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Synfacts 2019; 15(12): 1343
DOI: 10.1055/s-0039-1691094
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of pan-JAK Inhibitor PF-06263276

Contributor(s):
Philip Kocienski
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
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Further Information

Publication History

Publication Date:
18 November 2019 (online)

 
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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.


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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.


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