Reaction Steps
Sodium bis(trimethylsilyl)amide (1.0M in THF) (Aldrich, St. Louis, Mo.; 0.777 mL, 0.777 mmol) was added to a mixture of (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 (Example 146, Step 6) 141.2 mg, 0.222 mmol) and 6-chloropyridin-3-amine (Aldrich, St. Louis, Mo.; 57.1 mg, 0.444 mmol) in THF (2.5 mL) at 0° C., and the resulting dark brown solution was stirred at 0° C. for 30 min. Excess sodium bis(trimethylsilyl)amide was then quenched with saturated aqueous NH4Cl (2 mL), and the reaction mixture was partitioned between EtOAc (50 mL) and saturated aqueous NH4Cl (20 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic extracts were sequentially washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0 to 100% EtOAc/hexanes) furnished (R)-4-(2-(6-chloropyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (125.0 mg, 0.168 mmol, 76% yield) as a yellow-brown oil. 1H NMR (400 MHz, CDCl3) δ 12.12 (s, 1H), 8.74 (d, J=2.2 Hz, 1H), 8.50 (s, 1H), 8.28 (s, 1H), 8.18-8.24 (m, 1H), 7.21 (td, J=5.7, 2.4 Hz, 5H), 6.89 (s, 2H), 6.85 (d, J=8.6 Hz, 2H), 4.74-4.93 (m, 4H), 3.81 (s, 3H), 3.79 (s, 3H), 3.52-3.59 (m, 1H), 3.15 (br. s., 4H), 2.67 (s, 3H), 2.60 (s, 3H), 2.47-2.58 (m, 4H), 1.38 (d, J=6.7 Hz, 3H). m/z (ESI, +ve) 744.2 (M+H)+.
