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.
Subject(s)
Antiviral Agents/chemical synthesis , Carbamates/chemical synthesis , Hepacivirus/enzymology , Macrocyclic Compounds/chemical synthesis , Protease Inhibitors/chemical synthesis , Quinolines/chemical synthesis , Thiazoles/chemical synthesis , 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/pharmacologyABSTRACT
The Boehringer-Ingelheim phosphinoimidazoline (BIPI) ligands were applied to the formation of chiral quaternary centers in the asymmetric Heck reaction. Several different substrates were examined in detail, using more than 70 members of this new ligand class. Hammett relationships were determined through systematic variation of the ligand electronics. All substrates showed essentially the same Hammett behavior, where enantioselectivity increased as the ligands were made more electron-deficient. Ligand optimization has led to catalysts which give the highest enantioselectivities reported to date for these difficult systems.
