posted on 2023-11-23, 02:05authored byRussell
F. Algera, Christophe Allais, Husein Becirovic, Adam R. Brown, Bo Chen, Hugh J. Clarke, Paul E. Concannon, Yansheng Du, William Georgian, Johnny W. Lee, Taegyo Lee, Javier Magano, Carlos Perez Mandry, Ruchi Mehta, Eric Mull, Robert Pearson, Zhihui Peng, Jared L. Piper, John A. Ragan, Giselle Reyes, Haibo Shen, Daniel W. Ward, R. Matthew Weekly, Gerald A. Weisenburger, Pengcheng Xu, Hatice G. Yayla, Mengtan Zhang
Nirmatrelvir
is a potent, selective, and orally bioavailable inhibitor
of SARS-CoV-2 Mpro. In this paper, we report the development
of a magnesium sulfate (MgSO4)-mediated aminolysis for
the synthesis of (S)-2-amino-3-[(S)-2-oxopyrrolidin-3-yl]propenamide hydrogen chloride, the eastern
fragment of nirmatrelvir. Previous synthesis of this building block
required a protecting group, high equivalents of ammonia, and a long
reaction time and generated materials with moderate potency and high
levels of residual solvents. We determined that MgSO4,
a widely available and low-cost material, accelerates the desired
aminolysis reaction and suppresses the formation of impurities without
the need for high equivalents of ammonia or a protecting group. Our
understanding of the solubility profile of this intermediate facilitated
the development of a robust isolation protocol to purge byproducts
and generate high-potency materials regardless of the source of the
precursors. The MgSO4-mediated aminolysis process was demonstrated
to produce >350 kg of the building block per batch.