Ethyl 1-methyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate

571-55-1

60-34-4

231285-86-2

General procedure: Intermediate 65a: Synthesis of ethyl 1-methyl-5-(trifluoromethyl)pyrazole-4-carboxylate 1. methylhydrazine (1.2 mL, 22.7 mmol) was slowly added to a mixture of concentrated hydrochloric acid. 2. HCl (1.95 mL, 23.7 mmol) and EtOH (1.9 mL) were added to the mixture at 0 °C and stirred at that temperature for 30 min. 3. the reaction mixture was diluted with EtOH (7.7 mL). 4. the resulting ethanol solution of methylhydrazine hydrochloride was slowly added to a solution of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (4.00 mL, 20.7 mmol) in EtOH (58 mL) at 0°C. 5. The reaction mixture was allowed to warm slowly to room temperature and stirred overnight. 6. The light yellow solution was concentrated in vacuum and the residue was suspended in water (20 mL). 7. Alkalize the aqueous phase with saturated aqueous NaHCO3, add Na2CO3 (20 mL) and extract with EtOAc (3 x 30 mL). 8. The organic layers were combined, washed with brine (30 mL), dried over Na2SO4, filtered and concentrated in vacuum. 9. The residue was purified by column chromatography (eluent: 0-50% EtOAc in heptane) to afford ethyl 1-methyl-5-(trifluoromethyl)pyrazole-4-carboxylate (2.91 g, 13.09 mmol, 64% yield) as a colorless oil. Characterization data: 1H NMR (CDCl3, 400 MHz) δ/ppm: 7.93 (1H, s), 4.34 (2H, q, J = 7.2 Hz), 4.09 (3H, s), 1.37 (3H, t, J = 7.2 Hz). 19F NMR (CDCl3, 400 MHz) δ/ppm: -57.1. MS (Method 2): RT: 1.62 min, m/z 223.0 [M + H]+.