4-(4-Bromobenzyl)morpholine → 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-[4-(morpholin-4-ylmethyl)phenyl]pyrimidin-2-amine

関与物質

反応条件

反応手順

Tris(dibenzylideneacetone)dipalladium(0) (0.494 g, 0.54 mmol) and9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (0.375 g, 0.65 mmol) were dissolved in toluene (160 mL) in a 1 L reactor equipped with a condensor and activated at 100 °C for 6 min under argon. Then 5-fluoro-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amine (9.98 g, 36 mmol), 4-(4-bromobenzyl)morpholine (9.48 g, 37 mmol), Sodium tert- pentoxide (6.34 g, 57.60 mmol) and toluene (200 mL) were added. The reaction mixture became sticky yellowish green. It was stirred at 100 °C under argon. The reaction was followed by HPLC. After 3 h no conversion was obtained. The mixture was stirred overnight but the conversion did not move. Then the mixture was cooled to 50 ºC, Pd-complex (5 mol%) and Xantphos (6 mol%) as preactivated catalyst in toluene (100 ml) were added to the mixture, it was degassed carefully, then it was put under argon. Then the reaction mixture was heated at 100 ºC. After 1 h full conversion was detected. The reaction mixture was cooled to room temperature, diluted with dichloromethane (600 mL), extracted with water (4*500 mL), washed with brine (1*500 mL) and dried over Na2SO4. Filtration and concentration afforded orange brown solid. This solid was slurried in EtOAc ( 50 mL) and stirred at reflux point (78 °C) for 10 min. Then it was cooled to room temperature with stirring and filtered. The filtercake was washed with _n_ -pentane (80 mL). Orange filtercake was obtained which still had some impurity. The above obtained orange filtercake was slurried in EtOAc (80 mL) and stirred at 80 °C for 30 min. Then it was cooled to room t emperature and the precipitation was filtered. Yellow fine powder was obtained.

情報源と証拠