Practical Asymmetric Synthesis of a Non-Peptidic α<sub>v</sub>β<sub>3</sub> Antagonist

The development of a practical and highly convergent synthesis of an α<sub>v</sub>β<sub>3</sub> antagonist is described. The two key fragments present in this compound, a tetrahydropyrido[2,3-<i>b</i>]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 <i>N</i>-Boc 6-chloro-2-aminopyridine via directed <i>ortho</i>-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.