反应详情

TsOH monohydrate (1 eq.) 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 (Example 2, Step 3) in MeOH/THF 1:3 (0.03 M), and the solution was stirred at RT for 6 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 (91%). Triflic anhydride (3.5 eq) was added at 0° C. to a solution of this material in dry MeCN (0.05M), DIPEA (4.0 eq) was added and the mixture was stirred at 0° C. for 15 min, then further 4.0 eq of DIPEA were added; N,N-diethylethane-1,2-diamine (2 eq) was added, and the mixture was stirred at 70° C. for 2 h. After removal of the solvent EtOAc was added, the organic phase was washed with water and brine, dried over Na2SO4 and the solvent was removed in vacuo. The residue was hydrolysed with aq. 1N KOH in dioxane (75° C., 2 h) under degassed conditions; after quenching at 0° C. with 1N HCl evaporation to dryness gave a residue that was purified by RP-HPLC to afford the title compound (TFA salt, 25%). 1H NMR (600 MHz, DMSO-d6, 300 K) 1.15-1.37 (m, 3H), 1.22 (t, 7.1, 6H), 1.57 (bd, J 11.6, 1H), 1.67-1.74 (m, 2H), 1.84 (bd, J 11.6, 1H), 1.90-2.02 (m, 3H), 2.64-2.68 (m, 1H), 3.18 (q, J 7.1, 4H), 3.24-3.30 (m, 2H), 3.74 (bs, 2H), 3.86 (d, J 10.4, 1H), 3.95 (bd, J 15, 1H), 4.09 (d, J 10.8, 1H), 4.14 (d, J 10.4, 1H), 4.24 (bd, J 12.5, 1H), 4.28 (bd, J 12.5, 1H), 4.37 (d, J 10.8, 1H), 5.21 (bd, J 15, 1H), 7.20-7.22 (m, 3H), 7.48-7.51 (m, 1H), 7.69 (d, J 8.4, 1H), 7.90 (d, J 8.4, 1H), 8.55 (s, 1H); MS (ES+) m/z 516 (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 (91%)
4. stirringthe mixture was stirred at 0° C. for 15 min
5. stirringthe mixture was stirred at 70° C. for 2 h
6. customAfter removal of the solvent EtOAc
7. additionwas added
8. washthe organic phase was washed with water and brine
9. dry with materialdried over Na2SO4
10. customthe solvent was removed in vacuo
11. customwas hydrolysed with aq. 1N KOH in dioxane (75° C., 2 h) under degassed conditions
12. customafter quenching at 0° C. with 1N HCl evaporation to dryness
13. customgave a residue that
14. customwas purified by RP-HPLC