Reaction Steps
4-(5-(1,3-Dioxolan-2-yl)-2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (1.688 g, 3.262 mmol) and 5-fluoro-6-methoxypyridin-3-amine (0.477 g, 3.36 mmol) were dissolved in THF (28 mL) and the reaction flask was cooled in an ice water bath under nitrogen. Then, lithium bis(trimethylsilyl)amide (1.0 M solution in tetrahydrofuran, 9.5 mL, 9.5 mmol) was added, and the reaction was stirred under nitrogen for 35 min. Then, aqueous HCl (5.0 M, 4.5 mL, 22.50 mmol) and MeOH (5.8 mL) were added, and the reaction was warmed to room temperature and stirred. After 10 min, the reaction was treated with water (20 mL) and extracted with DCM. The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel filter (150 mL fritted filter with about 2 inches of silica gel; DCM to 100:1 DCM/MeOH). The fractions with product were collected, concentrated, and dried under high vacuum. LCMS showed mostly product, but some unhydrolyzed acetonide was also present. The material was dissolved in THF (20 mL) and MeOH (4.0 mL) and aqueous HCl (5.0 M, 2.0 mL, 10 mmol) was added, and the solution was stirred at room temperature. After 25 min, the reaction was diluted with water (20 mL) and DCM. The layers were separated, and the aqueous phase was extracted with DCM. The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and dried under high vacuum overnight to give 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)nicotinaldehyde (1.098 g). 1H NMR (CDCl3, 400 MHz) δ 12.58 (s, 1H), 9.92 (s, 1H), 9.25 (d, J=2.35 Hz, 1H), 8.75 (d, J=2.15 Hz, 1H), 8.03-7.97 (m, 2H), 7.21 (dd, J=15.06 Hz, 8.41 Hz, 4H), 6.87 (dd, J=11.15 Hz, 8.61 Hz, 4H), 4.89 (s, 2H), 4.85 (s, 2H), 4.04 (s, 3H), 3.82 (s, 3H), 3.79 (s, 3H), 2.61 (s, 3H). m/z (ESI, pos. ion) 596 (M+H)+.
