Oxalyl chloride → N-((5-((2-(4-(1-methylpiperidin-4-yl)phenyl)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)isobutyramide

Participants

Reaction Steps

A solution of Example B7 (0.045 g, 0.520 mmol) in DCE (3 mL) was treated with oxalyl chloride (0.046 mL, 0.520 mmol), stirred at RT for 5 min, then warmed to 80° C. for 0.5 h. The mixture was cooled to RT, added drop wise to a solution of 5-((2-(4-(1-methylpiperidin-4-yl)phenyl)pyridin-4-yl)oxy)pyridin-2-amine (0.125 g, 0.347 mmol) and DIEA (0.363 mL, 2.081 mmol) in THF (3 mL) and stirred at RT overnight. The mixture was treated with 1:1 1 N NaOH/brine, extracted with EtOAc (3×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via reverse-phase silica gel chromatography (MeCN/H2O with 0.1% TFA). The organics were removed under reduced pressure. The remaining aqueous layer was neutralized with 1N NaOH, extracted with EtOAc (3×) and the combined organics were dried over Na2SO4 and concentrated to dryness. The material was suspended in 1:1 MeCN/H2O, frozen and lyophilized to afford N-((5-((2-(4-(1-methylpiperidin-4-yl)phenyl)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)isobutyramide (23 mg, 14%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.10 (s, 1H), 10.85 (s, 1H), 8.51 (d, J=5.7 Hz, 1H), 8.28 (d, J=2.9 Hz, 1H), 8.09 (d, J=9.0 Hz, 1H), 7.93 (d, J=8.2 Hz, 2H), 7.75 (dd, J=9.0, 2.9 Hz, 1H), 7.46 (d, J=2.4 Hz, 1H), 7.31 (d, J=8.2 Hz, 2H), 6.84 (dd, J=5.6, 2.4 Hz, 1H), 2.84 (m, 2H), 2.66 (m, 1H), 2.17 (s, 3H), 1.94 (m, 2H), 1.75-1.59 (m, 5H), 1.08 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 474.3 (M+H+).

Provenance & Evidence