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With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 0.5h; |
To a stirring suspension of <strong>[6200-60-8]imidazo[1,2-a]pyridine-3-carboxylic acid</strong> (1) (71 mg, 0.39 mmol) in anhydrous dichloromethane (2 mL) was added dropwise oxalyl chloride (173 uL, 1.98 mmol). Then, a drop of anhydrous N,N-dimethylformamide was added and the reaction mixture was stirred at room temperature for 30 minutes. The solvent was concentrated. A stirring mixture of the acid chloride and 5-(azetidin-1-yl)-3-(4-methyl-3-nitrophenyl)-1,2,4-oxadiazole (109) (85 mg, 0.29 mmol) in anhydrous pyridine (2 mL) was stirred at room temperature for 30 minutes. The crude product was purified on silica gel using 10% MeOH in dichloromethane to give N-(5-(5-(azetidin-1-yl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (F77). 1H NMR (400 MHz, CD2Cl2) delta 10.10 (s, 1H), 9.51-9.48 (m, 1H), 8.65 (s, 1H), 7.94 (d, J=1.6 Hz, 1H), 7.86-7.83 (m, 1H), 7.71 (dd, J=1.6, 7.6 Hz, 1H), 7.64-7.60 (m, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.27-7.24 (m, 1H), 4.26-4.22 (m, 4H), 2.48-2.40 (m, 2H), 2.34 (s, 3H). MS m/z 374.15 (M+1)+. |
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With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; |
To a suspension of <strong>[6200-60-8]imidazo[1,2-a]pyridine-3-carboxylic acid</strong> (1) (4.09 g, 25.3 mmol) in dichloromethane (100 mL) and DMF (0.25 mL) at 0 C. was added oxalyl chloride (4.15 mL, 48.0 mmol) dropwise over 10 minutes. The reaction was slowly warmed to room temperature and stirred until complete conversion was detected by LCMS. The reaction was subsequently reduced to dryness and suspended in dichloromethane (100 mL) and was added a solution of methyl 3-amino-4-methylbenzoate (2) (4.6 g, 27.9 mmol) in dichloromethane (100 mL) and triethylamine (7.1 mL). Contents were stirred at room temperature for 4 hours and diluted with dichloromethane (100 mL). The reaction was washed with water, saturated NaHCO3, brine, dried over magnesium sulfate, filtered and reduced to dryness. The crude solid was triturated with diethyl ether to remove excess aniline and dried to afford methyl 3-(imidazo[1,2-a]pyridine-3-carboxamido)-4-methylbenzoate (3) as a white solid. MS m/z 310.1 (M+1)+.; To a suspension of 3-(imidazo[1,2-a]pyridine-3-carboxamido)-4-methylbenzoate (3) (5.43 g, 17.6 mmol) in THF (225 ml) and MeOH (150 mL) was added LiOH 3 M (17.5 mL) and water (50 mL). The reaction was stirred at room temperature for 12 hours then reduced in volume on roto-vap to remove THF and MeOH. The mixture was diluted with water (75 mL) and neutralized with HCl (17.5 mL of a 3M solution). The resulting precipitate was filtered, washed with water and dried under vacuum to afford 3-(imidazo[1,2-a]pyridine-3-carboxamido)-4-methylbenzoic acid (4) as a white solid. 1H NMR (400 MHz, d6-DMSO) delta 10.0 (s, 1H), 9.45 (dt, J=6.8, 1.2 Hz, 1H), 8.58 (s, 1H), 7.98 (d, J=2.0 Hz, 1H), 7.79 (dt, J=9.2, 1.2 Hz, 1H), 7.76 (dd, J=8.0, 1.6 Hz, 1H), 7.52 (ddd, J=9.2, 9.2, 1.2 Hz, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.17 (td, J=6.8, 1.2 Hz, 1H), 2.35 (s, 3H). MS m/z 296.1 (M+1)+. |
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With oxalyl dichloride; In dichloromethane; N,N-dimethyl-formamide; at 20℃; |
Step 1 : ImidazoH ,2-a]pyridine-3-carbonyl chloride A suspension of imidazo[1 ,2-a]pyridine-3-carboxylic acid (5.270 g, 32.5 mmol) in DCM (200 ml) was treated with oxalyl chloride (3.13 ml, 35.8 mmol) followed by the addition of DMF (0.252 ml, 3.25 mmol). The reaction mixture was stirred at RT overnight. The solvent was removed in vacuo to afford the title compound as a hydrochloride salt;1 H NMR (400 MHz, DMSO-d6) delta 9.48 (1 H, d), 8.77 (1 H, s), 7.99 (2H, m), 7.56 (1 H, t) |
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