Reaction Steps
6-(6-Methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)nicotinaldehyde (121.8 mg, 0.2734 mmol) and 2-aminopyridine (72.0 mg, 0.765 mmol) were suspended in dichloromethane (1.5 mL) and ethanol (1.5 mL) and tetraisopropoxytitanium (0.16 mL, 0.54 mmol) was added. The flask was fit with a reflux condenser and put in a preheated oil bath (70° C.) and stirred under nitrogen. After 5 hours, the reaction was diluted with DCM, and stirring was continued overnight. Then, more 2-aminopyridine (63.6 mg, 0.676 mmol) and Ti(OiPr)4 (0.18 mL, 0.61 mmol), and DCM were added, and stirring was continued at 70° C. for about 6 hours. Then, the reaction was cooled to room temperature, and sodium borohydride (38.9 mg, 1.028 mmol) was added. The reaction was stirred at room temperature for 25 minutes, and then aqueous 5N HCl (0.55 mL) was added. The flask was put in a preheated oil bath (50° C.) and stirring was continued overnight. Then, the reaction was cooled to room temperature, diluted with DCM and MeOH, and filtered through a Celite® (diatomaceous earth) pad, which was washed with a 1:1 mixture of DCM and MeOH. The filtrate was concentrated, treated with water, and filtered. The solid was washed with water, collected, treated with DMSO (about 1 mL), diluted with DCM, and filtered. The solid was washed with DCM, collected, and purified by prep HPLC (10% to 100% MeCN/water with 0.1% TFA over 30 minutes with a total flow rate of 100 mL/min) to give N-(6-methoxypyridin-3-yl)-3-(2-methyl-9H-purin-6-yl)-5-((pyridin-2-ylamino)methyl)pyridin-2-amine (62.7 mg, 52% yield). MS (ESI pos. ion) m/z 440 (M+H)+. 1H NMR (d6-DMSO, 400 MHz) δ 13.60 (br s, 1H), 12.63 (s, 1H), 9.80 (s, 1H), 9.01 (br s, 1H), 8.56 (s, 1H), 8.55 (d, J=2.54 Hz, 1H), 8.36 (d, J=2.35 Hz, 1H), 8.15 (dd, J=8.80 Hz, 2.74 Hz, 1H), 7.98 (d, J=6.26 Hz, 1H), 7.92 (t, J=7.43 Hz, 1H), 7.11 (d, J=9.0 Hz, 1H), 6.90 (t, J=6.46 Hz, 1H), 6.86 (d, J=9.0 Hz, 1H), 4.61 (s, 2H), 3.85 (s, 3H), 2.85 (s, 3H).
