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Early Clinical Development of Lufotrelvir as a Potential Therapy for COVID-19
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2023-02-03 , DOI: 10.1021/acs.oprd.2c00375 Christophe Allais 1 , David Bernhardson 1 , Adam R Brown 1 , Gary M Chinigo 2 , Jean-Nicolas Desrosiers 1 , Kenneth J DiRico 2 , Ian Hotham 1 , Brian P Jones 1 , Samir A Kulkarni 1 , Chad A Lewis 1 , Ricardo Lira 2 , Richard P Loach 2 , Peter D Morse 2 , James J Mousseau 2 , Matthew A Perry 2 , Zhihui Peng 1 , David W Place 1 , Anil M Rane 1 , Lacey Samp 1 , Robert A Singer 1 , Zheng Wang 1 , Gerald A Weisenburger 1 , Hatice G Yayla 2 , Joseph M Zanghi 1
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2023-02-03 , DOI: 10.1021/acs.oprd.2c00375 Christophe Allais 1 , David Bernhardson 1 , Adam R Brown 1 , Gary M Chinigo 2 , Jean-Nicolas Desrosiers 1 , Kenneth J DiRico 2 , Ian Hotham 1 , Brian P Jones 1 , Samir A Kulkarni 1 , Chad A Lewis 1 , Ricardo Lira 2 , Richard P Loach 2 , Peter D Morse 2 , James J Mousseau 2 , Matthew A Perry 2 , Zhihui Peng 1 , David W Place 1 , Anil M Rane 1 , Lacey Samp 1 , Robert A Singer 1 , Zheng Wang 1 , Gerald A Weisenburger 1 , Hatice G Yayla 2 , Joseph M Zanghi 1
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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.
中文翻译：
Lufotrelvir 作为 COVID-19 潜在疗法的早期临床开发
Lufotrelvir 被设计为首个用于治疗 COVID-19 的 3CL 蛋白酶抑制剂。 lufotrelvir 的开发面临着由于其差向异构化和降解倾向而导致稳定性相对较差的挑战。工艺开发的关键要素包括改善吲哚和内酰胺片段的供应路线、Claisen 添加以同系内酰胺、随后进行磷酸化反应以制备前药以及鉴定 lufotrelvir 的 DMSO 溶剂化形式，以实现长效期限存储。作为制备吲哚片段的新方法，使用草酰胺配体的铜催化 C-O 偶联得到了证实。控制与工艺相关的杂质对于适应肠胃外制剂至关重要。先分离 MEK 溶剂化物，然后分离 DMSO 溶剂化物，确保所有杂质都得到适当控制。
更新日期：2023-02-03
中文翻译：
Lufotrelvir 作为 COVID-19 潜在疗法的早期临床开发
Lufotrelvir 被设计为首个用于治疗 COVID-19 的 3CL 蛋白酶抑制剂。 lufotrelvir 的开发面临着由于其差向异构化和降解倾向而导致稳定性相对较差的挑战。工艺开发的关键要素包括改善吲哚和内酰胺片段的供应路线、Claisen 添加以同系内酰胺、随后进行磷酸化反应以制备前药以及鉴定 lufotrelvir 的 DMSO 溶剂化形式，以实现长效期限存储。作为制备吲哚片段的新方法，使用草酰胺配体的铜催化 C-O 偶联得到了证实。控制与工艺相关的杂质对于适应肠胃外制剂至关重要。先分离 MEK 溶剂化物，然后分离 DMSO 溶剂化物，确保所有杂质都得到适当控制。
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