Access to Phenolic Pyridopyridazinones and Phthalazinones Using THP Ether-Directed Ortho Lithiation

Route scouting, process research and development, and large-scale synthesis of phenol-substituted pyridopyridazinones (azaphthalazinones) and phthalazinones are reported. For the introduction of one of our key building blocks, 3-(trifluoromethyl)phenol, our identified large-scale route initially employed an unstable aryllithium, generated by bromine lithium exchange next to a phenolic hydroxy group protected as p-methoxybenzyl (PMB) ether. We found that instead, protecting the phenolic hydroxy group as tetrahydropyran (THP) ether in a bromine-free substrate and applying directed ortho metalation (DoM) generated the desired aryllithium in a stable form, suitable for use in a batch process on a large scale, which significantly facilitated the synthesis of our target molecules. The final process, a palladium-free, telescoped two-step sequence consisting of ketone formation by acylation with a mixed diester and cyclization with hydrazine, was demonstrated in our kilogram laboratory on a 0.5 kg scale for the pyridopyridazinone scaffold. Routes to the analogous phthalazinone scaffold were also investigated, and here, both phthalic anhydride and a mixed diester can serve as starting material. DFT calculations support our rationale regarding experimentally found differences between pyridine- and benzene-based intermediates. The target molecules were isolated as crystalline solids, and their structures were further confirmed by single crystal X-ray diffraction.