反应详情

To a vial charged with N-(4-methoxybenzyl)thiazol-2-amine (0.071 g, 0.322 mmol) was added THF (0.955 ml) and the mixture cooled in an ice water bath prior to the addition of lithium bis(trimethylsilyl)amide, 1.0M solution in tetrahydrofuran (0.351 ml, 0.351 mmol), faster than dropwise. After 15 mins of stirring a solution of 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) in THF (0.5 ml) was added dropwise, then washed with 0.2 ml THF and added. The mixture was stirred for 1 hr (ice melt) providing a turbid brown mixture with product as the primary species according to LC-MS (m/z=605). To the turbid brown solution was added MeOH and the mixture dried under reduced pressure. To the crude residue was added DCM (2 ml) and TFA (0.2 ml). After 2 hr the mixture was dried under reduced pressure and purified with a 25 g SNAP column ramping EtOAc in heptane (0-75%, 10% DCM throughout) to yield product as a sticky white solid which was lyophilized from MeOH/H2O affording product as a fluffy white solid, 4-(2-cyano-4-(trifluoromethyl)phenyl)-5-fluoro-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.074 g, 0.153 mmol, 52.3% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.39 (br. s., 2 H) 3.80-4.20 (m, 2 H) 6.87 (d, J=4.50 Hz, 1 H) 7.12 (dd, J=10.71, 2.01 Hz, 1 H) 7.20 (t, J=1.66 Hz, 1 H) 7.30 (d, J=4.69 Hz, 1 H) 7.41 (d, J=8.80 Hz, 1 H) 7.91-7.96 (m, 1 H) 8.35 (d, J=2.15 Hz, 1 H) 12.83 (br. s., 1 H). m/z (ESI) 485.2 (M+H)+.

1. temperaturethe mixture cooled in an ice water bath
2. additionwas added dropwise
3. washwashed with 0.2 ml THF
4. additionadded
5. customproviding a turbid brown mixture with product as the primary species
6. customthe mixture dried under reduced pressure
7. additionTo the crude residue was added DCM (2 ml) and TFA (0.2 ml)
8. customAfter 2 hr the mixture was dried under reduced pressure
9. custompurified with a 25 g SNAP column
10. customto yield product as a sticky white solid which