Process Development of the HCV NS5B Site D Inhibitor MK-8876

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• 作者：Michael J. Williams ; Qinghao Chen ; Lorenzo Codan ; Renee K. Dermenjian ; Spencer Dreher ; Andrew W. Gibson ; Xianliang He ; Yan Jin ; Stephen P. Keen ; Alfred Y. Lee ; David R. Lieberman ; Wei Lin ; Guiquan Liu ; Mark McLaughlin ; Mikhail Reibarkh ; Jeremy P. Scott ; Sophie Strickfuss ; Lushi Tan ; Richard J. Varsolona ; Feng Wen
• 刊名：Organic Process Research & Development
• 出版年：2016
• 出版时间：July 15, 2016
• 年：2016
• 卷：20
• 期：7
• 页码：1227-1238
• 全文大小：539K
• 年卷期：0
• ISSN：1520-586X

文摘

We describe the route development and multikilogram-scale synthesis of an HCV NS5B site D inhibitor, MK-8876. The key topics covered are (1) process improvement of the two main fragments; (2) optimization of the initially troublesome penultimate step, a key bis(boronic acid) (BBA)-based borylation; (3) process development of the final Suzuki–Miyaura coupling; and (4) control of the drug substance form. These efforts culminated in a 28 kg delivery of the desired active pharmaceutical ingredient.