Process Development and Pilot-Plant Synthesis of (2-Chlorophenyl)[2-(phenylsulfonyl)pyridin-3-yl]methanone

Routes to (2-chlorophenyl)[2-(phenylsulfonyl)pyridin-3-yl]methanone, 1, an intermediate in the manufacture of NK1-II inhibitor LY686017 are described which produce 1 in > 75% yield and 95% purity. A highly selective telescoped ortho lithation/condensation/oxidation process was developed and successfully scaled to the clinical pilot plant to produce 25 kg of 1. For the pilot-plant campaign, the lithiation step was developed to operate at -50 degrees C using commercial lithium diisopropylamide (LOA), and the oxidation step employed catalytic TEMPO as the primary and NaOCI as the terminal oxidant. After completion of the pilot-plant campaign second-generation approaches to 1 were developed to improve process greenness where the lithiation and condensation step were operated as warm as -10 degrees C, the highly efficient AZADO catalyst was used as a substitute for TEMPO in the Anelli-Montanari oxidation, and process mass intensity was reduced 25%.