Reaction Steps
To a stirred solution of methyl 7H-indolo[2,1-a][2]benzazepine-10-carboxylate, 13-cyclohexyl, 6-carboxylic acid, 3-methoxy (200 mg, 0.45 mmol), 2-(methylamino)-1-morpholinoethanone (86 mg, 0.54 mmol) and triethylamine (0.19 mL) in DMF (3 mL) was added HATU (205 mg, 0.54 mmol). The reaction mixture was stirred at rt for 2 h, diluted with H2O (˜12 mL) and the resulting solids were collected by filtration, washed with H2O and dried on the filter with aspirator vacuum for 1 h. The solids were dissolved into THF/MeOH (1:1, 4 mL) and 1M NaOH (aq.) (1.0 mL, 1.0 mmol). The reaction mixture was heated in a sealed tube with microwave irradiation at 85° C. for 20 min. The reaction was cooled, neutralized with 1M HCl (aq.) (1.0 mL, 1.0 mmol) and concentrated. The residue was slurried with H2O and the solids were collected by filtration, flushed with H2O, dried and purified by preparative HPLC (MeOH/H2O with an NH4OAc buffer) to yield 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-3-methoxy-6-[[methyl[2-(4-morpholinyl)-2-oxoethyl]amino]carbonyl]- (163 mg, 0.29 mmol, 63%) as a yellow solid and 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, 6-[[(carboxymethyl)methylamino]carbonyl]-13-cyclohexyl-3-methoxy- (13 mg, 0.03 mmol, 6%) as a yellow solid. Data for 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-3-methoxy-6-[[methyl[2-(4-morpholinyl)-2-oxoethyl]amino]carbonyl]-: 1HNMR (300 MHz, CDCl3) δ 8.26 (br s. 1H), 7.85 (d, J=8.4 Hz, 1H), 7.74 (dd, J=1.1, 8.4 Hz, 1H), 7.48 (d, J=8.8 Hz, 1H), 7.03 (dd, J=2.7, 8.8 Hz, 1H), 7.00-6.92 (m, 1H), 6.89 (br s, 1H), 5.23-5.06 (m, 1H), 4.47-4.31 (m, 1H), 3.87 (s, 3H), 3.78-3.37 (m, 6H), 3.05-2.73 (m, 5H), 2.13-1.69 (m, 6H), 2.08 (s, 3H), 1.46-1.13 (m, 4H). LCMS: m/e 570 (M−H)−, ret time 1.38 min, column A, 2 minute gradient. Data for 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, 6-[[(carboxymethyl)methylamino]carbonyl]-13-cyclohexyl-3-methoxy-. 1HNMR (300 MHz, DMSO-d6) δ 8.09 (s. 1H), 7.82 (d, J=9.5 Hz, 1H), 7.57 (d, J=8.4 Hz, 1H), 7.47 (d, J=9.5 Hz, 1H), 7.24-6.95 (m, 3H), 5.20-5.02 (m, 1H), 4.23-4.04 (m, 1H), 3.86 (s, 3H), 3.86-3.74 (m, 2H), 2.85 (s, 3H), 2.82-2.71 (m, 1H), 2.12-1.12 (m, 10H). LCMS: m/e 503 (M+H)+, ret time 2.83 min, column B, 3 minute gradient.
