Sodium Hydroxide → 3-(2-Fluoro-4-iodo-phenylamino)-1-prop-2-ynyl-1-H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (2-vinyloxy-ethoxy)-amide

Participants

Reaction Conditions

Reaction Steps

To a stirred solution of 3-(2-fluoro-4-iodo-phenylamino)-1-prop-2-ynyl-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (55.0 mg, 0.12 mmol) in anhydrous THF (1.0 mL) and MeOH (0.5 mL) under N2 was added freshly prepared 1N aqueous sodium hydroxide (0.24 ml, 2.0 eq). The reaction mixture was stirred at 65° C. for 1 h. The resultant reaction mixture was evaporated in vacuo and azeotroped with toluene (3×5 ml) to give a tan solid. The tan solid was redissolved in anhydrous THF (2.4 ml). EDCI (45.2 mg, 0.24 mmol, 2.0 eq) and HOBT (35.0 mg, 0.26 mmol, 2.2 eq) were added. The reaction mixture was stirred at room temperature. After 5 minutes O-(2-vinyloxy-ethyl)-hydroxylamine (14.6 mg, 0.14 mmol, 1.2 eq) and DIPEA (82.2 μL, 0.47 mmol, 4.0 eq) were added, and the reaction mixture was stirred at ambient temperature under N2 for 24 h. The reaction mixture was absorbed onto silica and purified by flash column chromatography (silica, ISCO, 45 mL/min, EtOAc:MeOH, gradient 100:1 to 50:50) to give the desired product as a yellow solid (34.4 mg, 56.0%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 11.72 (s, 1H), 8.60 (s, 1H), 8.37 (d, J=6.4 Hz, 1H), 7.79-7.47 (m, 3H), 7.24 (d, J=10.0 Hz, 1H), 6.50 (dd, J=14.0 Hz, 8.0 Hz, 1H), 6.35-6.15 (m, 1H), 5.31 (s, 2H), 4.27-4.11 (m, 1H), 4.11-3.90 (m, 4H), 3.92-3.70 (m, 2H); LC-MS (method D): [M+H]+=521.0, RT=2.18 min.

Provenance & Evidence