Abstract
A large-scale, chromatography-free synthesis of a potent and selective Cathepsin K inhibitor 1 is reported. The key asymmetric center was installed by addition of (R)-pantolactone to the in situ-generated ketene 4a. The final step of the convergent synthesis of 1 was completed via Suzuki coupling of aryl bromide 7a with unprotected aryl piperazine boronic acid 13. Residual palladium and iron generated in the Suzuki coupling were efficiently removed from crude 1 via a simple extractive workup using lactic acid.
MeSH terms
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Catalysis
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Cathepsin K
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Cathepsins / antagonists & inhibitors*
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Combinatorial Chemistry Techniques*
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / pharmacology
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Indicators and Reagents
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Magnetic Resonance Spectroscopy
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Molecular Structure
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Palladium / chemistry*
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Pentanoic Acids / chemical synthesis*
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Pentanoic Acids / pharmacology
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Piperazines / chemical synthesis*
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Piperazines / pharmacology
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Stereoisomerism
Substances
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Enzyme Inhibitors
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Indicators and Reagents
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Pentanoic Acids
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Piperazines
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Palladium
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Cathepsins
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Cathepsin K