反应详情

To a solution of {3-[5-fluoro-3-(tetrahydro-pyran-4-yl)-pyridin-2-yloxy]-cyclobutyl}-(1-methoxymethyl-1H-benzoimidazol-2-yl)-methanone (1.2 g) in THF (20 mL) at RT was added concentrated HCl (20 mL). The reaction mixture was stirred at RT for 1 h and then heated to 60° C. for 6 h. The mixture was partially concentrated, neutralized with saturated NaHCO3 and diluted with EtOAc. The aqueous phase was extracted with EtOAc (2×10 mL) and the combined organic extracts were washed with brine (10 mL), dried over MgSO4, filtered, and concentrated to get a residue, which was purified by flash column chromatography on silica gel (5% to 30% EtOAc in DCM) gave cis-(1H-benzoimidazol-2-yl)-{3-[5-fluoro-3-(tetrahydro-pyran-4-yl)-pyridin-2-yloxy]-cyclobutyl}-methanone and trans-(1H-benzoimidazol-2-yl)-{3-[5-fluoro-3-(tetrahydro-pyran-4-yl)-pyridin-2-yloxy]-cyclobutyl}-methanone (196 mg) as white solid. [M+1] 396 each. IC50 (uM) 0.00003 (cis) and 0.0005 (trans).

1. temperatureheated to 60° C. for 6 h
2. concentrationThe mixture was partially concentrated
3. additiondiluted with EtOAc
4. extractionThe aqueous phase was extracted with EtOAc (2×10 mL)
5. washthe combined organic extracts were washed with brine (10 mL)
6. dry with materialdried over MgSO4
7. filtrationfiltered
8. concentrationconcentrated
9. customto get a residue, which
10. customwas purified by flash column chromatography on silica gel (5% to 30% EtOAc in DCM)