[Synthesis]
Example 40: Synthesis of 4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-(2-methoxy-5-pyrimidinyl)-6-(4-morpholinyl)-1,3,5-triazin-2-amine
The target compound was synthesized according to Method A. To a solution of sodium methanol (0.090 g sodium) in methanol (12 mL) was added 0.486 g (3.03 mmol) of 2-chloro-5-nitropyrimidine, and the mixture was heated under reflux conditions for 1 hour. After completion of the reaction, the mixture was cooled, concentrated in vacuum, extracted with ethyl acetate and washed with water. The aqueous layer was extracted with chloroform, the organic layers were combined, dried over anhydrous sodium sulfate and concentrated to give 0.347 g (75% yield) of 2-methoxy-5-nitropyrimidine as a yellow powder.1H NMR (CDCl3) δ 9.31 (s, 2H), 4.17 (s, 3H); LCMS (APCI+) m/z: 156 (MH+, 100%).
0.342 g (2.20 mmol) of the above nitro compound was dissolved in methanol (20 mL), 0.30 g of 10% Pd/C catalyst was added, and the reaction was stirred for 18 hr under a hydrogen atmosphere (25 in/hr). After completion of the reaction, the reaction mixture was filtered through diatomaceous earth and the filtrate was concentrated to give 0.274 g (100% yield) of 5-amino-2-methoxypyrimidine as a colorless oil.1H NMR (DMSO-d6) δ 8.05 (s, 2H), 3.94 (s, 3H); LCMS (APCI+) m/z: 126 (MH+, 100%).
0.274 g (2.19 mmol) of the above amino compound was dissolved in tetrahydrofuran (3 mL), 1.25 mL of NaHMDS (2M THF solution) was added and stirred for 10 min. Then 0.31 g (0.78 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole solution in THF (5 mL) was added and stirring was continued for 90 minutes. After completion of the reaction, the reaction mixture was neutralized with acetic acid, diluted with water and extracted with ethyl acetate. The organic layer was washed sequentially with water and ammonia, dried and concentrated. Recrystallization by ethanol/dichloromethane gave 0.098 g (26% yield) of the target compound with melting point 255-258 °C.1H NMR (DMSO-d6) δ 10.07 (s, 1H), 8.88-8.74 (m, 2H), 8.15-7.42 (m, 3H), 6.97 (d, J = 8.0 Hz, 1H), 3.98 (s, 3H), 3.93 (s, 3H), 3.82-3.72 (m, 8H); Elemental Analysis Calculated Values C21H21F2N6O3: C, 52.0; H, 4.4; N, 26.0. Measured Values: C, 52.1; H, 4.5; N, 26.0%. |