Development of a Scalable Enantioselective Synthesis of JAK Inhibitor Upadacitinib
Michael J. Rozema, Lakshmi Bhagavatula, Alan Christesen, Travis B. Dunn, Andrew R. Ickes, Brian Kotecki, James C. Marek, Eric G. Moschetta, Westin H. Morrill, Mathew M. Mulhern, Michael Rasmussen, Troy E. Reynolds, Su Yu
Abstract
Process development of a six-stage synthesis of upadacitinib, a JAK1 inhibitor, is described. It is highlighted by an enantioselective and diastereoselective hydrogenation of a tetrasubstituted olefin to set the two pyrrolidine stereocenters. Preparation of the main fragments and strategies to link them together, optimization of the imidazole cyclization, and in-depth understanding of the formation of the urea moiety at the final stage are discussed.
Topics & Concepts
Enantioselective synthesisStereocenterChemistryPyrrolidineCombinatorial chemistryOlefin fiberTransfer hydrogenationMoietyProcess developmentImidazoleStereochemistryOrganic chemistryCatalysisBusinessProcess managementRutheniumQuinazolinone synthesis and applicationsChemical Synthesis and AnalysisSynthesis of heterocyclic compounds