1.3 Preparation of 4-bromo-3-difluoromethyl-1-methylpyrazole
1.3.a) Bromination reaction: bromine (Br2, 3g) was slowly added dropwise to a solution of 3-difluoromethyl-1-methylpyrazole (2.0g) in dichloromethane (80ml) at 25°C. The reaction mixture was stirred continuously for 22 hours. The reaction mixture was stirred continuously at 25°C for 22 h. After that, 0.1 M aqueous sodium thiosulfate solution (210 ml) was added to quench the reaction. After separation of the organic phase, the solvent was removed by distillation under reduced pressure (40 °C/5 mbar). The crude product (2.4 g, from 2.8 g of crude) was purified by column chromatography (SiO2, ethyl acetate/cyclohexane 1:6) to afford 4-bromo-3-difluoromethyl-1-methylpyrazole (1.4 g). Product characterization data: EI-MS [m/z]: 210, 212 [M]+; 1H-NMR (400MHz, CDCl3): δ= 3.9 (s, 3H), 6.68 (t, 1H), 7.43ppm (s, 1H); 13C-NMR (125MHz, CDCl3): δ= 39.84, 91.47, 110.48 , 132.10, 143.54ppm.
1.3.b) Bromination of N-bromosuccinimide (NBS): a solution of N-bromosuccinimide (NBS, 7.9 g, 0.04 mol) in dimethylformamide (DMF, 20 ml) was slowly added dropwise (slightly exothermic) to a solution of 3-difluoromethyl-1-methylpyrazole (5.0 g, 0.04 mol) in DMF (40 ml) at 3-5°C. The reaction mixture was then warmed to room temperature. The reaction mixture was then warmed to room temperature and stirring was continued for 2 hours. Upon completion of the reaction, the mixture was poured into a mixture of water (200 ml) and aqueous sodium hydroxide solution (5 ml) and extracted four times with methyl tert-butyl ether (MTBE, 100 ml). The combined organic phases were washed with saturated aqueous NaCl, dried over magnesium sulfate and filtered, and the solvent was removed under reduced pressure to give 4-bromo-3-difluoromethyl-1-methylpyrazole (9.5 g; purity: 94.5% (GC analysis); yield: 95.2%).
