Reaction Steps
To a solution of methyl 5-chloro-2,3′-bipyridine-3-carboxylate (1-2, 0.3 g, 1.20 mmol) in dioxane (6 mL) was added 3,5-dimethylphenyl boronic acid (0.452 g, 3.01 mmol), cesium carbonate (1.17 g, 3.61 mmol), tricyclohexylphosphine (0.101 g, 0.362 mmol), and tris(dibenzylideneacetone)-dipalladium (0.166 g, 0.181 mmol), and stirred at 95° C. overnight. The reaction was then cooled to room temperature, and partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate and filtered, concentrated and purified via normal phase chromatography (0->5% MeOH in DCM) afforded methyl 5-(3,5-dimethylphenyl)-2,3′-bipyridine-3-carboxylate as a yellow foam. ESI+ MS [MH]+ C20H18N2O2=319.25. To a solution of methyl 5-(3,5-dimethylphenyl)-2,3′-bipyridine-3-carboxylate (0.385 g, 1.20 mmol) in tetrahydrofuran (3 mL) and methanol (3 mL) was added potassium hydroxide (0.122 g, 2.17 mmol) and water (1.25 mL) and the system was stirred at room temperature overnight. The reaction mixture was then neutralized with 6N HCl to a pH of 2.0 and then concentrated in vacuo to afford 5-(3,5-dimethylphenyl)-2,3′-bipyridine-3-carboxylic acid as a bone powder in the form of a bis HCl salt. ESI+ MS [MH]+ C19H16N2O2=305.0. To a solution of the bis HCl salt form of 5-(3,5-dimethylphenyl)-2,3′-bipyridine-3-carboxylic acid (0.390 g, 1.03 mmol) and 3,4-dimethoxybenzylamine (0.173 g, 1.03 mmol) in dimethylformamide (5 mL) was added EDC (0.029 g, 0.191 mmol), HOBt (0.317 g, 2.06 mmol) and triethylamine (0.720 mL, 5.16 mmol) and the system was stirred in the microwave at 100° C. for 15 minutes. The system was cooled to room temperature, extracted with EtOAc, washed with water and dried over magnesium sulfate. The crude reaction mixture was purified using normal phase chromatography (0->10% MeOH in DCM) to afford the title compound (1-3) as a white powder. 1H NMR (500 MHz, CDCl3) δ 8.98-9.00 (m, 2H), 8.65-8.66 (m, 1H), 8.17 (d, J=2 Hz, 1H), 7.98-8.00 (m, 1H), 7.28-7.30 (m, 3H), 7.11 (s, 1H), 6.78 (d, J=8 Hz, 1H), 6.41-6.67 (m, 2H), 5.72 (br s, 1H), 4.42 (d, J=6 Hz, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 2.43 (s, 6H). HRMS [M+H] C28H27N3O3 calc'd 454.2125, found 454.2107.
