Reaction Steps
To a stirred solution of 6-(2,6-dichlorophenyl)-8-methyl-2-{4-[2-(1-piperidinyl)ethoxy]anilino}pyrido[2,3-d]pyrimidin-7(8H)-one (PD 166285 analogue B; Klutchko et al, J Med Chem, 1998, 41(17), 3276-3292) (230 mg, 0.44 mmol) in dry NMP (5 mL) was added 5-(bromomethyl)-1-methyl-4-nitro-1H-imidazole (122) (116 mg, 0.53 mmol). The resulting solution was then stirred at room temperature for 12 days before Et2O was added. The resulting precipitate was filtered and washed with EtOAc and CH2Cl2. The crude product was purified by precipitation from NMP/EtOAc (×2). The precipitate was filtered and dried under vacuum to give 1-[2-(4-{[6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}phenoxy)ethyl]-1-[(1-methyl-4-nitro-1H-imidazol-5-yl)methyl]piperidinium bromide (143) (100 mg, 31%) as a pale yellow powder, m.p. 176-178° C. 1H NMR [(CD3)2SO] δ 10.14 (s, 1H), 8.82 (s, 1H), 8.14 (s, 1H), 7.89 (s, 1H), 7.80 (d, J=8.9 Hz, 2H), 7.59 (dd, J=8.1, 0.7 Hz, 2H), 7.46 (dd, J=8.8, 7.4 Hz, 1H), 7.10 (d, J=9.1 Hz, 2H), 5.22 (bs, 2H), 4.61 (t, J=4.4 Hz, 2H), 4.17 (bs, 2H), 3.86 (s, 3H), 3.72-3.64 (m, 2H), 3.65 (s, 3H), 2.10-1.95 (m, 4H), 1.74 (bd, J=14.3 Hz, 2H), 1.60 (bd, J=14.3 Hz, 1H), 1.46-1.31 (m, 1H), 2 protons not observed. Analysis found: C, 48.33; H, 4.64; N, 13.32. C32H33BrCl2N8O4.3H2O.¼EtOAc requires: C, 48.31; H, 5.04; N, 13.66.
