Development of an Efficient Synthesis toward a 4,4-Difluoropiperidine Intermediate Bearing a Pyridine N-Oxide Motif at the Carbon Stereocenter

Abstract The synthesis of a 4,4-difluoropiperidine intermediate, a key component of an MRGPRX2 antagonist, is challenging due to the presence of a gem-difluoro moiety adjacent to a stereocenter which also bears a reactive pyridine N-oxide motif. The initial discovery chemistry route required chiral supercritical fluid chromatography (SFC) at the end of the synthesis to provide enantiopure product. XtalFluor-E was used for deoxyfluorination on a ketone adjacent to a p-pyridylmethyl position, resulting in very low yields due to the elimination of HF. After several unsuccessful attempts for a de novo asymmetric synthesis, we focused our attention on the process development for a more practical synthesis than the existing route. A much higher yielding deoxyfluorination was enabled by SF4 and HF. Furthermore, the chiral SFC was replaced by an efficient classical resolution at a much earlier stage of the synthesis, taking advantage of the basicity of the pyridine moiety before oxidation to the pyridine N-oxide. Although not all stages have been scaled up in the plant scale, the new synthesis is much more practical and has improved the overall yield from 12% to 23% for this challenging molecule.