Process Intensification and Integration Studies for the Generation of a Key Aminoimidazole Intermediate in the Synthesis of Lanabecestat

An improved synthetic procedure for the multistep synthesis of aminoimidazole 6, a key intermediate in the preparation of lanabecestat (AZD3293/LY3314814), is described. Under intensified conditions (high temperature and elevated pressure), the overall processing time and required amounts of reagents could be significantly reduced, thus potentially minimizing manufacturing costs and improving the sustainability footprint. Process integration of three sequential steps starting from ketone intermediate 2 has been attempted to set the stage for a potential multistep continuous manufacturing route. The process consists of initial formation of imine 3 by treatment of ketone 2 with ammonia and Ti(iPrO)4, cyclocondensation of 3 with thioamide 4 to form thiol 5, and aminolysis using ammonia and Zn(OAc)2, allowing the target building block 6 to be accessed in 47% overall yield.