Efficient, Protecting Group Free Kilogram-Scale Synthesis of the JAK1 Inhibitor GDC-4379

Abstract

The development of an improved kilogram-scale synthesis of the JAK1 inhibitor GDC-4379 for the treatment of asthma is described. The new process is highlighted by a step-economical construction of a 3-substituted-4-aminopyrazole employing a telescoped oximation and hydrazine condensation of a 1,3-dielectrophile to generate nitrosopyrazole and a novel copper-catalyzed NaBH4 reduction of the nitroso group. The endgame process features an amidation of aminopyrazole with acid chloride under Schotten–Baumann conditions to provide access to the penultimate intermediate. A selective N-1 alkylation of the pyrazole moiety was accomplished under phase-transfer conditions, which delivered GDC-4379 with a defined particle-size distribution suitable for micronization after recrystallization and wet milling.