N-[(4-methoxyphenyl)methyl]-1,3-thiazol-2-amine → 4-(2-cyano-4-(trifluoromethyl)phenyl)-6-fluoro-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide

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Reaction Steps

To a vial charged with N-(4-methoxybenzyl)thiazol-2-amine (2.83 g, 12.86 mmol) was added THF (38.2 ml) and the mixture cooled in an ice water bath prior to the addition of lithium bis(trimethylsilyl)amide, 1.0M solution in tetrahydrofuran (14.03 ml, 14.03 mmol), faster than dropwise. After 15 min, a solution of 4-(2-cyano-4-(trifluoromethyl)phenyl)-6-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl chloride (4.92 g, 11.69 mmol) in THF (30 ml) was added. The mixture was allowed to warm to rt over 1.5 h, providing a brown solution and product as the primary species according to LC-MS (m/z=605). The solution was added to ice, diluted with EtOAc and extracted with water (brine added to help resolve emulsion). The layers were separated and the aqueous phase was extracted with EtOAc. The combined organics were dried with Na2SO4, filtered, and dried under reduced pressure. To the crude material was added DCM (70 ml) and the resulting light brown solution cooled in an ice water bath prior to the addition of TFA (20 ml) and the mixture stirred at 0° C. for 20 mins and at room temperature for 1 h affording a purplish solution. The mixture was concentrated under reduced pressure and the resulting brownish oil purified with a 330 g ISCO gold column ramping EtOAc in heptane (0-45%, then isocratic at 45% with 10% DCM isocratic throughout, sample loaded with DCM providing product (˜3.9 g) as a slightly off-white solid. The solid was triturated with MeOH to afford a white solid, 4-(2-cyano-4-(trifluoromethyl)phenyl)-6-fluoro-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (3.208 g, 6.62 mmol, 56.6% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.80-3.88 (m, 2 H) 4.28-4.35 (m, 2 H) 6.64 (d, J=11.64 Hz, 1 H) 6.84 (d, J=4.69 Hz, 1 H) 7.23 (d, J=6.75 Hz, 1 H) 7.27 (d, J=4.60 Hz, 1 H) 7.77 (d, J=8.61 Hz, 1 H) 8.09 (dd, J=8.90, 1.96 Hz, 1 H) 8.41 (d, J=1.66 Hz, 1 H) 12.81 (s, 1 H). m/z (ESI) 485.2 (M+H)+.

Provenance & Evidence