Details

Autor(en) / Beteiligte

• Algera, Russell F.
• Allais, Christophe
• Becirovic, Husein
• Brown, Adam R.
• Chen, Bo
• Clarke, Hugh J.
• Concannon, Paul E.
• Du, Yansheng
• Georgian, William
• Lee, Johnny W.
• Lee, Taegyo
• Magano, Javier
• Perez Mandry, Carlos
• Mehta, Ruchi
• Mull, Eric
• Pearson, Robert
• Peng, Zhihui
• Piper, Jared L.
• Ragan, John A.
• Reyes, Giselle
• Shen, Haibo
• Ward, Daniel W.
• Weekly, R. Matthew
• Weisenburger, Gerald A.
• Xu, Pengcheng
• Yayla, Hatice G.
• Zhang, Mengtan

Titel

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

Ist Teil von

• Organic process research & development, 2023-12, Vol.27 (12), p.2271-2279

Ort / Verlag

American Chemical Society

Erscheinungsjahr

2023

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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.