反应详情

To a vial charged with 2-(5-fluoro-2H-benzo[b][1,4]oxazin-4(3H)-yl)-5-(trifluoromethyl)benzonitrile (0.445 g, 1.381 mmol) was added DCM (5.52 ml). The resulting solution was cooled in an ice water bath prior to the addition of chlorosulfonic acid (0.367 ml, 5.52 mmol), faster than dropwise. After 90 mins of stirring LC-MS of the resulting yellow/brown suspension indicated two peaks (˜2:1) with desired product mass as the main mass (M+23) with consumption of starting material. The mixture was added to ice, diluted with water and extracted with EtOAc (2×). The combined organics were dried under reduced pressure and purified with a 40 HP spherical silica column (15 m spherical, Interchim) ramping EtOAc in heptane (0-35%, 10% DCM throughout) yielding near complete separation of isomers. NMR analysis of the first eluted peak confirmed the desired regiochemistry 4-(2-cyano-4-(trifluoromethyl)phenyl)-5-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl chloride (0.123 g, 0.292 mmol, 21.17% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.91-4.02 (m, 2 H) 4.37 (br. s., 2 H) 6.97 (dd, J=9.10, 1.56 Hz, 1 H) 7.20 (d, J=8.61 Hz, 1 H) 7.64 (dd, J=9.10, 7.34 Hz, 1 H) 7.77 (dd, J=8.61, 2.15 Hz, 1 H) 7.97 (d, J=1.76 Hz, 1 H). m/z (ESI) 443.1 (M+Na)+.

1. temperatureThe resulting solution was cooled in an ice water bath
2. customtwo peaks (˜2:1) with desired product mass as the main mass (M+23) with consumption of starting material
3. additionThe mixture was added to ice
4. additiondiluted with water
5. extractionextracted with EtOAc (2×)
6. customThe combined organics were dried under reduced pressure
7. custompurified with a 40 HP spherical silica column (15 m spherical, Interchim)
8. customyielding near complete separation of isomers