1. Efficient large-scale synthesis of BILN 2061, a potent HCV protease inhibitor, by a convergent approach based on ring-closing metathesis.
- Author
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Yee NK, Farina V, Houpis IN, Haddad N, Frutos RP, Gallou F, Wang XJ, Wei X, Simpson RD, Feng X, Fuchs V, Xu Y, Tan J, Zhang L, Xu J, Smith-Keenan LL, Vitous J, Ridges MD, Spinelli EM, Johnson M, Donsbach K, Nicola T, Brenner M, Winter E, Kreye P, and Samstag W
- Subjects
- Antiviral Agents chemistry, Antiviral Agents pharmacology, Carbamates chemistry, Carbamates pharmacology, Chromatography, High Pressure Liquid, Cyclization, Hepacivirus drug effects, Macrocyclic Compounds chemistry, Macrocyclic Compounds pharmacology, Molecular Structure, Protease Inhibitors chemistry, Protease Inhibitors pharmacology, Quinolines chemistry, Quinolines pharmacology, Thiazoles chemistry, Thiazoles pharmacology, Antiviral Agents chemical synthesis, Carbamates chemical synthesis, Hepacivirus enzymology, Macrocyclic Compounds chemical synthesis, Protease Inhibitors chemical synthesis, Quinolines chemical synthesis, Thiazoles chemical synthesis
- Abstract
A multistep scalable synthesis of the clinically important hepatitis C virus (HCV) protease inhibitor BILN 2061 (1) is described. The synthesis is highly convergent and consists of two amide bond formations, one etherification, and one ring-closing metathesis (RCM) step, using readily available building blocks 2-5. The optimization of each step is described at length. The main focus of the paper is the study of the RCM step and the description of the main problems faced when scaling up to pilot scale this highly powerful but very challenging synthetic operation. Eventually, the RCM reaction was smoothly scaled up to produce >400 kg of cyclized product.
- Published
- 2006
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