Commercial Route Development of Sigma-2 Receptor Modulator, CT1812 Leveraging Photoflow, and HTS Technologies

A second-generation synthesis of CT1812, a sigma-2 receptor modulator (ligand), was developed from readily available starting materials to support late-stage clinical needs. An AIBN-induced thermal benzylic bromination in DCE was replaced by a visible-light-induced continuous flow process in MeCN operating at room temperature. High throughput screening was employed to overcome the unexpected challenges encountered in the hydrogenation of alkyne 13 in the penultimate step. The rationale for a polymorph switch from the originally developed monofumarate anhydrate to the more thermodynamically stable hemifumarate dihydrate is also described. The new convergent route proceeds in eight steps (longest linear sequence (LLS) = 6) as compared to the original med chem route (12 steps; LLS = 9) and has been successfully demonstrated on a 100 kg scale.