Hydrochloric Acid → 1-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea, hydrochloride salt

Temperature

0 °C

Bis-(trifluoroacetoxy)-iodobenzene (Aldrich, 3.09 g, 7.20 mmol, 1.4 eq) was added to a solution of 1-(4-(2-carbamoylpyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea (2.19 g, 5.14 mmol, 1.0 eq), water (0.241 mL, 13.4 mmol, 2.6 eq) and pyridine (1.62 mL, 20 mmol, 3.9 eq) in DMF (20 mL) at room temperature and the reaction mixture was stirred for 5 h. The reaction mixture was quenched with 1 N HCl and the aqueous solution extracted with Et2O, discarding the organic layer. The aqueous layer was neutralized with 1 N NaOH and extracted with EtOAc. The combined organic layers were washed with 10% aq LiCl, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with 0-5% MeOH in CHCl3) and the appropriate fractions were concentrated in vacuo. The residue was dissolved in THF (50 mL) cooled to 0° C. and treated with anhydrous HCl (4N, 10 mL, 40 mmol, 7.8 eq). The reaction mixture was allowed to warm to room temperature and stirred for 2 h resulting in a heterogeneous solution. The solution was filtered and the solid washed with Et2O and dried in vacuo to afford the title compound (1.38 g, 63%) as a solid. 1H NMR (DMSO-d6)

1. customThe reaction mixture was quenched with 1 N HCl
2. extractionthe aqueous solution extracted with Et2O
3. extractionextracted with EtOAc
4. washThe combined organic layers were washed with 10% aq LiCl
5. dry with materialdried (Na2SO4)
6. filtrationfiltered
7. concentrationconcentrated in vacuo
8. customThe residue was purified by silica gel chromatography (eluting with 0-5% MeOH in CHCl3)
9. concentrationthe appropriate fractions were concentrated in vacuo
10. dissolutionThe residue was dissolved in THF (50 mL)
11. temperatureto warm to room temperature
12. stirringstirred for 2 h
13. customresulting in a heterogeneous solution
14. filtrationThe solution was filtered
15. washthe solid washed with Et2O
16. customdried in vacuo

ORD record

ord-7f023706c85645408836ed785f6de27d

Source dataset

uspto-grants-2010_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07714138B2