Journal of Organic Chemistry 2004-03-19

An efficient synthesis of an alphavbeta3 antagonist.

Nobuyoshi Yasuda, Yi Hsiao, Mark S Jensen, Nelo R Rivera, Chunhua Yang, Kenneth M Wells, James Yau, Michael Palucki, Lushi Tan, Peter G Dormer, Ralph P Volante, David L Hughes, Paul J Reider

Index: J. Org. Chem. 69 , 1959-1966, (2004)

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Abstract

A practical preparation of an alpha(v)beta(3) antagonist is reported. The antagonist consists of three key components, a tetrahydronaphthyridine moiety, a beta-alanine moiety, and a central imidazolidone moiety. The tetrahydronaphthyridine component was prepared using two different methods, both of which relied on variations of the Friedländer reaction to establish the desired regiochemistry. The beta-alanine component was prepared using Davies' asymmetric 1,4-addition methodology as the key stereo-defining step. The central imidazolidone portion was created from these two components using an effective three-step cyclization protocol. Thus, a highly convergent process for the drug candidate was defined.