Synthesis of Nirmatrelvir: Development of Magnesium Sulfate-Mediated Aminolysis for the Manufacture of the Eastern Fragment

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.