反应详情

Cat. TsOH monohydrate was added to a suspension of methyl 14′-cyclohexyl-2,2-dimethylspiro[1,3-dioxane-5,7′-indolo[1,2-e][1,5]benzoxazocine]-11′-carboxylate in MeOH/THF 1:2 (0.03 M), and the solution was stirred at RT for 3 h. Filtration on a pad of neutral alumina using EtOAc as eluent afforded after evaporation of the solvent in vacuo methyl 14-cyclohexyl-7,7-bis(hydroxymethyl)-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (quant). This material was dissolved in dry MeCN (0.2M) and DIPEA (4.0 eq) and trifluoromethane sulfonic anhydride (3.5 eq) was added at 0° C. The mixture was stirred at 0° C. for 15 min, then more DIPEA (4 eq) was added at RT. Tert-butyl 4-(2-aminoethyl)piperazine-1-carboxylate (2 eq) was added, and the mixture was stirred at 70° C. for 1 h. After removal of the solvent in vacuo EtOAc was added, the solution was washed with H2O and brine, dried over Na2SO4 and the solvent was removed in vacuo. The crude methyl 1-{2-[4-(tert-butoxycarbonyl)piperazin-1-yl]ethyl}-14′-cyclohexylspiro[azetidine-3,7′-indolo[1,2-e][1,5]benzoxazocine]-11′-carboxylate was taken in DCM/TFA 3:1 (0.13M) and stirred at RT for 2 h. The mixture was evaporated to dryness and the residual material was dissolved in EtOAc. The solution was washed with sat. aq. NaHCO3 and brine. The organic phase was dried over Na2SO4 and the solvent evaporated in vacuo. The residue was dissolved in dry dioxane (0.06M) and sulfamide (5 eq) was added. The mixture was stirred at reflux for 3 h, then overnight at RT. The residue obtained after evaporation was purified by FC (EtOAc/MeOH, 9:1) to afford the title compound in 40% yield. (ES+) m/z 622 (M+H)+.

1. filtrationFiltration on a pad of neutral alumina
2. customafforded
3. customafter evaporation of the solvent in vacuo methyl 14-cyclohexyl-7,7-bis(hydroxymethyl)-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (quant)
4. dissolutionThis material was dissolved in dry MeCN (0.2M)
5. stirringThe mixture was stirred at 0° C. for 15 min
6. stirringthe mixture was stirred at 70° C. for 1 h
7. customAfter removal of the solvent in vacuo EtOAc
8. additionwas added
9. washthe solution was washed with H2O and brine
10. dry with materialdried over Na2SO4
11. customthe solvent was removed in vacuo
12. stirringstirred at RT for 2 h
13. customThe mixture was evaporated to dryness
14. dissolutionthe residual material was dissolved in EtOAc
15. washThe solution was washed with sat. aq. NaHCO3 and brine
16. dry with materialThe organic phase was dried over Na2SO4
17. customthe solvent evaporated in vacuo
18. dissolutionThe residue was dissolved in dry dioxane (0.06M)
19. stirringThe mixture was stirred
20. temperatureat reflux for 3 h
21. customovernight
22. customat RT
23. customThe residue obtained
24. customafter evaporation
25. customwas purified by FC (EtOAc/MeOH, 9:1)