Development of a Scalable Route to a Dual NK-1/Serotonin Receptor Antagonist

The evolution of a process for the preparation of a new heterocyclic dual NK1/serotonin receptor antagonist is described. The final synthesis features a telescoped sequence in which an iron(III)-catalyzed Grignard coupling is followed by a benzylic chlorination utilizing trichlorocyanuric acid to construct an unsymmetrical 2,4,6-trisubstituted pyridine. Etherification of a 4,4′-arylhydroxymethane substituted piperidine fragment completes the synthesis of the active pharmaceutical ingredient in 44% overall yield.