N,N-Dimethylsulfamide → 7H-indolo[2,1-a][2]benzazepine-10-carboxamide

Participants

Reaction Steps

To a stirred solution of methyl 7H-indolo[2,1-a][2]benzazepine-10-carboxylate, 13-cyclohexyl, 6-carboxylic acid (200 mg, 0.48 mmol), 3(R)-methyl-1-benzoylpiperazine hydrochloride (130 mg, 0.58 mmol) and triethylamine (0.20 mL) in DMF (3 mL) was added HATU (220 mg, 0.58 mmol). The reaction mixture was stirred at rt for 1 h, diluted with H2O (˜5 mL) stirred for 30 min, and the solids (290 mg) collected by filtration and flushed with H2O. The crude solids were dissolved into MeOH/THF (1:1, 4 mL) and treated with 1M aqueous NaOH (0.75 mL). The reaction mixture was stirred and heated at 80° C. with microwave irradiation for 15 min in a sealed tube. The clear solution was diluted with H2O (5 mL), neutralized with 1M aqueous HCl (0.75 mL) and concentrated to remove organic solvents. The resultant solids (257 mg) were collected by filtration and washed with H2O. To a stirred solution of the crude solids (145 mg, 56% of total collected, ˜0.25 mmol), N,N-dimethylsulfamide (155 mg, 1.25 mmol) and DMAP (150 mg, 1.25 mmol) in dimethylacetamide (2 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (190 mg, 1.0 mmol). The reaction solution was stirred at 50° C. for 2 h, diluted with water (5 mL) and the resulting solids were collected by filtration. The mother liquor was concentrated and the solids and the mother liquor were independently purified by preparative HPLC (MeOH/2O with NH4OAc buffer) to yield 7H-indolo[2,1-a][2]benzazepine-10-carboxamide, 6-[(4-benzoyl-1-piperazinyl)carbonyl]-13-cyclohexyl-N-[(dimethylamino)sulfonyl] (79 mg total, 52 mg from solids and 27 mg from mother liquor, 0.11 mol, 42% over 3 steps) as a yellow solid. 1H NMR (500 MHz, CDCl3) δ 9.07 (br s, 1H), 8.10 (s, 1H), 7.91 (d, J=8.2 Hz, 1H), 7.59 (d, J=8.6 Hz, 1H), 7.54-7.45 (m, 3H), 7.44-7.35 (m, 6H), 6.89 (s, 1H), 5.16 (br s, 1H), 4.36 (br s, 1H), 3.63-3.37 (m, 8H), 3.07 (s, 6H), 2.90-2.79 (m, 1H), 2.12-1.14 (m, 10H). LCMS: m/e 678 (M−H)−, ret time 1.66 min, column A, 2 minute gradient.

Provenance & Evidence