Preparation of 2,4,8-trisubstituted pyrido[2,3-d]pyrimidin-7-one has been demonstrated by a small, but limited, number of methods. In general, these methods either include lengthy synthetic sequence (e.g., more than 5 steps in the longest linear sequence from commercially available starting materials) or are not conducive for use in structure-activity relationship studies [e.g., not amenable to multi-dimensional (>or=2-D) array syntheses]. Doherty, J. B. et al., (Merck, U.S. Pat. No. 6,809,199) discloses an eight-step method to prepare intermediates with structures similar to (II) wherein C4 and N8 have already been substituted with phenyl groups. Mauro, A. et al. (Pharmacia, US 2004/0009993) reported a nine-step method to prepare intermediates with structures similar to (II) wherein C4 is substituted with C1-C6 alkyl or C1-C6 arylalkyl and N8 has been connected with a phenyl group. Adams, J. L. et al. (SmithKline Beecham: WO 02/059083; WO 03/088972; Tetrahedron Letters, 2003, Vol. 44, pages 4567-4570) discloses a four-step method to prepare intermediates with structures similar to (II) wherein the C4 position has already been substituted via a Suzuki cross coupling reaction and N8 is substituted with alkyl or aryl.
However, despite all of these methods there still remains a need for an efficient method to prepare 2,4,8-trisubstituted pyrido[2,3-d]pyridine-7-one that can independently optimize the substituents at C2 and C4.