jo048082n_si_001.pdf (1.62 MB)
Practical Asymmetric Synthesis of a Non-Peptidic αvβ3 Antagonist
journal contribution
posted on 2005-03-04, 00:00 authored by Stephen P. Keen, Cameron J. Cowden, Brian C. Bishop, Karel M. J. Brands, Antony J. Davies, Ulf H. Dolling, David R. Lieberman, Gavin W. StewartThe development of a practical and highly convergent synthesis of an αvβ3 antagonist is described.
The two key fragments present in this compound, a tetrahydropyrido[2,3-b]azepine ring system
and a chiral 3-aryl-5-oxopentanoic acid, were constructed independently and then coupled at a
late stage using a Wittig reaction. The pyridoazepine moiety was prepared from N-Boc 6-chloro-2-aminopyridine via directed ortho-metalation/alkylation followed by in situ cyclization. A Suzuki
reaction was then used to attach the propionaldehyde side-chain required for Wittig coupling. The
coupling partner was prepared from asymmetric methanolysis of a 3-substituted glutaric anhydride
followed by elaboration of the acid moiety to the requisite β-keto phosphorane. Using this route,
kilogram quantities of the desired drug candidate were prepared.
History
Usage metrics
Categories
Keywords
methanolysiazepine ring systemketometalationWittig reactiontetrahydropyridoacid moietycyclizationkilogram quantitiesα v β 3 antagonistpropionaldehydeAntagonistelaborationarylfragmentpyridoazepine moietychlorocompoundphosphoraneBocchiralPractical Asymmetric Synthesisdrug candidateSuzuki reactionorthoconvergent synthesisanhydridequantity
Licence
Exports
RefWorks
BibTeX
Ref. manager
Endnote
DataCite
NLM
DC