Curia´s Patented Process For Intermediates Useful For Upadacitinib

Upadacitinib (ABT-494) is a potent, selective JAK1 inhibitor developed by AbbVie and approved by the U.S. FDA for the treatment of rheumatoid arthritis. Its synthesis has been widely described in the literature and generally follows a convergent strategy based on the preparation of two key intermediates, commonly referred to as Fragment A and Fragment B. These fragments are coupled, followed by cyclization to construct the characteristic imidazopyrrolopyrazine core. Subsequent functional group modifications yield the final active pharmaceutical ingredient.

While the overall synthetic logic is consistent across reported methods, variations exist in how the fragments—particularly Fragment B — are prepared. For example, WO2013/043826 describes generating Fragment B via conversion of an intermediate acid chloride using trimethylsilyldiazomethane, a reagent considered unstable and highly toxic. Another approach, disclosed in WO2017/066775, involves formation of a sulfoxonium salt followed by lithium bromide treatment to obtain a protected cis-(3R,4S)-pyrrolidine intermediate. These routes highlight both the complexity and safety considerations associated with manufacturing this molecule.