Sodium Hydroxide → 3-(6-(6-(2,4-Difluorophenyl)imidazo[2,1-b]oxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-2,2-dimethylpropan-1-ol

Temperature

-78 °C

To a 50 mL round-bottom flask was added 3,3-dimethyldihydrofuran-2,5-dione (1.0 g, 7.80 mmol) in THF (25 mL) to give a colorless solution. This solution was cooled to about −78° C. followed by the addition of LAH (1.48 g, 39.0 mmol) in 3 batches. The reaction was warmed to ambient temperature and allowed to stir for about 2 h. 1N NaOH (about 10 mL) and EtOAc (about 10 mL) were added and the reaction was allowed to stir for about 1 h. The reaction was filtered though Celite® and the organic layer was separated, dried over MgSO4 and concentrated under reduced pressure to give a clear colorless oil. To this oil a solution of Dess-Martin periodinane (3.1 g, 7.3 mmol) in DCM (5 mL) was added dropwise and the reaction was allowed to stir for about 1 h. The reaction was then concentrated under reduced pressure, suspended in Et2O, filtered through a short plug of silica gel and subsequently concentrated under reduced pressure. To the resulting oil was added 5-[6-(2,4-difluorophenyl)-imidazo[2,1-b]oxazol-5-yl]-pyridin-2-yl-hydrazine (0.25 g, 0.76 mmol; prepared using C from Example #2, step A with 2-fluoropyridine-5-boronic acid [Asymchem], D with hydrazine) and MeOH (5 mL) followed by heating to about 60° C. for about 1 h. Then the reaction was cooled to ambient temperature and iodobenzene diacetate (0.246 g, 0.764 mmol) was added and the reaction was allowed to stir for about 1 h. The reaction was then concentrated under reduced pressure and purified by silica gel chromatography (40 g of SiO2, gradient from 0% to 10% MeOH in EtOAc) to provide the title compound as a white solid (0.01 g, 3%): LC/MS (Table 1, Method a) R=1.93 min; MS m/z: 424.2 (M+H)+.

1. customto give a colorless solution
2. temperatureThe reaction was warmed to ambient temperature
3. stirringto stir for about 1 h
4. filtrationThe reaction was filtered though Celite®
5. customthe organic layer was separated
6. dry with materialdried over MgSO4
7. concentrationconcentrated under reduced pressure
8. customto give a clear colorless oil
9. stirringto stir for about 1 h
10. concentrationThe reaction was then concentrated under reduced pressure
11. filtrationfiltered through a short plug of silica gel
12. concentrationsubsequently concentrated under reduced pressure
13. temperatureby heating to about 60° C. for about 1 h
14. temperatureThen the reaction was cooled to ambient temperature
15. stirringto stir for about 1 h
16. concentrationThe reaction was then concentrated under reduced pressure
17. custompurified by silica gel chromatography (40 g of SiO2, gradient from 0% to 10% MeOH in EtOAc)

ORD record

ord-3c61602021e24da7aa94ce4f251d378f

Source dataset

uspto-grants-2010_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07790741B2