741717-63-5

591-50-4

155377-19-8

741717-63-5

Part I: Preparation of preferred intermediates Preparation of 1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid Ethyl 3-trifluoromethyl-1H-pyrazole-4-carboxylate (2.5 g, 12.0 mmol), copper(I) iodide (0.69 g, 3.6 mmol), and potassium carbonate (3.49 g, 25.3 mmol) were placed in a round-bottomed flask and toluene (12 mL) was added as a solvent. The system was purged with argon to remove oxygen. Subsequently, iodobenzene (1.61 mL, 14.4 mmol) and racemic trans-N,N'-dimethyl-cyclohexane-1,2-diamine (1.16 mL, 7.2 mmol) were added to the reaction system. The reaction mixture was heated and stirred under argon protection in an oil bath at 110°C for 24 hours. Upon completion of the reaction, it was cooled to room temperature, the reaction mixture was diluted with ethyl acetate and filtered through a bed of diatomaceous earth. The organic phase washings were combined and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (Isco 120g column, elution gradient 0→30% ethyl acetate/hexane) to afford ethyl 1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylate (2.91 g, 85% yield) as an off-white solid. The structure of the product was confirmed by NMR spectroscopy. Ethyl 1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylate (1.25 g, 4.4 mmol) was dissolved in methanol (20 mL), 1N aqueous sodium hydroxide (17.3 mL) was added, and the hydrolysis reaction was carried out by stirring overnight at room temperature. After the reaction was completed, the reaction mixture was concentrated under reduced pressure and acidified with 1N aqueous hydrochloric acid to pH~1. The resulting slurry was extracted with dichloromethane, and the organic layers were combined, washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration and concentration under reduced pressure, 1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (1g, 89% yield) was obtained as an off-white solid, which could be used for the subsequent reaction without further purification.LCMS analysis: calculated value of C11H7F3N2O2 (m/e) 256, measured value 255 (M-H).