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

Abstract

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.

Continuous Manufacturing of Active Pharmaceutical Ingredients: Current Trends and Perspectives

“…Unlike condensation, the goal of evaporation is to remove a desired portion of the solvent to produce a viscous, highly concentrated liquid. [51,138] This makes evaporation different from traditional drying techniques, which produce a solid product. Here, we will discuss more novel applications of evaporation during the continuous manufacturing of APIs.…”

“…Evaporation is the process in which a liquid is turned into vapor after being boiled past the liquid‘s latent heat of vaporization. Unlike condensation, the goal of evaporation is to remove a desired portion of the solvent to produce a viscous, highly concentrated liquid [51,138] . This makes evaporation different from traditional drying techniques, which produce a solid product.…”

Process Development of a Suzuki Reaction Used in the Manufacture of Lanabecestat

“…The wet cake was dried under reduced pressure at 50 °C to afford 2b (51.15 kg) in 71% yield (assay adjusted), 100% HPLC purity (area%) and 96.2% HPLC assay as an off-white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.46 (d,J = 1.6 Hz,1H),8.36 (d,J = 2.3 Hz,1H),1H),1H),2H),2H),3.11 (tdd,J = 7.0,9.2,11.7 Hz,2H), 2.91−2.84 (m, 2H), 2.04 (s, 3H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 152.…”

“…We recently disclosed the Phase III route to lanabecestat, which involved a late-stage Suzuki coupling to install the pyridine side-chain (Scheme ). The Suzuki coupling is a common reaction used in the manufacture of pharmaceuticals and is the most common biaryl bond forming reaction. − The final stage, to generate the active pharmaceutical ingredient (API) (lanabecestat (+)-camsylate) is a salt formation with (+)-camphor sulfonic acid.…”