反应详情

A roundbottom 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, 48.52 mg, 0.069 mmol), pyrimidin-2-amine (7.84 mg, 0.082 mmol), and THF (343 μl) to give a clear, lightly-colored solution. The flask was cooled in an ice-bath for 5 min, then lithium bis(trimethylsilyl)amide (1M in THF) (144 μl, 0.144 mmol) was added dropwise over 30 s to give a light-yellow solution. After 5 min, the cooling bath was removed. After 20 min, the mixture was diluted with TFA (0.5 mL), then concentrated. The residue was taken up in DCM (1 mL) and TFA (0.5 mL) and stirred for 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, eluting with 5 to 10% MeOH/DCM, then with 20 to 40% of 2N ammonia in methanol solution dissolved in DCM). The fractions containing product were combined and concentrated. The residue was taken up in DCM and filtered through cotton. The filtrate was concentrated, and the residue was taken up in 10% MeOH/DCM and filtered through cotton. The filtrate was concentrated to give N-(pyrimidin-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 (13.66 mg, 0.026 mmol) as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.37 (d, J=4.7 Hz, 2 H), 7.69 (d, J=8.5 Hz, 1 H), 7.59-7.48 (m, 2 H), 7.33 (s, 1 H), 7.25 (dd, J=1.8, 8.6 Hz, 1 H), 6.83 (t, J=4.6 Hz, 1 H), 6.41 (d, J=8.6 Hz, 1 H), 5.83 (br. s., 1 H), 4.25 (br. s., 2H), 3.59 (br. s., 2 H), 3.38 (br. s., 2 H), 2.87 (br. s., 2 H), 2.33 (br. s., 1 H), 2.23 (br. s., 1 H). m/z (ESI) 518.4 (M+H)+.

1. customto give a clear, lightly-colored solution
2. temperatureThe flask was cooled in an ice-bath for 5 min
3. customto give a light-yellow solution
4. customthe cooling bath was removed
5. waitAfter 20 min
6. additionthe mixture was diluted with TFA (0.5 mL)
7. concentrationconcentrated
8. concentrationThe mixture was concentrated
9. dissolutionthe residue was dissolved in MeOH
10. washThe column was eluted with MeOH
11. concentrationThe basic fraction was concentrated
12. customThe residue was further purified by chromatography on silica gel (12 g
13. washeluting with 5 to 10% MeOH/DCM
14. dissolutionwith 20 to 40% of 2N ammonia in methanol solution dissolved in DCM)
15. additionThe fractions containing product
16. concentrationconcentrated
17. filtrationfiltered through cotton
18. concentrationThe filtrate was concentrated
19. filtrationfiltered through cotton
20. concentrationThe filtrate was concentrated