Triethylamine → 7-(4-Bromo-2-chlorophenylamino)-8-fluoro-4-methylquinazoline-6-carboxylic acid (2-vinyloxy-ethoxy)-amide

Participants

Reaction Steps

To a solution of 7-(4-bromo-2-chlorophenylamino)-8-fluoro-4-methylquinazoline-6-carboxylic acid (47 mg, 0.11 mmol) in DMF (2 mL) was added HOBt (26.0 mg, 0.170 mmol), Et3N (0.060 mL, 0.044 mmol), O-(2-vinyloxy-ethyl)-hydroxylamine (15 mg, 0.15 mmol), and EDCI (30 mg, 0.16 mmol) at room temperature. The resulting solution was stirred for 7 days at room temperature. The reaction mixture was diluted with EtOAc, and washed with saturated aqueous NH4Cl, brine, saturated aqueous NaHCO3, and brine. The organic layer was dried over MgSO4, filtered, concentrated in vacuo to give the crude material which was purified by silica gel flash column chromatography (1.5 to 2% MeOH in CH2Cl2) to afford 24 mg (42%) of 7-(4-bromo-2-chlorophenylamino)-8-fluoro-4-methylquinazoline-6-carboxylic acid (2-vinyloxy-ethoxy)-amide. To a solution of the vinyl ether (24.0 mg, 0.048 mmol) in EtOH (2 mL) was added 1 N aqueous HCl (0.21 mL) at room temperature. After stirring for 3 hours at room temperature, pH of the reaction mixture was adjusted to 6 to 7 with 1 N aqueous NaOH, and extracted with EtOAc. The organic layer was washed with water, dried over MgSO4, filtered, and concentrated in vacuo to give the crude material which was purified by silica gel flash column chromatography (5 to 10 to 20% MeOH in CH2Cl2 with 1% Et3N) to afford 7-(4-bromo-2-chlorophenylamino)-8-fluoro-4-methylquinazoline-6-carboxylic acid (2-hydroxyethoxy)-amide (5 mg, 22%). MS APCI (−) m/z 467, 469 (M-, Br, Cl pattern) detected; 1H NMR (400 MHz, CD3OD) δ 9.06 (s, 1H), 8.38 (s, 1H), 7.60 (d, 1H), 7.35 (dd, 1H), 6.86 (dd, 1H), 4.10 (t, 2H), 3.81 (t, 2H), 2.99 (s, 3H).

Provenance & Evidence