Water → N-(1-((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)-2-methylpropan-2-yl)-2-(1H-imidazol-1-yl)isonicotinamide

温度

50 °C

To a solution of 2-(1H-imidazol-1-yl)isonicotinic acid (1.00 g, 5.29 mmol), in DMF (41 mL) at room temperature, was added HOBt.H2O (891 mg, 5.82 mmol), EDCI.HCl (1.11 g, 5.82 mmol), 4-amino-5-(2-amino-2-methylpropoxy)-1H-benzo[c][1,2,6]thiadiazine 2,2-dioxide hydrochloride (1.70 g, 5.29 mmol) and triethylamine (1.54 mL, 11.1 mmol). The reaction was heated to 50° C. for one hour, and upon completion was cooled to room temperature, filtered and the filtrate was purified by HPLC (10-90% acetonitrile in water), then the purified product was washed in boiling ethanol for thirty minutes, then cooled to room temperature. The solid was collected by vacuum filtration, sodium carbonate (178 mg) in water (50 mL) was added and the mixture was heated to 60° C. until in solution, then was cooled to 0° C. and neutralized with hydrochloric acid (1N). The white solid was collected by vacuum filtration and dried under vacuum at 50° C. (295 mg). Sodium carbonate (87.3 mg) in water (7 mL) was added to the white solid and the mixture was heated to 60° C. until in solution. The warm solution was filtered, cooled to room temperature, and neutralized with hydrochloric acid (1N). The white solid was collected by vacuum filtration and dried under vacuum at 50° C. to yield N-(1-((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)-2-methylpropan-2-yl)-2-(1H-imidazol-1-yl)isonicotinamide as a white solid (171 mg, 7% yield). 1H NMR (DMSO-d6, 400 MHz): δ 1.50 (s, 6H), 4.41 (s, 2H), 6.62 (d, J=8.0 Hz, 1H), 6.79 (d, J=8.0 Hz, 1H), 7.14 (s, 1H), 7.47 (t, J=8.4 Hz, 1H), 7.63 (dd, J=6.0 Hz, 1H), 7.81 (s, 1H), 8.00 (d, J=8.0 Hz, 1H), 8.47 (s, 1H), 8.58 (m, 3H), 11.00 (s, 1H). MS 456 (MH+).

1. temperatureupon completion was cooled to room temperature
2. filtrationfiltered
3. customthe filtrate was purified by HPLC (10-90% acetonitrile in water)
4. washthe purified product was washed
5. customfor thirty minutes
6. temperaturecooled to room temperature
7. filtrationThe solid was collected by vacuum filtration, sodium carbonate (178 mg) in water (50 mL)
8. additionwas added
9. temperaturethe mixture was heated to 60° C. until in solution
10. temperaturewas cooled to 0° C. and neutralized with hydrochloric acid (1N)
11. filtrationThe white solid was collected by vacuum filtration
12. customdried under vacuum at 50° C. (295 mg)
13. additionSodium carbonate (87.3 mg) in water (7 mL) was added to the white solid
14. temperaturethe mixture was heated to 60° C. until in solution
15. filtrationThe warm solution was filtered
16. temperaturecooled to room temperature
17. filtrationThe white solid was collected by vacuum filtration
18. customdried under vacuum at 50° C.

ORDレコード

ord-b5933ecff91e47f9963df322e7f3408a

出典データセット

uspto-grants-2016_06

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US09371317B2