Synthesis
The general procedure for the synthesis of indazole-4-carboxylic acid from 4-bromo-1H-indazole was as follows: sodium hydride (60% dispersed in mineral oil, 1.11 eq.) was added batchwise to an anhydrous tetrahydrofuran (7 L/mol) solution of 4-bromo-1H-indazole (1.00 eq.) at room temperature. The resulting solution was stirred at room temperature for 30 minutes and subsequently cooled to -60°C. A cyclohexane solution of 1.3 M sec-butyl lithium (2.1 eq.) was slowly added while keeping the internal temperature below -50 °C. Stirring of the reaction mixture was continued at -50 °C for 2 hours. Subsequently, a steady stream of anhydrous carbon dioxide gas was passed into the reaction mixture for 1 hour. While maintaining the carbon dioxide gas stream, the reaction mixture was allowed to gradually warm up to room temperature. Brine (6 L/mol) was added and the pH of the mixture was adjusted with concentrated hydrochloric acid to 5. The mixture was extracted with warm ethyl acetate (3 x 8 L/mol), the organic phases were combined, washed with a small amount of brine, dried over anhydrous sodium sulfate and concentrated. Finally, indazole-4-carboxylic acid was purified by silica gel column chromatography or crystallization.
