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

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-di...

Full description

Saved in:
Bibliographic Details
Published in:Organic process research & development 2021-11, Vol.25 (11), p.2537-2550
Main Authors: Stumpf, Andreas, Burkhard, Johannes, Xu, Di, Marx, Andreas, Lao, David, Ochsenbein, Miriam, Ranjan, Rohit, Angelaud, Remy, Gosselin, Francis
Format: Article
Language:English
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:1083-6160
1520-586X
DOI:10.1021/acs.oprd.1c00302