Hydrochloric Acid → 2-ethyl-1-(2-methylpropyl)-2H-pyrazolo[3,4-c][1,8]naphthyridin-4-amine

Temperature

80 °C

Hydrochloric acid (15 mL of 1M) was added to a solution of 2-tert-butoxycarbonylamino-3-pyridylboronic acid (3.31 g, 13.9 mmol), prepared as described in Parts A and B of Example 15, in 1-propanol (15 mL), and the resulting mixture was heated at 80° C. for one hour and allowed to cool to ambient temperature. Solid sodium carbonate (2.69 g, 25.4 mmol) was added with stirring followed by a solution of 4-bromo-1-ethyl-5-(2-methylpropyl)-1H-pyrazole-3-carbonitrile (1.78 g, 6.95 mmol), prepared as described in Example 2, in 1-propanol (4 mL). Triphenylphosphine (109 mg, 0.42 mmol) was added, and the reaction was evacuated and backfilled with nitrogen three times and stirred for five minutes. A solution of palladium (II) acetate (31 mg, 0.14 mmol) in warm toluene (0.5 mL) was added. The reaction was twice evacuated and backfilled with nitrogen and then heated at 100° C. overnight. An analysis by HPLC indicated the reaction was incomplete, and additional triphenylphosphine (109 mg, 0.42 mmol) and palladium (II) acetate (31 mg, 0.14 mmol) were added. The reaction was twice evacuated and backfilled with nitrogen at heated at reflux for three days. The 1-propanol was removed under reduced pressure, and the residue was dissolved in chloroform (100 mL). The resulting solution was washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on a HORIZON HPFC system as described in Example 15. The resulting solid (200 mg) was recrystallized from acetonitrile (20 mL) after hot filtration, isolated by filtration, washed with cold acetonitrile, and dried overnight in a vacuum oven at 60° C. to provide 0.17 g of 2-ethyl-1-(2-methylpropyl)-2H-pyrazolo[3,4-c][1,8]naphthyridin-4-amine as off-white needles, mp 273-276° C.

1. customprepared
2. temperatureto cool to ambient temperature
3. customprepared
4. customthe reaction was evacuated
5. stirringstirred for five minutes
6. customThe reaction was twice evacuated
7. temperatureheated at 100° C. overnight
8. customThe reaction was twice evacuated
9. temperatureat heated
10. temperatureat reflux for three days
11. customThe 1-propanol was removed under reduced pressure
12. dissolutionthe residue was dissolved in chloroform (100 mL)
13. washThe resulting solution was washed with water
14. dry with materialdried over magnesium sulfate
15. filtrationfiltered
16. concentrationconcentrated under reduced pressure
17. customThe crude product was purified by chromatography on a HORIZON HPFC system
18. customThe resulting solid (200 mg) was recrystallized from acetonitrile (20 mL)
19. filtrationafter hot filtration
20. customisolated by filtration
21. washwashed with cold acetonitrile
22. customdried overnight in a vacuum oven at 60° C.

ORD record

ord-3d7f523eb3564b519570f1351b53248c

Source dataset

uspto-grants-2015_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09145410B2