反应详情

Hydrogenate a mixture of (E)-[4-(3-fluoro-6H-dibenzo[b,e]oxepin-11-ylidenemethyl)-2-nitro-phenyl]-((7R,8aR)-hexahydro-pyrrolo[2,1-c][1,4]oxazin-7-yl)-amine (52 g, 0.107 mol), triethylamine (33 mL, 0.237 mol) and 5% platinum on carbon (18 g) in tetrahydrofuran (450 mL) at room temperature at 50 psi for 2 h. Filter off the catalyst, rinse with tetrahydrofuran, and concentrate to obtain a brown foam. Dissolve the foam in anhydrous tetrahydrofuran (500 mL) and cool in an ice bath. Add triphosgene (31.5 g, 0.106 mol) in tetrahydrofuran (450 mL) dropwise over 30 min and stir at room temperature for 16 h. Concentrate the solution, dissolve in 5% methanol in dichloromethane and purify through a short silica gel plug. Concentrate to obtain a brown solid. Suspend the solid in saturated sodium bicarbonate (1.5 L) and stir on the rotary evaporator for one hour. Filter and dry in vacuo. Dissolve in warm 1:1 methanol/dichloromethane (approximately 6 L) and treat with poly (4-vinylpyridine) 2% cross-linked resin (170 g). Stir the slurry for 30 min and filter through diatomaceous earth. Concentrate the filtrate to approximately 1.5 L volume and collect the resulting solids by filtration. Dry at 80° C./20 mm Hg overnight to obtain the title compound as a white solid (38.1 g, 74%). [α]D20−20.5 (c=1.0 in DMSO). 1H NMR (400 MHz, DMSO-d6) δ 1.48 (m, 1H), 2.02 (m, 1H), 2.19 (m, 2H), 2.52 (m, 1H), 2.91 (d, 1H), 3.03 (d, 1H), 3.25 (t, 1H), 3.50 (t, 1H), 3.79 (d, 1H), 3.88 (d, 1H), 4.95 (m, 1H), 5.03 (broad s, 1H), 5.60 (broad s, 1H), 6.59 (m, 2H), 6.78 (m, 2H), 6.97 (s, 1H), 7.02 (d, 1H), 7.25 (t, 1H), 7.38 (t, 1H), 7.48-7.61 (m, 3H), 10.72 (s, 1H, NH). LC-MS m/z 484.0 [M+H]+.

1. filtrationFilter off the catalyst
2. washrinse with tetrahydrofuran
3. concentrationconcentrate
4. customto obtain a brown foam
5. temperaturecool in an ice bath
6. concentrationConcentrate the solution
7. dissolutiondissolve in 5% methanol in dichloromethane
8. custompurify through a short silica gel plug
9. concentrationConcentrate
10. customto obtain a brown solid
11. stirringstir on the rotary evaporator for one hour
12. filtrationFilter
13. customdry in vacuo
14. dissolutionDissolve
15. temperaturein warm 1:1 methanol/dichloromethane (approximately 6 L)
16. additiontreat with poly (4-vinylpyridine) 2% cross-linked resin (170 g)
17. stirringStir the slurry for 30 min
18. filtrationfilter through diatomaceous earth
19. concentrationConcentrate the filtrate to approximately 1.5 L volume
20. customcollect the resulting solids
21. filtrationby filtration
22. customDry at 80° C./20 mm Hg overnight