反应详情

A mixture of isoquinolin-7-yl trifluoromethanesulfonate (Description 117, 1.04 g, 3.75 mmol), cesium carbonate (1.6 g, 4.88 mmol), benzophenone imine (747 mg, 4.13 mmol), BINAP (100 mg, 0.16 mmol) and palladium acetate (18 mg, 0.08 mmol) in tetrahydrofuran (15 ml) was degassed (N2×3) then heated at reflux for 18 h. More BINAP (100 mg, 0.16 mmol) and palladium acetate (18 mg, 0.08 mmol) were added and the reaction heated for a further 24 h. The reaction was then cooled to room temperature and partitioned between ethyl acetate (100 ml) and water (100 ml). The aqueous layer was extracted with more ethyl acetate (50 ml) and the combined organic layers were evaporated. The residue was taken up in tetrahydrofuran (40 ml) and 2N hydrochloric acid (aq. 10 ml) was added. After 2 h, the THF was evaporated, 3N hydrochloric acid (aq. 100 ml) was added and the mixture washed with ethyl acetate (2×75 ml). The aqueous layer was then basified by addition of 47% aqueous sodium hydroxide solution and extracted with dichloromethane (3×50 ml). The combined organic layers were dried (Na2SO4) and evaporated to give crude isoquinolin-7-amine (198 mg) which was reacted directly with [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61 to give the title compound (100 mg, 8%). m/z (ES+) 346 (M+H)+.

1. customwas degassed (N2×3)
2. temperaturethen heated
3. temperatureat reflux for 18 h
4. temperaturethe reaction heated for a further 24 h
5. custompartitioned between ethyl acetate (100 ml) and water (100 ml)
6. extractionThe aqueous layer was extracted with more ethyl acetate (50 ml)
7. customthe combined organic layers were evaporated
8. addition2N hydrochloric acid (aq. 10 ml) was added
9. customthe THF was evaporated
10. addition3N hydrochloric acid (aq. 100 ml) was added
11. washthe mixture washed with ethyl acetate (2×75 ml)
12. additionThe aqueous layer was then basified by addition of 47% aqueous sodium hydroxide solution
13. extractionextracted with dichloromethane (3×50 ml)
14. dry with materialThe combined organic layers were dried (Na2SO4)
15. customevaporated