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To a stirring suspension of imidazo[1 ,2-a]pyridine-3-carboxylic acid (1 ) (3.0 g, 18.5 mmol) in anhydrous dichloromethane (50 mL) at 0 C was added dropwise oxalyl chloride (4.84 mL, 55.5 mmol). Then, three drops of anhydrous DMF was added and the reaction mixture was stirred at room temperature for 15 minutes. The solvent was concentrated and the crude solid was added to a stirring solution of 3-amino-4- fluorobenzonitrile (48) (2.5 g, 18.5 mmol) in anhydrous pyridine (50 mL) at room temperature. The reaction was stirred for 20 minutes and quenched with water (200 mL) with stirring for another 10 minutes. Then the precipitate was filtered and dried in air to yield N-(5-cyano-2-fluorophenyl)imidazo[1 ,2-a]pyridine-3-carboxamide (49). 1 H NMR (400MHz, c/6-DMSO) delta 10.40 (s, 1 H), 9.43 (td, J = 1 .2, 6.8 Hz, 1 H), 8.63 (s, 1 H), 8.21 (dd, J = 2.0, 7.2 Hz, 1 H), 7.78-7.84 (m, 2H), 7.54-7.63 (m, 2H), 7.22 (dt, J = 1 .2, 6.8, 1 H). MS m/z 281 .1 (M+1 ) +. |
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A mixture of 4-fluoro-3-nitrobenzonitrile (5.0 g, 30.1 mmol) and Fe powder (5.05 g, 90.3 mmol) in AcOH (100 mL) was heated at 80 C for 1 hour under N2. Then the solvent was removed under vacuum and water (200 mL) was added to the residue. The solution was adjusted to pH 6 by addition of Na2C03 and extracted with DCM (2 x 200 mL). The organic layers were combined, dried over Na2S04, filtered and concentrated to yield 3- amino-4-fluorobenzonitrile (48), which was used without further purification. MS m/z 137.0 (M+1 ) +. To a stirring suspension of imidazo[1 ,2-a]pyridine-3-carboxylic acid (1 ) (3.0 g, 18.5 mmol) in anhydrous dichloromethane (50 mL) at 0 C was added dropwise oxalyl chloride (4.84 mL, 55.5 mmol). Then, three drops of anhydrous DMF was added and the reaction mixture was stirred at room temperature for 15 minutes. The solvent was concentrated and the crude solid was added to a stirring solution of 3-amino-4- fluorobenzonitrile (48) (2.5 g, 18.5 mmol) in anhydrous pyridine (50 mL) at room temperature. The reaction was stirred for 20 minutes and quenched with water (200 mL) with stirring for another 10 minutes. Then the precipitate was filtered and dried in air to yield N-(5-cyano-2-fluorophenyl)imidazo[1 ,2-a]pyridine-3-carboxamide (49). 1 H NMR (400MHz, c/6-DMSO) delta 10.40 (s, 1 H), 9.43 (td, J = 1 .2, 6.8 Hz, 1 H), 8.63 (s, 1 H), 8.21(dd, J = 2.0, 7.2 Hz, 1 H), 7.78-7.84 (m , 2H), 7.54-7.63 (m , 2H), 7.22 (dt, J = 1 .2, 6.8, 1 H). MS m/z 281 .1 (M+1 ) +. NH2OH (10 mL, 32.1 mmol) was added in one portion to a stirred suspension of N-(5- cyano-2-fluorophenyl)imidazo[1 ,2-a]pyridine-3-carboxamide (49) (3.6 g, 12.85 mmol) in EtOH (100 mL). The resulting suspension was heated at 70 C for 3 hours and then the solvent was removed to yield N-(2-fluoro-5-(N'- hydroxycarbamimidoyl)phenyl)imidazo[1 ,2-a]pyridine-3-carboxamide (50). 1 H NMR (400MHz, c/6-DMSO) delta 10.21 (s, 1 H), 9.70 (s, 1 H), 9.45 (td, J = 1 .2, 7.2 Hz, 1 H), 8.61 (s, 1 H), 7.95 (dd, J = 2.4, 7.6 Hz, 1 H), 7.79 (td, J = 1 .2, 8.8 Hz, 1 H), 7.51 -7.60 (m , 2H), 7.31 -7.37 (m, 1 H), 7.19 (dt, J = 1 .2, 6.8, 1 H), 5.88 (s, 2H). MS m/z 314.1 (M+1 ) +. |
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