posted on 2021-11-11, 17:07authored byAndreas Stumpf, Johannes Burkhard, Di Xu, Andreas Marx, David Lao, Miriam Ochsenbein, Rohit Ranjan, Remy Angelaud, Francis Gosselin
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.