反应详情

温度

50 °C

2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodobenzoic acid methyl ester. To a solution of methyl 2-amino-4-iodobenzoate (EXAMPLE 4, Step B, 1.6 g, 5.8 mmol) in DCM (45 mL) at room temperature was added 4-chlorosulfonyl-2,1,3-benzothiadiazole (1.76 g, 7.51 mmol), and pyridine (0.93 mL, 11 mmol). The mixture was stirred at room temperature overnight, poured into 1 N HCl (200 mL), and extracted with DCM (2×100 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by flash chromatography (hexanes/EtOAc) to afford the title sulfonamide as a tan solid (1.87 g, 68%). MS (ESI): calculated for C14H10IN3O4S2, 474.9; m/z found, 474 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.26 (br s, 1H), 8.40 (dd, J=7.0, 1.0 Hz, 1H), 8.24 (dd, J=8.8, 1.0 Hz, 1H), 8.12 (d, J=1.5 Hz, 1H), 7.74 (dd, J=8.8, 7.0 Hz, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.32 (dd, J=8.5, 1.5 Hz, 1H), 3.91 (s, 3H). B. 2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodobenzoic acid. To a stirred suspension of 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodobenzoic acid methyl ester (1.87 g, 3.93 mmol) in THF (20 mL) at room temperature was added LiOH (2 M in H2O, 18 mL). The resulting orange mixture was stirred overnight at room temperature then poured into 0.5 M HCl (150 mL) causing precipitation of the desired benzoic acid. After stirring the mixture for several minutes to complete precipitation, the product was collected by suction filtration and air-dried to afford the acid as a tan solid (1.24 g, 69%). 1H NMR (500 MHz, CDCl3): 11.03 (br s, 1H), 8.34 (dd, J=7.2, 1.1 Hz, 1H), 8.19 (dd, J=8.8, 1.1 Hz, 1H), 8.09 (d, J=1.6 Hz, 1H), 7.69 (dd, J=8.8, 7.2 Hz, 1H), 7.56 (d, J=8.5 Hz, 1H), 7.30 (dd, J=8.5, 1.6 Hz, 1H), (COOH not observed). C. Benzo[1,2,5]thiadiazole-4-sulfonic acid [5-iodo-2-(morpholine-4-carbonyl)-phenyl]-amide. The title compound was prepared from the HATU-mediated coupling of 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodobenzoic acid and morpholine and purified as described in EXAMPLE 1, Step K. MS (ESI): mass calculated for C17H15IN4O4S2, 530.0; m/z found, 531 [M+H]+, 553 [M+Na]+. HPLC (reverse phase): RT═8.50 min. 1H NMR (400 MHz, CDCl3): (rotameric broadening) 8.91 (s, 1H), 8.31 (dd, J=7.0, 0.9 Hz, 1H), 8.27 (dd, J=8.8, 0.9 Hz, 1H), 7.97 (d, J=1.5 Hz, 1H), 7.74 (dd, J=8.8, 7.0 Hz, 1H), 7.41 (dd, J=8.1, 1.6 Hz, 1H), 6.78 (d, J=8.1 Hz, 1H), 3.75-3.05 (br m, 8H). D. Quinoxaline-5-sulfonic acid [5-iodo-2-(morpholine-4-carbonyl)-phenyl]-amide. Zinc powder (1.1 g, 19 mmol) was added to a mixture of benzo[1,2,5]thiadiazole-4-sulfonic acid [5-iodo-2-(morpholine-4-carbonyl)-phenyl]amide (1.0 g, 1.9 mmol) and AcOH (20 mL), and the resulting mixture was heated at 50° C. for 1 h with vigorous stirring. The mixture was filtered through a pad of diatomaceous earth, rinsing well with methanol, and the clear solution was concentrated to a yellow solid. This material was dissolved in methanol (20 mL) and added to a mixture of glyoxal sodium bisulfite adduct (1.5 g, 5.7 mmol), AcOH (0.85 mL), NaOAc (0.16 g, 2.0 mmol), and H2O (6 mL). The reaction was allowed to proceed under reflux for 3 h, then was diluted with EtOAc (200 mL) and filtered through a pad of diatomaceous earth, rinsing well with EtOAc. The filtrate was washed with H2O (100 mL) and brine (100 mL), then was dried and concentrated to a yellow solid. Purification by flash chromatography gave the titled compound as a light yellow solid (0.69 g, 70%).

1. custompurified
2. filtrationThe mixture was filtered through a pad of diatomaceous earth
3. washrinsing well with methanol
4. concentrationthe clear solution was concentrated to a yellow solid
5. dissolutionThis material was dissolved in methanol (20 mL)
6. temperatureunder reflux for 3 h
7. filtrationfiltered through a pad of diatomaceous earth
8. washrinsing well with EtOAc
9. washThe filtrate was washed with H2O (100 mL) and brine (100 mL)
10. customwas dried
11. concentrationconcentrated to a yellow solid
12. customPurification by flash chromatography