Allais Christophe, Bernhardson David, Brown Adam R, Chinigo Gary M, Desrosiers Jean-Nicolas, DiRico Kenneth J, Hotham Ian, Jones Brian P, Kulkarni Samir A, Lewis Chad A, Lira Ricardo, Loach Richard P, Morse Peter D, Mousseau James J, Perry Matthew A, Peng Zhihui, Place David W, Rane Anil M, Samp Lacey, Singer Robert A, Wang Zheng, Weisenburger Gerald A, Yayla Hatice G, Zanghi Joseph M
Chemical Research and Development, Pfizer Inc., Groton, Connecticut06340, United States.
Medicine Design, Pfizer Inc., Groton, Connecticut06340, United States.
Org Process Res Dev. 2023 Feb 3. doi: 10.1021/acs.oprd.2c00375.
Lufotrelvir was designed as a first in class 3CL protease inhibitor to treat COVID-19. Development of lufotrelvir was challenged by its relatively poor stability due to its propensity to epimerize and degrade. Key elements of process development included improvement of the supply routes to the indole and lactam fragments, a Claisen addition to homologate the lactam, and a subsequent phosphorylation reaction to prepare the prodrug as well as identification of a DMSO solvated form of lufotrelvir to enable long-term storage. As a new approach to preparing the indole fragment, a Cu-catalyzed C-O coupling using oxalamide ligands was demonstrated. The control of process-related impurities was essential to accommodate the parenteral formulation. Isolation of an MEK solvate followed by the DMSO solvate ensured that all impurities were controlled appropriately.
卢伏特瑞韦被设计为首个用于治疗新冠肺炎的3CL蛋白酶抑制剂。卢伏特瑞韦的开发面临挑战，因为其容易发生差向异构化和降解，稳定性相对较差。工艺开发的关键要素包括改进吲哚和内酰胺片段的供应路线、通过克莱森加成反应使内酰胺同系化、随后进行磷酸化反应以制备前药，以及鉴定卢伏特瑞韦的二甲基亚砜溶剂化物以实现长期储存。作为制备吲哚片段的一种新方法，展示了使用草酰胺配体的铜催化碳-氧偶联反应。控制与工艺相关的杂质对于肠胃外制剂来说至关重要。分离出甲乙酮溶剂化物，随后得到二甲基亚砜溶剂化物，确保了所有杂质都得到适当控制。
