An efficient hydrogenation protocol under continuous flow conditions was developed for the synthesis of underrepresented semi-saturated bicyclic fragments containing highly sp 3-rich skeletons for fragment-based drug discovery (FBDD) programs. Excellent yields were generally achieved by using Pd/C (10 % w/w) and RaNi at 25–150 °C under 4–100 bar of hydrogen pressure. The generated fragments, with appropriate physicochemical properties, present diverse hydrogen-bonding pharmacophores and useful vectors for their synthetic elaboration in the optimization stage. Successive, simple functionalizations in continuous flow were accomplished to demonstrate the opportunity to develop multi-step continuous flow synthesis of valuable starting points for FBDD campaigns. A conclusive quality control (QC) was essential to discard those structures which do not fit the typical fragment library parameters.
14 Feb 2019