反应详情

A mixture of 2-(aminomethyl)-1,1,1-trifluoro-4-[5-fluoro-2-(methyloxy)phenyl]-4-methyl-2-pentanol (Intermediate 18, 743 mg, 2.4 mmol), 4-bromo-6-methyl-1-[3-(methyloxy)phenyl]-1H-indazole (Intermediate 16, 657 mg, 2.07 mmol), tris(dibenzylideneacetone)dipalladium(0) (117 mg, 0.13 mmol), racemic-BINAP (141 mg, 0.23 mmol) and sodium tert-butoxide (429 mg, 4.46 mmol) in toluene (30 mL) was heated under reflux in an atmosphere of nitrogen for 2 hours. The mixture was cooled, combined with crude product from a similar smaller scale preparation (260 mg input of Intermediate 18), and diluted with toluene (100 mL) and ethyl acetate (50 mL). The resulting solution was washed successively with 1M hydrochloric acid (75 mL), 8% aqueous sodium bicarbonate (75 mL) and brine (75 mL), passed through a hydrophobic rit and evaporated under reduced pressure. The residue was purified by silica gel chromatography using the Flashmaster II (70 g cartridge) eluting with a 0:100 to 50:50 cyclohexane:ethyl acetate gradient over 60 minutes to give impure product (970 mg). Further purification using the Flashmaster II (100 g cartridge) eluting with a 100:0 to 75:25 dichloromethane:tert-butyl methyl ether gradient over 50 minutes gave the title compound (72 mg). A quantity of less pure material (137 mg) was also obtained.

1. temperatureunder reflux in an atmosphere of nitrogen for 2 hours
2. temperatureThe mixture was cooled
3. washThe resulting solution was washed successively with 1M hydrochloric acid (75 mL), 8% aqueous sodium bicarbonate (75 mL) and brine (75 mL)
4. customevaporated under reduced pressure
5. customThe residue was purified by silica gel chromatography
6. washeluting with a 0:100 to 50:50 cyclohexane