Synthesis
General procedure for the synthesis of 4-iodo-1-methyl-1H-pyrazole-3-carboxylic acid from ethyl 4-iodo-1H-pyrazole-3-carboxylate and iodomethane: NaH (60% dispersion in mineral oil, 0.72 g, 18 mmol, 1.2 eq.) was added batchwise to ethyl 4-iodo-1H-pyrazole-3-carboxylate (4.2 g, 15 mmol, 1.0 eq.) in a The mixture was again cooled to 0 °C and iodomethane (1.0 mL, 16.5 mmol, 1.1 eq.) was slowly added. After the reaction mixture solidified, the cold bath was removed and the reaction was continued for 1 h at room temperature. The progress of the reaction was monitored by analytical HPLC to confirm complete consumption of the feedstock and then the reaction was quenched by the slow addition of water (0.5 mL) followed by the slow addition of 2 M NaOH solution (1.0 equiv) under stirring. The reaction mixture was stirred at room temperature until the ester groups were completely hydrolyzed (1-2 hours). The light yellow suspension was filtered and the yellow solid product was collected. The filtrate was concentrated under vacuum and washed with hexane to remove the mineral oil. The aqueous layer and the solid product were combined and the pH was adjusted to 12 with 6N HCl. The aqueous layer was extracted with EtOAc (3 times), the organic phases were combined, washed with brine, dried over anhydrous Na2SO4, and concentrated to give 4-iodo-1-methyl-1H-pyrazole-3-carboxylic acid as a light yellow solid, which can be used without further purification.
