3-Acetyl-2-methylimidazo[1,2-a]pyridine

504-29-0

1694-29-7

29096-60-4

Example 1: Synthesis of 3-acetyl-2-methylimidazo[1,2-A]pyridine 1. To a stirred solution of 2-aminopyridine (1.035 g, 11 mmol) in 1,2-dimethoxyethane (5 mL) was added sodium bicarbonate (0.924 g, 11 mmol) and 3-chloro-2,4-pentanedione (2 g, 14.8 mmol). The non-homogeneous reaction mixture was refluxed for about 16 hours and then cooled to room temperature. The volatiles were removed under vacuum. The residue was diluted with water (50 mL) and extracted with dichloromethane (3 x 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by silica gel column chromatography using ethyl acetate/hexane (6:4) as eluent to afford 1-(2-methylimidazo[1,2-a]pyridin-3-yl)ethanone (1 g, yield 38% based on 3-chloro-2,4-pentanedione, 54% based on 2-aminopyridine) as a solid. 2. Bromine (0.163 mL, 3.1 mmol) was added to 1-(2-methylimidazo[1,2-a]pyridin-3-yl)ethanone (500 mg, 2.8 mmol) in 33% hydrobromic acid in acetic acid solution (5 mL, w/v) and stirred at 0°C. The mixture was stirred at room temperature for about 1.5 hours. The reaction mixture was diluted with ether (50 mL) and stirred for about 30 minutes. The resulting solid was filtered and washed with ether (2 x 10 mL) to give 2-bromo-1-(2-methylimidazo[1,2-a]pyridin-3-yl)ethanone (581 mg, 80%) as a solid. 3. To a solution of 2-bromo-1-(2-methylimidazo[1,2-a]pyridin-3-yl)ethanone (2.5 g, 9.88 mmol) in ethanol (25 mL) was added ethyl 3-thioureido-benzoate (2.213 g, 9.88 mmol) and the mixture was refluxed overnight. The ethanol was removed under vacuum and the residue was diluted with ether (75 mL) and stirred for 30 minutes. The solid was filtered and dried under vacuum to give ethyl 3-[4-(2-methylimidazo[1,2-a]pyridin-3-yl)thiazol-2-ylamino]benzoate (2.8 g, 75%) as a solid. 4. To a stirred solution of ethyl 3-[4-(2-methylimidazo[1,2-a]pyridin-3-yl)thiazol-2-ylamino]benzoate (300 mg, 0.79 mmol) in methanol:dichloromethane (15 mL:6 mL) was slowly added 50% aqueous hydroxylamine (6 mL) at 0 °C. After stirring for about 10 minutes at 0°C, a solution of sodium hydroxide (240 mg dissolved in 1.5 mL of water) was added dropwise for about 15 minutes, brought to room temperature and stirred for about 3 hours. The volatiles were evaporated under vacuum below 35°C, diluted with water (6 mL) and cooled to 0°C. The pH was adjusted to about 7 using 2N hydrochloric acid and stirred for about 30 minutes. The resulting solid was filtered, washed with water (75 mL) and dried under vacuum for about 5 h to give 3-acetyl-2-methylimidazo[1,2-A]pyridine (150 mg, 51%) as an off-white solid. MS m/z 366.0 (M++1), melting point 170.4 °C. 1H NMR (DMSO-D6, 200 MHz) δ 2.52 (s, 3H) 7.00 (dd, 1H), 7.10 (s, 1H), 7.2-7.4 (m, 3H), 7.53 (d, 1H), 7.67 (d, 1H), 8.20 (s, 1H), 9.03 (s, OH), 9.05 (d, 1H), 10.54 (s, NH), 11.18 (s, NH).