反应详情

温度

22.5 °C

Sodium hydride (12.18 g, 55-65% m/m, Fluka 71620) is suspended in tetrahydrofuran (60 mL) and a solution of 4-methylimidazole (24.5 g) in tetrahydrofuran (65 mL) is slowly added to the stirred suspension at 20-25° C. Gentle cooling is necessary to maintain the temperature at 20-25° C. during the addition. After completion of the addition, the reaction mixture is stirred for additional 15 minutes at 20-25° C., until gas evolution had ceased. A solution of 3-fluoro-5-trifluoromethyl-phenylamine (XIX) (25 g) in 1-methyl-2-pyrrolidone (125 mL) is added slowly to the reaction mixture and the mixture is stirred for additional 15 minutes at 20-25° C. Then, the reaction mixture is heated at an oil bath temperature of 100° C. to distill off the volatile solvent (tetrahydrofuran). Finally, the temperature is raised to 165° C. (oil bath) and the reaction mixture is stirred for 22 hours at this temperature. For work up, the reaction mixture is poured onto water (500 mL) and the water phase is extracted with t-butyl methyl ether (2×500 mL). The t-butyl methyl ether phases are combined and are extracted with water (2×500 mL). The organic layer is dried on anhydrous magnesium sulfate (19 g) and the solvent is evaporated at 45° C. under reduced pressure to obtain crude 3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenylamine as a yellowish solid. The crude product is contaminated with at least 1 regioisomer. The crude product is dissolved in toluene (93.4 g) at 80-90° C. and the solution is allowed to cool down to room temperature. Crystallization occurred at ca. 35-40° C. The suspension is stirred for additional 2 hours at room temperature and the product is isolated by filtration. The filter cake is washed with ice-cold toluene (25 mL) and dried in vacuo at 50° C. to obtain pure 5-(4-methyl-imidazol-1-yl)-3-trifluoromethyl-phenylamine (I). GC-MS: m/z 241, 222, 213, 200, 186, 172, 160.

1. temperatureGentle cooling
2. additionduring the addition
3. additionAfter completion of the addition
4. stirringthe mixture is stirred for additional 15 minutes at 20-25° C
5. temperatureThen, the reaction mixture is heated at an oil bath temperature of 100° C.
6. distillationto distill off the volatile solvent (tetrahydrofuran)
7. temperatureFinally, the temperature is raised to 165° C. (oil bath)
8. stirringthe reaction mixture is stirred for 22 hours at this temperature
9. additionFor work up, the reaction mixture is poured onto water (500 mL)
10. extractionthe water phase is extracted with t-butyl methyl ether (2×500 mL)
11. extractionare extracted with water (2×500 mL)
12. dry with materialThe organic layer is dried on anhydrous magnesium sulfate (19 g)
13. customthe solvent is evaporated at 45° C. under reduced pressure
14. customto obtain crude 3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenylamine as a yellowish solid
15. temperatureto cool down to room temperature
16. customCrystallization
17. customoccurred at ca. 35-40° C
18. stirringThe suspension is stirred for additional 2 hours at room temperature
19. customthe product is isolated by filtration
20. washThe filter cake is washed with ice-cold toluene (25 mL)
21. customdried in vacuo at 50° C.