The JAK family of tyrosine kinases consists of four enzymes that play a central role in cytokine and growth factor mediated signal transduction. Recently, Pfizer has disclosed PF-06651600 (1) as the first selective JAK3 inhibitor with oral bioavailability for various clinical indications, for example alopecia areata, rheumatoid arthritis, Crohn’s disease and ulcerative colitis. Due to positive results from a Phase II study, a breakthrough therapy designation from the FDA was received for (1) to treat patients with alopecia areata in September 2018. As the program has progressed from discovery to clinical studies, increasing amounts of API have been required. This presentation will describe the evolution of the synthesis of this compound from early discovery to early development, with a focus upon the challenges encountered and the solutions identified to provide for mg to multi- kilogram amounts of material. The compound possesses a reactive acrylamide moiety, a unique 6-methyl-3-amino substituted piperidine and a pyrrolo-pyrimidine ring system. Each of these fragments required the development of robust conditions for their synthesis and subsequent union to obtain (1) efficiently. Finally, the isolation of the compound in high purity, yield and as a stable solid form will be presented.

Synthesis of selective JAK3 inhibitor PF-06651600: Discovery to early clinical supplies

2019 Fall National Meeting

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