Synthesis of deuterium‐, tritium‐, and carbon‐14‐labeled BILN2061, a potent hepatitis C virus protease inhibitor

Hepatitis C virus (HCV) serine protease is a target for antiviral therapy against HCV infection, a leading cause of liver transplantation in the US. BILN2061, (1 S , 4 R , 6 S , 7 Z , 14 S , 18 R )‐14‐cyclopentyloxycarbonylamino‐18‐[2‐(2‐isopropylamino‐thiazol‐4‐yl)‐7‐methoxyquinolin‐4‐yloxy]‐2,15‐dioxo‐3,16‐diazatricyclo[14.3.0.0 4,6 ]nonadec‐7‐ene‐4‐carboxylic acid, is a potent inhibitor of HCV and the first compound in this class of cyclic peptides in human trials. Here, we report the synthesis of deuterium‐labeled BILN2061 with isotopic enrichment of 99%, tritium‐labeled BILN2061 with a specific activity of 17.1 GBq/mmol, and carbon‐14‐labeled BILN2061 with a specific activity of 1.83 GBq/mmol. The isotopes were incorporated via a Hantzsch thiazole synthesis of labeled isopropyl thiourea and α ‐bromoketone intermediate. The preparation of labeled isopropyl thiourea is reported. Copyright © 2005 John Wiley & Sons, Ltd.