Reaction Steps
(R)-5-(1-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)-2-fluoropyridin-3-ylboronic acid (9.27 g, 26.2 mmol), 4-chloro-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (Example 51) (11.47 g, 29.8 mmol), bis-(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (Aldrich, St. Louis, Mo.) (1.820 g, 2.57 mmol), and potassium acetate (8.17 g, 83.0 mmol) were suspended in a mixture of 1,4-dioxane (150 mL) and water (30 mL). The resulting mixture was sparged with nitrogen (for about 30 sec) and then stirred at 100° C. for 3.5 h. The reaction mixture was then allowed to cool to 25° C., water (150 mL) was added, and the resulting mixture was extracted with EtOAc (3×300 mL). The organic extracts were combined, dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 3% MeOH/DCM) furnished (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 (13.63 g, 79% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.44 (dd, J=9.0, 2.3 Hz, 1H), 8.25 (d, J=1.8 Hz, 1H), 7.24 (d, J=5.7 Hz, 2H), 7.22 (d, J=5.5 Hz, 2H), 6.86 (t, J=8.9 Hz, 4H), 4.83 (s, 2H), 4.80 (s, 2H), 3.81 (s, 3H), 3.79 (s, 3H), 3.54-3.61 (m, 1H), 3.40 (d, J=3.7 Hz, 4H), 2.55 (s, 3H), 2.44 (d, J=2.7 Hz, 2H), 2.27-2.39 (m, 2H), 1.44 (s, 9H), 1.40 (d, J=6.7 Hz, 3H). 19F NMR (377 MHz, CDCl3) δ −67.83 (d, J=9.2 Hz, 0.7 F), −70.47 (d, J=5.7 Hz, 0.3 F). m/z (ESI, +ve) 658.4 (M+H)+.
