反应详情

A round-bottom flask was charged with tert-butyl 4-(2-(7-((perfluorophenoxy)sulfonyl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (INTERMEDIATE AA, 37.7 mg, 0.053 mmol), pyrazin-2-amine (7.61 mg, 0.080 mmol, TCI America, Portland, Oreg.), and THF (1 mL) to give a clear, colorless solution. The flask was cooled in a dry ice-acetone bath for 5 min, then lithium bis(trimethylsilyl)amide (1M in THF) (112 μL, 0.112 mmol) was added dropwise over 30 s to give a light-yellow solution. After 20 min, the flask was lowered into an ice bath. After another 30 min, TFA (3 drops) was added via syringe, and the mixture was concentrated. The residue was dissolved in DCM (1 mL) and TFA (0.5 mL). After 20 min, the mixture was concentrated, and the residue was dissolved in MeOH and loaded onto a 500 mg SCX-2 ion exchange column. The column was eluted with MeOH then with 2N ammonia in methanol. The basic fraction was concentrated. The residue was further purified by chromatography on silica gel (12 g column, 10% MeOH/DCM, then 20% of a 2N ammonia in methanol solution dissolved in DCM) to give N-(pyrazin-2-yl)-4-(2-(1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (13.49 mg, 0.026 mmol) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.08 (s, 1 H), 8.02 (s, 1 H), 7.86 (br. s., 1 H), 7.72 (dd, J=1.7, 8.6 Hz, 2 H), 7.59 (d, J=1.9 Hz, 1 H), 7.54 (d, J=8.1 Hz, 1 H), 6.43 (d, J=8.5 Hz, 1 H), 5.87 (br. s., 1 H), 4.27 (br. s., 2 H), 3.61-3.53 (m, J=6.1 Hz, 5 H), 3.09 (br. s., 2 H), 2.39-2.30 (m, 1 H). m/z (ESI) 518.4 (M+H)+.

1. customto give a clear, colorless solution
2. temperatureThe flask was cooled in a dry ice-acetone bath for 5 min
3. customto give a light-yellow solution
4. customthe flask was lowered into an ice bath
5. waitAfter another 30 min
6. concentrationthe mixture was concentrated
7. dissolutionThe residue was dissolved in DCM (1 mL)
8. waitAfter 20 min
9. concentrationthe mixture was concentrated
10. dissolutionthe residue was dissolved in MeOH
11. washThe column was eluted with MeOH
12. concentrationThe basic fraction was concentrated
13. customThe residue was further purified by chromatography on silica gel (12 g column, 10% MeOH/DCM
14. dissolution20% of a 2N ammonia in methanol solution dissolved in DCM)