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

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-[[(2R)-4-benzoyl-2-methyl-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 8.21 (s, 1H), 7.88 (d, J=8.6 Hz, 1H), 7.60-7.44 (m, 4H), 7.43-7.32 (m, 6H), 6.82 (br s, 1H), 5.21 (br s, 1H), 4.34 (br s, 1H), 4.58-3.34 (m, 7H), 3.06 (s, 6H), 2.87-2.78(m, 1H), 2.12-1.00 (m, 13H). LCMS: m/e 692 (M−H)−, ret time 1.69 min, column A, 2 minute gradient.

1. stirringstirred for 30 min
2. filtrationthe solids (290 mg) collected by filtration
3. customflushed with H2O
4. dissolutionThe crude solids were dissolved into MeOH/THF (1:1, 4 mL)
5. additiontreated with 1M aqueous NaOH (0.75 mL)
6. stirringThe reaction mixture was stirred
7. temperatureheated at 80° C. with microwave irradiation for 15 min in a sealed tube
8. additionThe clear solution was diluted with H2O (5 mL)
9. concentrationconcentrated
10. customto remove organic solvents
11. filtrationThe resultant solids (257 mg) were collected by filtration
12. washwashed with H2O
13. stirringThe reaction solution was stirred at 50° C. for 2 h
14. filtrationthe resulting solids were collected by filtration
15. concentrationThe mother liquor was concentrated
16. customthe solids and the mother liquor were independently purified by preparative HPLC (MeOH/2O with NH4OAc buffer)

ORD record

ord-8fee52242a024daeaf26bedf1c4586d3

Source dataset

uspto-grants-2009_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07473688B2