反应详情

To a solution of 3,5-difluoro-4-(4-methoxy-benzylamino)-benzoic acid (9.00 g, 30.7 mmol) obtained in Step B in acetonitrile (150 ml), N-ethyldiisopropylamine (16.0 ml, 92.1 mmol), HOBt (4.15 g, 30.7 mmol) and WSCI (5.88 g, 30.7 mmol) were added, followed by stirring at room temperature for 10 minutes. To this, 1-ethyl-piperazine (4.68 ml, 368 mmol) was added, followed by stirring at room temperature for 62 hours. N-Ethyldiisopropylamine (5.35 ml, 30.7 mmol), HOBt (2.07 g, 15.3 mmol) and WSCI (2.94 g, 15.3 mmol) were added at room temperature, followed by stirring for 22 hours. The solvent was distilled off under reduced pressure, followed by dissolution in ethyl acetate (300 ml), which was washed with saturated aqueous sodium chloride solution (100 ml) and saturated sodium hydrogencarbonate aqueous solution (100 ml). Subsequently, the organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. This was purified by silica gel column chromatography (dichloromethane/methanol=50/1 to 25/1), to obtain the desired compound as a brown oil (11.8 g, 99%).

1. stirringby stirring at room temperature for 62 hours
2. stirringby stirring for 22 hours
3. distillationThe solvent was distilled off under reduced pressure
4. dissolutionfollowed by dissolution in ethyl acetate (300 ml)
5. washwhich was washed with saturated aqueous sodium chloride solution (100 ml) and saturated sodium hydrogencarbonate aqueous solution (100 ml)
6. dry with materialSubsequently, the organic layer was dried over sodium sulfate
7. distillationthe solvent was distilled off under reduced pressure
8. customThis was purified by silica gel column chromatography (dichloromethane/methanol=50/1 to 25/1)