Synfacts 2020; 16(07): 0751
DOI: 10.1055/s-0040-1707023
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of GDC-0022

Philip Kocienski
Sirois LE. * et al. Genentech, Inc., South San Francisco, USA
Process Development Overcomes a Challenging Pd-Catalyzed C−N Coupling for the Synthesis of RORc Inhibitor GDC-0022.

Org. Process Res. Dev. 2020;
24: 567-578
Further Information

Publication History

Publication Date:
17 June 2020 (online)



Retinoid-related orphan receptor γ (RORc) is a transcription factor and nuclear receptor implicated in proinflammatory cytokine production. GDC-0022 is a RORc inhibitor. The key step in the synthesis depicted was the Buchwald–Hartwig coupling of bromoarene G with pyrrolidine H on an 8.0 kg scale using just 1 mol% of catalyst.



For a multikilogram-scale synthesis of pyrrolidine H, see: L. E. Sirois et al. Org. Process Res. Dev. 2018, 22, 728. Cyclization of D using n-BuLi (2.5 equiv) and diisopropylamine (0.2 equiv) gave sultam E as a mixture of diastereoisomers that slowly equilibrated to the desired trans-sultam E (dr = 93:7).