反应详情

A vial was charged with 1-(4-chloro-2-methoxyphenyl)-N-(4-methoxybenzyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (INTERMEDIATE BBBBB, 42.9 mg, 0.078 mmol), (4-fluorophenyl)boronic acid (21.95 mg, 0.157 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (1.610 mg, 3.92 μmol), chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(ii) dichloromethane (2.97 mg, 3.92 μmol), and potassium phosphate (49.9 mg, 0.235 mmol). The vial was flushed with Ar (g), then THF (0.4 mL) and water (0.04 mL) were added in sequence. The vial was sealed and placed in a 110° C. heating bath overnight, then the mixture was cooled and extracted with EtOAc (3×). The combined organic extracts were concentrated. The residue was taken up in DCM (1 mL), TFA (0.5 mL), and triflic acid (0.05 mL) (8:40 am). After 45 min, the mixture was concentrated. The residue was taken up in EtOAc. The organic solution was washed with saturated aq. sodium bicarbonate solution (2×), dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (25-g Interchim 15 micron column, 10% MeOH/DCM) to give 1-(4′-fluoro-3-methoxy-[1,1′-biphenyl]-4-yl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (28.7 mg, 0.059 mmol, 75% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=13.04 (s, 1H), 8.69 (d, J=5.8 Hz, 1H), 8.64 (d, J=1.5 Hz, 1H), 8.56 (s, 1H), 8.23 (d, J=6.2 Hz, 1H), 8.09 (d, J=5.4 Hz, 1H), 7.95 (dd, J=1.9, 8.9 Hz, 1H), 7.91-7.83 (m, 2H), 7.78 (d, J=8.9 Hz, 1H), 7.46-7.39 (m, 3H), 7.38-7.31 (m, 2H), 7.02 (d, J=6.4 Hz, 1H), 3.75 (s, 3H). m/z (ESI) 487.2 (M+H)+.

1. customThe vial was flushed with Ar (g)
2. additionTHF (0.4 mL) and water (0.04 mL) were added in sequence
3. customThe vial was sealed
4. customplaced in a 110° C.
5. temperatureheating bath overnight
6. temperaturethe mixture was cooled
7. extractionextracted with EtOAc (3×)
8. concentrationThe combined organic extracts were concentrated
9. concentrationthe mixture was concentrated
10. washThe organic solution was washed with saturated aq. sodium bicarbonate solution (2×)
11. dry with materialdried over sodium sulfate
12. filtrationfiltered
13. concentrationconcentrated
14. customThe residue was purified by chromatography on silica gel (25-g Interchim 15 micron column, 10% MeOH/DCM)