反应详情

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)+.

1. temperaturethe mixture cooled in an ice water bath
2. customproviding a brown solution and product as the primary species
3. additionThe solution was added to ice
4. extractionextracted with water (brine added to help resolve emulsion)
5. customThe layers were separated
6. extractionthe aqueous phase was extracted with EtOAc
7. dry with materialThe combined organics were dried with Na2SO4
8. filtrationfiltered
9. customdried under reduced pressure
10. additionTo the crude material was added DCM (70 ml)
11. temperaturethe resulting light brown solution cooled in an ice water bath
12. additionto the addition of TFA (20 ml)
13. customaffording a purplish solution
14. concentrationThe mixture was concentrated under reduced pressure
15. customthe resulting brownish oil purified with a 330 g ISCO gold column
16. customThe solid was triturated with MeOH