2,4-DIFLUORO-3-METHYLBENZOIC ACID

74-88-4

1583-58-0

112857-68-8

1. To a stirred solution of diisopropylamine (1.7 g, 16.4 mmol) in anhydrous THF (30 mL) was slowly added a 2.6 M solution of n-butyllithium (n-BuLi, 1.1 g, 16.4 mmol) under nitrogen protection, the reaction temperature was maintained at -30 °C, and stirring was continued for 1 h at this temperature. 2. The reaction system was cooled to -78 °C and a solution of anhydrous THF (10 mL) of 2,4-difluorobenzoic acid (1.0 g, 6.3 mmol) was added slowly and dropwise, followed by the addition of iodomethane (2.2 g, 15.7 mmol). 3. The reaction mixture was gradually warmed to 50 °C and stirred at this temperature for 2 hours. 4. Upon completion of the reaction, the mixture was returned to room temperature and the reaction was quenched with saturated aqueous ammonium chloride (NH4Cl) solution. 5. The aqueous layer was separated and extracted with ethyl acetate (3 x 25 mL). The organic phases were combined and dried over anhydrous sodium sulfate (Na2SO4). 6. Concentrate under reduced pressure to remove the solvent, and the resulting crude product was purified by silica gel column chromatography, the eluent being a solvent mixture of ethyl acetate/petroleum ether. 7. The target fraction was collected and concentrated under reduced pressure to give a white solid product, 2,4-difluoro-3-methylbenzoic acid (0.77 g, 70% yield). 8. The product was characterized by mass spectrometry (ESI) m/z: 172 [M+H]+, corresponding to the molecular formula C8H6F2O2; 1H NMR (400 MHz, CDCl3) δ: 2.2 (s, 3H), 7.0 (m, 1H), 7.9 (m, 1H).