Trifluoroacetic acid → 4-(2-methoxy-4-(trifluoromethyl)phenyl)-3-oxo-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide

Participants

Reaction Steps

To a vial charged with 4-(2-methoxy-4-(trifluoromethyl)phenyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl chloride (120 mg, 0.285 mmol) and N-(4-methoxybenzyl)-1,2,4-thiadiazol-5-amine (69.3 mg, 0.313 mmol) was added THF (948 μl) and the mixture cooled in a dry ice bath at −78 C. Then lithium bis(trimethylsilyl)amide (341 μl, 0.341 mmol) was added dropwise. The mixture was stirred at −78 C for 30 min, then warmed to 0 C for 30 min until conversion to the product by LCMS. The solution was added to ice, diluted with EtOAc (5 mL) and brine (5 mL) and extracted three times with EtOAc (3×5 mL). The combined organics were dried with Na2SO4, filtered, and dried under reduced pressure. To the crude material was added DCM (1 ml) and TFA (548 μl, 7.11 mmol) and the mixture stirred at rt for 1 hr until deprotection occurred by LCMS. The mixture was concentrated and purified using reverse-phase HPLC with a Waters-Xbridge C18, 19×100 mm, 10 m column with a gradient 5-95% acetonitrile and water with 0.1% TFA to give 4-(2-methoxy-4-(trifluoromethyl)phenyl)-3-oxo-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (80 mg, 0.164 mmol, 57.0% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 3.81 (s, 3 H) 4.89 (s, 2 H) 6.38 (d, J=8.42 Hz, 1 H) 7.31 (dd, J=8.45, 1.86 Hz, 1 H) 7.36 (d, J=1.89 Hz, 1 H) 7.50 (d, J=8.08 Hz, 1 H) 7.55-7.62 (m, 2 H) 8.15 (s, 1 H). m/z ESI 485.0 (M−H)−.

Provenance & Evidence