Reaction Steps
2,2,2-Trifluoroacetic acid (45.9 mL, 596 mmol) was added (over about 10 min) to a solution of (R)-tert-butyl 4-(1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoropyridin-3-yl)ethyl)piperazine-1-carboxylate (7.00 g, 10.64 mmol) in DCM (106 mL) at 0° C., and the resulting mixture was stirred at 25° C. for 2 h. The reaction mixture was then concentrated in vacuo (5 torr, 25° C.) to provide a viscous oil, which was taken up in DCM (100 mL) and cooled to 0° C. Ice (20 mL) was added, followed by solid sodium bicarbonate (added in portions to the rapidly stirred mixture until gas evolution ceased). Water (300 mL) and DCM (50 mL) were then added. The organic layer was separated, and the aqueous layer was extracted with DCM (2×150 mL). All organic extracts were then combined, dried over sodium sulfate, and filtered through a 0.45 μM ZAPCAP filter (Sigma-Aldrich Corp., St. Louis, Mo.). The clear filtrate was partially concentrated in vacuo (final volume, 100 mL) and cooled to 0° C. Triethylamine (5.93 mL, 42.6 mmol) and methanesulfonyl chloride (1.647 mL, 21.28 mmol) (added dropwise) were then sequentially added, and the resulting mixture was stirred at 0° C. for 1 h. Saturated aqueous NaHCO3 (50 mL) was added, and the resulting mixture was partitioned between DCM (150 mL) and water (200 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (3×100 mL). All organic layers were then combined, dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 20 to 100% (10% MeOH/EtOAc)/hexane) provided (R)-4-(2-fluoro-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (6.28 g, 9.88 mmol, 93% yield) as a white foam. 1H NMR (400 MHz, CDCl3) δ 8.45 (dd, J=9.0, 2.3 Hz, 1H), 8.27 (s, 1H), 7.23 (t, J=8.0 Hz, 4H), 6.87 (t, J=8.6 Hz, 4H), 4.82 (s, 2H), 4.81 (s, 2H), 3.81 (s, 3H), 3.80 (s, 3H), 3.63 (q, J=6.8 Hz, 1H), 3.20 (br. s., 4H), 2.73 (s, 3H), 2.59-2.67 (m, 2H), 2.55 (s, 3H), 2.49-2.54 (m, 2H), 1.41 (d, J=6.7 Hz, 3H). 19F NMR (377 MHz, CDCl3) δ −67.44 (d, J=9.2 Hz, 0.92 F), −70.10 (br. s., 0.08 F). m/z (ESI, +ve) 636.2 (M+H)+.
