Citric Acid → N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]phenyl}methyl)-6-(methyloxy)-1H-indole-2-carboxamide

Participants

Reaction Steps

Methyl 6-(methyloxy)-1H-indole-2-carboxylate (0.025 g, 0.13 mmol) was dissolved in THF:methanol:water/1:1:1 (3 mL) and lithium hydroxide (0.01 g, 0.38 mmol) was added. The reaction was stirred for 1 h, at which time another portion of lithium hydroxide (0.01 g, 0.38 mmol) was added. The reaction was stirred for 1 h, acidified with 10% aqueous citric acid to pH 4-5 and extracted with EtOAc (3×5 mL). The organic extracts were combined, dried over Na2SO4, filtered and evaporated. To the crude intermediate was added 3-{[5-(aminomethyl)-2-chlorophenyl]oxy}-5-chlorobenzonitrile (0.025 g, 0.085 mmol), DIPEA (0.025 mL, 0.13 mmol) and DMF (1 mL) and then stirred overnight. Purification was accomplished by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA). The desired fractions were neutralized and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered and evaporated to afford the title compound (0.015 g, 26%) as a tan solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.38 (d, 1H), 8.88-8.93 (m, 1H), 7.77 (d, 1H), 7.59 (d, 1H), 7.42-7.48 (m, 2H), 7.35 (d, 1H), 7.26 (dd, 1H), 7.23 (d, 1H), 7.04 (d, 1H), 6.84 (d, 1H), 6.66 (dd, 1H), 4.47 (d, 2H), 3.73 (s, 3H). MS: m/z 466.2 (M+1).

Provenance & Evidence