver three key fragments. A cyclohexyl ketone fragment was manufactured in a four-step telescope, avoiding chromatography, delivering 27 kg in 52% yield. A phenol fragment was prepared via iridium catalyzed C-H borylation in two-steps, delivering 12 kg in 81% yield. Finally, an enantiopure [2.2.1] bicyclic fragment was accessed in four-steps through an organocatalytic desymmetrization – Curtius rearrangement sequence, providing 18 kg in 62% yield. We report details of the innovative chemistry, project strategy, and timelines that led to successful delivery, as well as the challenges encountered. This manufacture included an unplanned 4-week hold due to COVID-19 shutdowns and loss of an entire batch due to ethylene glycol contamination of the dioxane solvent during the isocyante hydrolysis step of a Curtius rearrangement.