The general procedure for the synthesis of 6-chloro-5-fluoro-1H-indazole from 4-chloro-2,5-difluorobenzaldehyde was as follows: a mixed solution of 4-chloro-2,5-difluorobenzaldehyde (20.6 g, 105.0 mmol) and hydrazine hydrate (77.2 mL, 1575.2 mmol, 15 eq.) in n-butanol (35 mL) was stirred and reacted for 3 days at 140 °C. Upon completion of the reaction, the mixture was cooled to room temperature and slowly poured into ice water (750 mL). Subsequently, the mixture was stirred vigorously for 2 h. The precipitated orange solid was collected by filtration. The filtrate was extracted with ethyl acetate (3 x 250 mL), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrated residue was combined with the previously collected orange solid and purified by medium pressure liquid chromatography (MPLC, Biotage system, gradient elution, 25% ethyl acetate/hexane) to give 2.81 g (16% yield) of the target product, 6-chloro-5-fluoro-1H-indazole, as a white solid. The product was characterized by 1H-NMR (300 MHz, DMSO-d6): δ 13.3 (broad single peak, 1H), 8.09 (single peak, 1H), 7.80-7.76 (multiple peaks, 2H); ES-MS m/z 171.2/173.2 [M+H]+, retention time (RT) 3.02 min.
