4-Fluoro-1H-indole-2-carboxylic acid

A solution of 32 (4.8 g, 31 mmol) in 4percent NHStep 3 To a solution of 34 (179 mg, 1.00 mmol) in anhydrous DMF (2.0 mL) were added NH4Cl (160 mg, 3.00 mmol), EDCI (395 mg, 2.20 mmol), HOBt (297 mg, 2.20 mmol) and TEA (303 mg, 3.00 mmol) at RT. After stirring at RT for 3 h, the mixture was quenched with H2O (10 mL) the resulting mixture was extracted with EtOAc (3*6 mL). The combined extracts were dried and concentrated. The residue was purified by SiO2 chromatography eluting with petroleum ether/EtOAc (5:1 to 3:1) to afford 130 mg (73%) of 4-fluoro-1H-indole-2-carboxamide (36) as a white solid. LCMS (ESI) m/z: 179.1 [M+H]+.A solution of 32 (4.8 g, 31 mmol) in 4% NH4OH (60 mL) was added to a suspension of ferrous hydroxide that was prepared from ferrous sulfate heptahydrate (52.45 g, 188.7 mmol) and concentrated NH4OH (23 mL) in water (200 mL). The mixture was maintained at the boiling point for five minutes. The ferric hydroxide was separated by filtration and washed repeatedly with dilute NH4OH and water. The filtrate was acidified with dilute HCl. The resulting solid was collected by filtration to afford 1.2 g (22%) of General procedure: (5-Chloro-7-fluoro-1H-indole-2-yl)-carboxylic acid (5a) (50 mg, 0.23 mmol), N, N-diisopropylethylamine (82 mul, 0.47 mmol) and 2-(7-Aza-1H-benzotriazole-1-yl)-1, 1, 3, 3-tetramethyluronium hexafluorophosphate (89 mg, 0.23 mmol) were dissolved in 550 mul N, N-dimethylformamide. After stirring for 10 min 4-methyl-piperazin 6a (26 mul, 0.23 mmol) was added and the reaction mixture was stirred for 16 h at 20 C. The solvent was evaporated under reduced pressure and the crude product was purified using chromatography method P1, yielding 37 mg (53%) of the title compound.General procedure: (5-Chloro-7-fluoro-1H-indole-2-yl)-carboxylic acid (5a) (50 mg, 0.23 mmol), N, N-diisopropylethylamine (82 mul, 0.47 mmol) and 2-(7-Aza-1H-benzotriazole-1-yl)-1, 1, 3, 3-tetramethyluronium hexafluorophosphate (89 mg, 0.23 mmol) were dissolved in 550 mul N, N-dimethylformamide. After stirring for 10 min 4-methyl-piperazin 6a (26 mul, 0.23 mmol) was added and the reaction mixture was stirred for 16 h at 20 C. The solvent was evaporated under reduced pressure and the crude product was purified using chromatography method P1, yielding 37 mg (53%) of the title compound.