反应详情

温度

23 °C

2-Methyl-3-butyn-2-ol (48 μL, 0.44 mmol) was added to a solution of triphosgene (42 mg, 0.14 mmol) and pyridine (38 μL, 0.47 mmol) in CH2Cl2 (1.0 mL) at 23° C. Gas evolution was observed during addition of the alcohol, and a precipitate was observed to form. The resulting slurry was stirred at 23° C. for 1 h. Stirring was ceased, the solid was allowed to settle to the bottom of the flask, and the supernatant was added via cannula to a slurry of 4-[1-(4-trifluoromethoxyphenyl)-1H-[1,2,4]triazol-3-yl]-phenylamine (100 mg, 0.312 mmol) and Pyridine (38 μL, 0.47 mmol) in CH2Cl2 (1.0 mL) at 23° C. A thick precipitate was observed to form. At this point, TLC analysis indicated some starting material remained, so an equivalent amount of triphosgene/pyridine/alcohol was combined as above, and the resulting supernatant was again added to the aniline mixture. After stirring for another 3 h at 23° C., the reaction mixture was diluted with 30% EtOAc/hexanes (10 mL), and a fine white precipitate was filtered on a coarse frit. The clear yellow filtrate was concentrated, and the resulting yellow oil was purified by silica gel chromatography (Biotage 10 g SNAP column, eluted with a 10% to 25% to 50% EtOAc/hexanes gradient) to provide the title compound (55 mg, 41%) as a white solid: mp 164-165° C.; 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 8.13 (d, J=8.7 Hz, 2H), 7.79 (d, J=9.0 Hz, 2H), 7.53 (d, J=8.5 Hz, 2H), 7.38 (d, J=8.8 Hz, 2H), 6.73 (s, 1H), 2.61 (s, 1H), 1.77 (s, 6H); ESIMS m/z 431 (M+H); HRMS-ESI (m/z): [M]+ calcd for C21H17F3N4O3, 430.125. found, 430.126.

1. customto form
2. stirringStirring
3. customto form
4. stirringAfter stirring for another 3 h at 23° C.
5. filtrationa fine white precipitate was filtered on a coarse frit
6. concentrationThe clear yellow filtrate was concentrated
7. customthe resulting yellow oil was purified by silica gel chromatography (Biotage 10 g SNAP column
8. washeluted with a 10% to 25% to 50% EtOAc/hexanes gradient)