Magano J.
* et al. Pfizer Worldwide R&D, Groton, USA
Development of a Scalable Synthesis for an Inhaled pan-JAK Inhibitor.
Org. Process Res. Dev. 2019;
23: 1990-2000
Key words
PF-06263276 - Suzuki–Miyaura cross-coupling - imidazole ring formation - amidation - dimethylsulfamoyl protecting group
Significance
PF-06263276 is a pan-Janus kinase inhibitor that is of interest for the treatment of inflammatory diseases. The synthesis depicted is a telescoped variant of the discovery synthesis (P. Jones et al. J. Med. Chem. 2017, 60, 767). A notable feature is the three-step conversion of nitrile D into crystalline imidazole dihydrochloride H in 81% yield.
Comment
The dimethylsulfamoyl protecting group on indazole D served two purposes. It enhanced the electrophilicity of the nitrile group, and it increased the stability of the imidate E. Unfortunately, hydrolysis of the dimethylsulfamoyl group required 35% aqueous sulfuric acid at 105 °C for sixteen hours.
