Over a series of 10 aromatic amines we show the rate of CDI mediated amidation to be significantly enhanced upon introduction of imidazole • HCl as a proton source for acid catalysis. Our work supports and provides an application for previous investigations into the imidazolium effect, thus increasing the scope of CDI as an amide-coupling reagent with aromatic amines. The influence of the relative pK a of the amines studied on the rate of reaction was also investigated.

A brief comparison of the early manufacturing routes to AZD7545 is given. Process development of the preferred long-term manufacturing route is reported in detail, and changes from the initial kilogram-scale route are discussed. Scale-up experience from the pilot-plant manufacture is included in the discussion of each stage. Noteworthy aspects throughout the development of AZD7545 concerned chemical hazards, mechanisms, analysis, and impurities, upon which this case study will focus.