1,3-Benzoxazol-5-amine → n-(3-(4-(Bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-yl)benzo[d]oxazol-5-amine

Participants

Reaction Conditions

Reaction Steps

A mixture of 4-(2-fluoro-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.900 g, 1.448 mmol) and benzo[d]oxazol-5-amine (0.388 g, 2.90 mmol) in THF (20 mL) was cooled to −20° C. and treated with 1.0 M lithium bis(trimethylsilyl)amide in THF (5.07 mL, 5.07 mmol) added dropwise. The mixture was allowed to slowly warm to ambient temperature. The reaction mixture was diluted with water (50 mL) and extracted with CH2Cl2 (3×50 mL). The combined organic extracts were dried over Na2SO4. The solution was filtered and concentrated to give the crude product as a tan solid. This was purified by chromatography through a SiliCycle SiliaSep pre-packed silica gel column (120 gram), eluting with a gradient of 0% to 10% MeOH in CH2Cl2 over 30 min to give N-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-yl)benzo[d]oxazol-5-amine as a tan oil. This was treated with trifluoromethanesulfonic acid (0.916 mL, 10.32 mmol) in trifluoroacetic acid (7.75 mL, 101 mmol) and heated at 70° C. for 20 min. The mixture was cooled to ambient temperature and concentrated in vacuo. The crude residue was diluted with DCM (20 mL) and neutralized with sodium bicarbonate (10 g). The mixture was stirred vigorously for 10 min. Then water (10 mL) was added dropwise and allowed to stir for 5 min. The mixture was filtered through a fine-fritted funnel The collected solid was rinsed with water to wash away sodium bicarbonate. The yellow solid was washed with diethyl ether and recrystallized from hot DMF to give N-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-yl)benzo[d]oxazol-5-amine (0.300 g, 0.605 mmol, 46.9% yield) as a light-yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 12.11 (s, 1H); 8.68 (s, 2H); 8.50 (s, 1H); 8.29 (s, 1H); 7.90 (s, 1H); 7.72 (d, J=11.35 Hz, 3H); 3.51 (s, 2H); 3.12 (s, 4H); 2.87 (s, 3H); 2.50 (m, 7H). m/z (ESI, +ve ion) 496.1 (M+H)+.

Provenance & Evidence