Practical and Scalable Method for Manufacturing AZD4604, A Potent and Selective JAK1 Inhibitor

The development of a scalable process for the manufactureof apotent and selective JAK1 inhibitor intended for the inhaled treatmentof asthma is described. The initial milligram-scale synthetic protocolswere unsuitable for larger-scale synthesis, which led to a systematicevaluation of the reaction conditions to identify the optimized reactionconditions for the Suzuki/Buchwald-Hartwig coupling, deprotectionof the tosyl group, chemoselective nitro-reduction, and developingmild conditions for the amide coupling of a sensitive amino acid.This work also highlights mitigating critical issues associated withthe synthesis of poorly soluble compounds, slurry-to-slurry metal-catalyzedcoupling protocols. The optimized amide coupling conditions usingchiral amino acid produced the desired active pharmaceutical ingredient(API) in high overall yield and good high-performance liquid chromatography(HPLC) purity.