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A mixture comprising 7-bromoimidazo[1 ,2-a]pyridine-3-carboxylic acid (13c )(1 .8 g, approximately 7.47 mmol) and thionyl chloride (10 mL, 137 mmol) under N2 was heated at reflux for 1 .5 hours. The reaction mixture was concentrated in vacuo and azeotroped with toluene. Methyl 3-amino-4-fluorobenzoate (7) (1 .263 g, 7.47 mmol) (pre-dried at 45 °C) was added followed by pyridine and the mixture was stirred at room temperature under N2 overnight. The reaction mixture was diluted with EtOAc and washed with H20. The resulting solid was collected by filtration. The filtrate was dried (MgS04) and concentrated in vacuo and triturated with ether to afford a cream solid. The solids were combined and dried at 45 °C to afford the title compound (33). 1 H NMR (400MHz, d6- DMSO) delta 10.3 (1 H, s), 9.4 (1 H, d), 8.6 (1 H, s), 8.3 (1 H, m), 8.2 (1 H, s), 7.9 (1 H, m), 7.5 (1 H, t), 7.4 (1 H, d), 3.9 (3H, s). MS m/z 392 (M+H)+. |
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To the solution of compound 7-bromoimidazo[1,2-a]pyridine-3-carboxylic acid (Intermediate 1) (1.26 Kg, 5.23 mol) in DMAC (15 L) was added dropwise SOCl2 (1.86 kg, 15.6 mol) at 10 °C in 30 min. To the resulting mixture warmed to 20°C was added compound <strong>[369-26-6]methyl 3-amino-4-fluorobenzoate</strong> (884 g, 5.23 mol) in DMAC (3.0 L) over 30 min. After addition, the reaction temperature went up to 30 °C. HPLC showed the reaction went to completion within 5 min. To the reaction mixture was added water (20 L) over 20 min. The mixture was filtered and dried under vacuum to afford the title compound as a white solid; 1 H NMR (400 MHz, DMSO-d6) delta 3.87 (s, 3 H) 7.57 (dd, J=7.28, 2.01 Hz, 1 H) 7.51 (dd, J=10.16, 8.66Hz, 1 H) 7.90 (td, J=4.33, 2.38 Hz, 1 H) 8.29 (m, 2H) 8.90 (s, 1 H) 9.43 (d, J=7.53 Hz, 1 H) 10.78 (s, 1 H) Rt 6.90 mins; MS m/z 394.0 {M+H}+; Method 10 min LC |
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Step 1 : 3-[(7-Bromo-imidazo[1 ,2-a]pyridine-3-carbonyl)-amino]-4-fluoro-benzoic acid methyl esterTo the solution of compound 7-bromoimidazo[1 ,2-a]pyridine-3-carboxylic acid (Intermediate A step 3) (1 .26 Kg, 5.23 mol) in DMAC (15 L) was added dropwise SOCI2 (1.86 kg, 15.6 mol) at 10 °C in 30 min. To the resulting mixture warmed to 20°C was added compound <strong>[369-26-6]methyl 3-amino-4-fluorobenzoate</strong> (884 g, 5.23 mol) in DMAC (3.0 L) over 30 min. After addition, the reaction temperature went up to 30 °C. HPLC showed the reaction went to completion within 5 min. To the reaction mixture was added water (20 L) over 20 min. The mixture was filtered and dried under vacuum to afford the title compound as a white solid;1 H NMR (400 MHz, DMSO-cfe) delta 3.87 (s, 3 H) 7.57 (dd, J=7.28, 2.01 Hz, 1 H) 7.51 (dd, J=10.16, 8.66Hz, 1 H) 7.90 (td, J=4.33, 2.38 Hz, 1 H) 8.29 (m, 2H) 8.90 (s, 1 H) 9.43 (d, J=7.53 Hz,1 H) 10.78 (s, 1 H)Rt 6.90 mins; MS m/z 394.0 {M+H}+; Method 10 |