Reaction Steps
A catalytic amount of 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 (as prepared in Example 2, Step 3) 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 with EtOAc afforded after removal 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). Triflic anhydride (2.8 eq) was added at 0° C. to a solution of this material in dry MeCN (0.05M), DIPEA (3.0 eq) was added and the mixture was stirred at 0° C. for 15 min, then further 3.0 eq of DIPEA were added; iPrNH2 (2 eq) was added, the mixture was transferred to a closed vessel and stirring was continued at 70° C. for 4 h. 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 (65° C., overnight); evaporation to dryness gave a residue that was purified by RP-HPLC affording the title compound (15%) and 14′-cyclohexyl-1-isopropylspiro[azetidine-3,7′-indolo[1,2-e][1,5]benzoxazocine]-111′-carboxylic acid (4%). 1H NMR (400 MHz, DMSO-d6, 330 K) δ 1.14-1.38 (m, 3H), 1.56-2.04 (m, 7H), 2.64-2.76 (m, 1H), 3.87 (d, J 15.6, 1H), 4.11 (d, J 6.1, 1H), 4.17 (d, J 12.5, 1H), 4.36 (d, J 6.1, 1H), 4.44 (d, J 12.5, 1H), 4.55 (d, J 6.3, 1H), 4.59 (d, J 6.1, 1H), 5.14 (d, J 15.4, 1H), 7.20-7.24 (m, 3H), 7.47 (bt, J 6.6, 1H), 7.66 (d, J 8.3, 1H), 7.85 (d, J 8.3, 1H), 8.38 (s, 1H); MS (ES+) m/z 418 (M+H)+.
