ABSTRACT
An efficient general methodology for the synthesis of 4-quinolinyl ethers is demonstrated via a highly reactive SNAr reaction of 4-quinolinyl sulfones with a range of structurally diversified 1°, 2°, and 3° alcohols with a wide substrate scope and high yields. By adapting this methodology, a convergent synthesis of a complex target of HCV NS3/4a protease inhibitor BI 201420 was accomplished.
Subject(s)
Hepatitis C , Viral Nonstructural Proteins , Antiviral Agents , Ethers , Hepacivirus , Humans , Protease Inhibitors/pharmacology , SulfonesABSTRACT
A chromatography-free, asymmetric synthesis of the C2-symmetric P-chiral diphosphine t-Bu-SMS-Phos was developed using a chiral auxiliary-based approach in five steps from the chiral auxiliary in 36% overall yield. Separtion and recovery of the auxiliary were achieved with good yield (97%) to enable recycling of the chiral auxiliary. An air-stable crystalline form of the final ligand was identified to enable isolation of the final ligand by crystallization to avoid chromatography. This synthetic route was applied to prepare up to 4 kg of the final ligand. The utility of this material was demonstrated in the asymmetric hydrogenation of trifluoromethyl vinyl acetate at 0.1 mol % Rh loading to access a surrogate for the pharmaceutically relavent chiral trifluoroisopropanol fragment in excellent yield and enantiomeric excess (98.6%).
ABSTRACT
A highly concise and convergent synthesis of HCV polymerase inhibitor Deleobuvir (BI 207127, 1) was achieved, featuring efficient Pd-catalyzed one-pot borylation-Suzuki coupling where TFP was identified as the unique ligand effective for these transformations.
Subject(s)
Acrylates/chemical synthesis , Acrylates/pharmacology , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Acrylates/chemistry , Antiviral Agents/chemistry , Benzimidazoles/chemistry , Catalysis , Hepacivirus/drug effects , Hepacivirus/enzymology , Ligands , Molecular Structure , Palladium/chemistryABSTRACT
A highly convergent large scale synthesis of a 15-membered macrocyclic hepatitis C virus (HCV) protease inhibitor BI 201302 was achieved, in which the key features are the practical macrocyclization by Ru-catalyzed ring-closing metathesis (0.1 mol % Grela catalyst, 0.1-0.2 M concentration) and the efficient sulfone-mediated SNAr reaction.
Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Hepacivirus/drug effects , Peptides, Cyclic/chemical synthesis , Peptides, Cyclic/pharmacology , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Antiviral Agents/chemistry , Catalysis , Cyclization , Molecular Structure , Peptides, Cyclic/chemistry , Protease Inhibitors/chemistryABSTRACT
[reaction: see text] The first practical and economical process for synthesis of 2,3-disubstituted indole compounds has been developed with high regioselectivity by palladium-catalyzed indolization of 2-bromo- or chloroanilines and their derivatives with internal alkynes.