Abstract
The development of a convergent and highly stereoselective synthesis of an HCV NS3/4a protease inhibitor possessing a unique spirocyclic and macrocyclic architecture is described. A late-stage spirocyclization strategy both enabled rapid structure-activity relationship studies in the drug discovery phase and simultaneously served as the basis for the large scale drug candidate preparation for clinical use. Also reported is the discovery of a novel InCl3-catalyzed carbonyl reduction with household aluminum foil or zinc powder as the terminal reductant.
MeSH terms
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Antiviral Agents / chemical synthesis*
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Antiviral Agents / chemistry
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Antiviral Agents / pharmacology*
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Drug Discovery
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Hepacivirus / drug effects*
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Hepatitis C / drug therapy*
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Heterocyclic Compounds, 4 or More Rings / chemical synthesis*
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Heterocyclic Compounds, 4 or More Rings / chemistry
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Heterocyclic Compounds, 4 or More Rings / pharmacology
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Macrocyclic Compounds / chemical synthesis*
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Macrocyclic Compounds / chemistry
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Macrocyclic Compounds / pharmacology*
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Molecular Structure
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Spiro Compounds / chemical synthesis*
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Spiro Compounds / chemistry
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Spiro Compounds / pharmacology*
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Structure-Activity Relationship
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Viral Nonstructural Proteins / antagonists & inhibitors*
Substances
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Antiviral Agents
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Heterocyclic Compounds, 4 or More Rings
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MK-8831
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Macrocyclic Compounds
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Spiro Compounds
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Viral Nonstructural Proteins