ABSTRACT
A potent reversible inhibitor of the cysteine protease cathepsin-S was prepared on large scale using a convergent synthetic route, free of chromatography and cryogenics. Late-stage peptide coupling of a chiral urea acid fragment with a functionalized aminonitrile was employed to prepare the target, using 2-hydroxypyridine as a robust, nonexplosive replacement for HOBT. The two key intermediates were prepared using a modified Strecker reaction for the aminonitrile and a phosphonation-olefination-rhodium-catalyzed asymmetric hydrogenation sequence for the urea. A palladium-catalyzed vinyl transfer coupled with a Claisen reaction was used to produce the aldehyde required for the side chain. Key scale up issues, safety calorimetry, and optimization of all steps for multikilogram production are discussed.
Subject(s)
Alkenes/chemical synthesis , Cathepsins/antagonists & inhibitors , Cathepsins/chemistry , Enzyme Inhibitors/chemical synthesis , Urea/chemical synthesis , Vinyl Compounds/chemical synthesis , Alkenes/chemistry , Calorimetry/methods , Catalysis , Cyclization , Enzyme Inhibitors/pharmacology , Indicators and Reagents/chemistry , Models, Molecular , Molecular Structure , Palladium/chemistry , Rhodium/chemistry , Stereoisomerism , Urea/chemistry , Vinyl Compounds/chemistryABSTRACT
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.
ABSTRACT
[structure: see text] The new BIPI ligands are phosphinoimidazolines that can be electronically tuned in three different ligand regions to explore electronic effects in asymmetric catalysis. Their application to the asymmetric Heck reaction (AHR) in the creation of a chiral quaternary center is described. Enantioselectivity is shown for the first time to depend linearly on phosphine electron density. Changing the ligand basicity by variation of the R(2) or R(3) substituents reverses facial selectivity.
