反应详情

To a suspension of ketone 5 (10.4 g, 0.045 mol) in 2-PrOH (520 mL) was added methylamine (33.7 mL of a 2.0 M solution in THF, 0.067 mol). A clear, amber solution formed after ca 15 minutes, and a precipitate gradually formed a few minutes later. After 1.5 hours, the reaction mixture was cooled in an ice/water bath, NaBH4 (2.6 g, 0.067 mol) was added, and stirring was continued at 0° C. for 35 minutes. The reaction mixture was stirred at room temperature for 15 hours. MeOH (ca 2 mL) was added to quench any excess NaBH4 (no gas evolution was observed), and the solvents were removed under reduced pressure. The residue was partitioned between 1N HCl (500 mL) and EtOAc (250 mL). The aqueous layer was separated, adjusted to pH 7-8 with solid NaHCO3, and washed with EtOAc (200 mL). A precipitate formed during the wash, which was collected by vacuum filtration and dried to give 6-[trans-4-(methylamino)cyclohexyl]-3H-benzoxazol-2-one 15 (5.0 g, 46%). The organic layer was separated, and TLC analysis (89:10:1 CH2Cl2:MeOH:NH4OH) showed it contained compound 15. Compound 15 was also shown by TLC analysis to be present in the initial EtOAc extraction. The organic extracts were combined, concentrated under reduced pressure, dissolved in a minimal amount of MeOH, and a solid was precipitated out with diethyl ether. The solid was collected by vacuum filtration and dried to give 15 (1.6 g, 13%) as the HCl salt. To the aqueous layer (ca 1L), which also showed the presence of additional 15 by TLC, was added solid NaCl (ca 80 g), and the solution was concentrated under reduced pressure to approximately half its original volume. A solid formed and was collected by vacuum filtration and dried to give 15 (1.3 g, 12%). The solids were combined to give 6-[trans-4-(methylamino)cyclohexyl]-3H-benzoxazol-2-one 15 (7.9 g, 73%): 1H NMR (500 MHz, CD3OD): δ 7.10 (d, J=1.5 Hz, 1H), 7.03 (dd, J=8, 1.5 Hz, 1H), 6.98 (d, J=8 Hz, 1H), 2.67-2.52 (m, 2H), 2.49 (s, 3H), 2.15-2.12 (m, 2H), 1.97-1.94 (m, 2H), 1.61-1.52 (mi, 2H), 1.38-1.30 (m, 2H).

1. customA clear, amber solution formed after ca 15 minutes
2. customa precipitate gradually formed a few minutes
3. temperaturethe reaction mixture was cooled in an ice/water bath
4. waitwas continued at 0° C. for 35 minutes
5. stirringThe reaction mixture was stirred at room temperature for 15 hours
6. customto quench any excess NaBH4 (no gas evolution
7. customwere removed under reduced pressure
8. customThe residue was partitioned between 1N HCl (500 mL) and EtOAc (250 mL)
9. customThe aqueous layer was separated
10. washwashed with EtOAc (200 mL)
11. customA precipitate formed during the wash, which
12. filtrationwas collected by vacuum filtration
13. customdried