Pfizer’s drug for the treatment of patients infected with COVID-19, Paxlovid, contains most notably nirmatrelvir, along with ritonavir. Worldwide demand is projected to be in the hundreds of metric tons per year, to be produced by several generic drug manufacturers. Here we show a 7-step, 3-pot synthesis of the antiviral nirmatrelvir, arriving at the targeted drug in 70% overall yield. Critical amide bond-forming steps utilize new green technology that completely avoids traditional peptide coupling reagents, as well as epimerization of stereocenters. Likewise, dehydration of a primary amide to the corresponding nitrile is performed and avoids use of the Burgess reagent and chlorinated solvents. DFT calculations for various conformers of nirmatrelvir predict that two rotamers about the tertiary amide would be present with an unusually high rotational barrier. Direct comparisons with the original literature procedures highlight both the anticipated decrease in cost and environmental footprint associated with this route, potentially expanding the availability of this important drug worldwide.

辉瑞用于治疗 COVID-19 感染患者的药物 Paxlovid 最显着地包含尼马曲韦和利托那韦。预计全球需求量将达到每年数百公吨，由几家仿制药制造商生产。在这里，我们展示了抗病毒药物奈玛特韦的 7 步 3 罐合成，以 70% 的总产率获得靶向药物。关键的酰胺键形成步骤利用新的绿色技术，完全避免了传统的肽偶联试剂，以及立体中心的差向异构化。同样，将伯酰胺脱水为相应的丁腈，避免使用 Burgess 试剂和氯化溶剂。nirmatrelvir 的各种构象异构体的 DFT 计算预测，大约叔酰胺的两个 rotamers 将存在异常高的旋转势垒。与原始文献程序的直接比较突出了与该途径相关的成本和环境足迹的预期降低，从而有可能扩大这种重要药物在全球范围内的可用性。