反应详情

To N-(3-fluoro-4-(3-(4-(2-hydroxyethyl)phenyl)pyridin-4-yloxy)phenyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide (Compound C of Example 67, 40 mg, 0.077 mmol) in THF (1 mL) was added DIPEA (27 uL, 0.154 mmol) followed by methanesulfonyl chloride (Aldrich, 7 uL, 0.092 mmol). After stirring at rt for 30 min, the reaction was concentrated in vacuo. The residue was dissolved in 3 mL of ethanol and transferred to a pressure tube. Ammonium hydroxide (7 mL) was added and the tube was sealed and heated at 50° C. for 8 h. After cooling to rt, the reaction was diluted with EtOAc (10 mL), washed with water (2×10 mL) then brine (1×10 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by prep HPLC. The appropriate fractions were concentrated to remove methanol and basified with saturated sodium bicarbonate solution. The aqueous layer was extracted with EtOAc (2×20 mL) and the pooled organic extracts were washed with brine (1×10 mL), dried over anhydrous Na2SO4, and concentrated. The residue was dissolved in dioxane (2 mL) and charged with 1N HCl in ether (1 mL). The solution was concentrated and the resulting solid was lyophilized from acetonitrile/water to give the HCl salt of the title compound (24 mg, 53%) as a white solid. 1H NMR (DMSO-d6) δ 12.13 (s, 1H), 8.74 (s, 1H), 8.55-8.51 (m, 2H), 8.09 (dd, 1H, J=6.4, 2 Hz), 8.03 (m, 1H), 7.64 (d, 2H, J=6 Hz), 7.63 (m, 1H), 7.54-7.41 (m, 6H), 7.38 (d, 2H, J=8.4 Hz), 7.04 (d, 1H, J=6 Hz), 6.68 (t, 1H, J=6.8 Hz), 3.02 (m, 2H), 2.89 (m, 2H); MS(ESI+) m/z 521.27 (M+H)+.

1. concentrationthe reaction was concentrated in vacuo
2. dissolutionThe residue was dissolved in 3 mL of ethanol
3. customtransferred to a pressure tube
4. additionAmmonium hydroxide (7 mL) was added
5. customthe tube was sealed
6. temperatureheated at 50° C. for 8 h
7. temperatureAfter cooling to rt
8. additionthe reaction was diluted with EtOAc (10 mL)
9. washwashed with water (2×10 mL)
10. dry with materialbrine (1×10 mL), dried over anhydrous Na2SO4
11. concentrationconcentrated in vacuo
12. customThe crude product was purified by prep HPLC
13. concentrationThe appropriate fractions were concentrated
14. customto remove methanol
15. extractionThe aqueous layer was extracted with EtOAc (2×20 mL)
16. washthe pooled organic extracts were washed with brine (1×10 mL)
17. dry with materialdried over anhydrous Na2SO4
18. concentrationconcentrated
19. dissolutionThe residue was dissolved in dioxane (2 mL)
20. additioncharged with 1N HCl in ether (1 mL)
21. concentrationThe solution was concentrated