反应详情

A round-bottom flask was charged with N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (33.3 mg, 0.172 mmol) and THF (718 μl) to give a clear solution. The flask was cooled in a dry ice-acetone bath for 5 min, then lithium bis(trimethylsilyl)amide (1M in THF) (172 μl, 0.172 mmol) was added drop wise. The flask was removed from the cooling bath for 3 min, then recooled in the bath. A solution of perfluorophenyl 1-(4-chloro-2-methoxyphenyl)isoquinoline-6-sulfonate (INTERMEDIATE NNN, 74.12 mg, 0.144 mmol) in THF (0.6 mL with a 0.4 mL-flask wash) was added drop wise. After another minute, the flask was transferred to an ice-water bath. After 10 min of stirring, the mixture was concentrated, and the residue was taken up in DCM (1 mL) and TFA (0.5 mL). The mixture was stirred for 30 min, then diluted with MeOH and concentrated. The residue was purified by chromatography on silica gel (25-g Interchim column, 25-75% EtOAc/Heptane) to give white solid. The solid was taken up in EtOAc, filtered, washed with EtOAc (3×), dried under a stream of N2 (g), then dried under vacuum to give 1-(4-chloro-2-methoxyphenyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (25.5 mg, 0.059 mmol, 41.0% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=8.69 (d, J=5.7 Hz, 1H), 8.57 (d, J=1.9 Hz, 1H), 8.48 (s, 1H), 8.13 (d, J=5.6 Hz, 1H), 7.89-7.89 (m, 0H), 7.91-7.81 (m, 1H), 7.75 (d, J=8.9 Hz, 1H), 7.37 (d, J=8.1 Hz, 1H), 7.32 (d, J=1.9 Hz, 1H), 7.20 (dd, J=1.9, 8.1 Hz, 1H), 3.68 (s, 3H). m/z (ESI) 433.0 (M+H)+.

1. customto give a clear solution
2. temperatureThe flask was cooled in a dry ice-acetone bath for 5 min
3. customThe flask was removed from the cooling bath for 3 min
4. additionwas added drop wise
5. customAfter another minute, the flask was transferred to an ice-water bath
6. concentrationthe mixture was concentrated
7. stirringThe mixture was stirred for 30 min
8. additiondiluted with MeOH
9. concentrationconcentrated
10. customThe residue was purified by chromatography on silica gel (25-g Interchim column, 25-75% EtOAc/Heptane)
11. customto give white solid
12. filtrationfiltered
13. washwashed with EtOAc (3×)
14. dry with materialdried under a stream of N2 (g)
15. customdried under vacuum