1,1'-Carbonyldiimidazole → 2-[(4-ethynyl-2-fluorophenyl)amino]-3,4-difluoro-N-(2-hydroxyethoxy)benzamide

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Reaction Steps

The product of Example 1, Step C, 3,4-difluoro-2-[(4-ethynyl-2-fluorophenyl)amino]benzoic acid (349 mg, 1.20 mmol) was dissolved in dry THF (15 mL), to which was added carbonyldiimidazole (CDI) (389 mg, 2.40 mmol). Within 10 minutes, a bright yellow solution was obtained and conversion to the imidazolide was confirmed by TLC (50% EtOAc/hexanes). A solution of 2-(aminooxy)ethanol (370 mg, 4.80 mmol) in THF (5 mL) was then added and the mixture stirred for 15 hours at room temperature. The reaction solvent was removed under reduced pressure and the residue partitioned between 1 M HCl (100 mL) and EtOAc (100 mL). The EtOAc layer was then washed with water (100 mL) and saturated NaCl solution (100 mL), dried (Na2SO4), and the solvent removed under reduced pressure to afford an oil which was purified by flash column chromatography on silica gel (50% EtOAc/hexanes) to give 2-[(4-ethynyl-2-fluorophenyl)amino]-3,4-difluoro-N-(2-hydroxyethoxy)benzamide as a pale yellow solid (232 mg, 55%); m.p. (EtOAc/hexanes) 158-161° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.80 (br s, 1 H), 8.84 (br s, 1 H), 7.43 (ddd, J=8.8, 5.9, 1.9 Hz, 1 H), 7.34 (dd, J=12.2, 1.9 Hz, 1 H), 7.25 (ddd, J=9.9, 9.0, 7.3 Hz, 1 H), 7.16 (ddd, J=8.3, 1.9, 0.9 Hz, 1 H), 6.79 (ddd, J=9.1, 8.3, 4.9 Hz, 1 H), 4.71 (br s, 1 H), 4.10 (s, 1 H), 3.84 (t, J=5.0 Hz, 2 H), 3.56 (t, J=5.0 Hz, 2 H). Anal. Calcd for C17H13F3N2O3: C, 58.5; H, 4.1; N, 8.0. Found: C, 58.3; H, 3.7; N, 8.0.

Provenance & Evidence