反应详情

温度

-78 °C

To a THF (20 mL) solution of 3-amino-5-bromo-2-chloropyridine (1.197 g, 5.77 mmol, Asymchem, Morrisville, N.C.)) at −78° C. was added a THF solution of lithium bis(trimethylsilyl)amide (1.0 M, 11.5 mL, 11.5 mmol, Aldrich, St. Louis, Mo.). The solution was maintained for 5 min at −78° C. and then 3-(difluoromethoxy)benzenesulfonyl chloride (1.40 g, 5.77 mmol, Aldrich, St. Louis, Mo.) was added as a solid in a single portion. The solution was allowed to warm to rt, and maintained 1 h. The solution was poured into saturated aqueous NH4Cl (100 mL) and the resulting mixture was extracted with EtOAc (100 mL). The organic layer was dried (Na2SO4) and concentrated for purification by MPLC (CombiFlash® Companion®, Teledyne Isco, Lincoln, Nebr.). The residue was taken up in minimal CH2Cl2 and absorbed onto a 25 g silica loading cartridge and passed through a Redi-Sep® pre-packed silica gel column (Teledyne Isco, Lincoln, Nebr.) (120 g) using a gradient of 98:2 Hexanes:EtOAc to 100% EtOAc to afford N-(5-bromo-2-chloropyridin-3-yl)-3-(difluoromethoxy)benzenesulfonamide (2.235 g, 93.6% yield) as a colorless oil. LCMS (ESI positive ion) m/z: 414.9 (M+1); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.54 (t, J=72.38 Hz, 1H); 7.33-7.42 (m, 2H); 7.51 (t, J=8.07 Hz, 1H); 7.58 (t, J=1.91 Hz, 1H); 7.61-7.68 (m, 1H); 8.13 (d, J=2.25 Hz, 1H); 8.19 (d, J=2.25 Hz, 1H).

1. temperatureto warm to rt
2. temperaturemaintained 1 h
3. extractionthe resulting mixture was extracted with EtOAc (100 mL)
4. dry with materialThe organic layer was dried (Na2SO4)
5. concentrationconcentrated for purification by MPLC (CombiFlash® Companion®, Teledyne Isco, Lincoln, Nebr.)
6. customabsorbed onto a 25 g silica loading cartridge