Synthesis of the HCV Protease Inhibitor Vaniprevir (MK-7009) Using Ring-Closing Metathesis Strategy

• Published in: Journal of organic chemistry Vol. 77; no. 8; pp. 3820 - 3828
• Main Authors: Kong, Jongrock, Chen, Cheng-yi, Balsells-Padros, Jaume, Cao, Yang, Dunn, Robert F, Dolman, Sarah J, Janey, Jacob, Li, Hongmei, Zacuto, Michael J
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 20.04.2012; Amer Chemical Soc
• Subjects: Catalysis; Catalysts: preparations and properties; Chemistry; Chemistry, Organic; Cyclization; Exact sciences and technology; General and physical chemistry; Hepacivirus - drug effects; Heterocyclic compounds; Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Indoles - chemical synthesis; Indoles - chemistry; Molecular Structure; Organic chemistry; Physical Sciences; Preparations and properties; Protease Inhibitors - chemical synthesis; Protease Inhibitors - chemistry; Ruthenium - chemistry; Science & Technology; Theory of reactions, general kinetics. Catalysis. Nomenclature, chemical documentation, computer chemistry; RCM; CATALYSTS; SCALE; Isoindoline derivative; Ruthenium; Nitrogen heterocycle; Metathesis; Transition metal; Dienic compound; Isoindole derivatives; Macrocycle; Cyclization; Chemical synthesis; Platinoid; Catalyst; Oxygen nitrogen heterocycle
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo3001595

A highly efficient synthesis of Vaniprevir (MK-7009) has been accomplished in nine linear steps and 55% overall yield. The key features of this synthesis include a cost-effective synthesis of the isoindoline subunit and efficient construction of the 20-membered macrocyclic core of Vaniprevir (MK-7009) utilizing ring-closing metathesis technology. A high-performing ring-closing metathesis protocol has been achieved by simultaneous slow addition of the ruthenium catalyst (0.2 mol %) and the diene substrate at a concentration of 0.13 M.