Hydrochloric Acid → 6-Chloro-N-(4-fluorophenyl)picolinamide

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Reaction Conditions

Reaction Steps

[A1 is N, A2 is Cl—C, A3, A4 and A5 are CH, R1 is 4-fluorophenyl, X is NR2 and R2 is H in the compound of formula I] Concentrated sulfuric acid (98% by weight, 127.5 g, 1.3 mol) is added to 2-chloro-6-trichloromethylpyridin (NP, 231 g, 1 mol) over a period of three hours at 135° C. The resulting mixture is stirred for three hours at 135° C. A viscous melted mass is obtained consisting of a mixture of intermediate IVa1 and Va1 with R1 being H and Hal being Cl, corresponding to a yield of >95% based on NP. This intermediate product shows a strong infrared band at 1770cm−1 indicating a carbonylchloride group. 13C-NNR (TMS/nitromethane-d3): δ=130.2 (CH-5), 135.3 (CH-3), 143.7 (C-2), 151.4 (CCl-6), 151.5 (CH-4), 164.1 (C═O) ppm. The mass is added to a mixture of 4-fluoroaniline (166.4 g 1.5 mol), triethylamine (202.0 g, 2 mol) and toluene (752 g) at temperatures between 20 and 80° C. over a period of 45 minutes. The resulting reaction mixture is heated to temperatures between 80 and 100° C. and stirred for one hour. The mixture is treated with 500 ml of hydrochloric acid (1.0% by weight) at 80° C. and the phases are separated. The resulting solution of N-(4-fluorophenyl) 2-chloro-pyrid-6-ylinecarboxamide in toluene is used for the preparation of N-(4-fluorophenyl) 2-(3-trifluoromethylphenoxy)-pyrid-6-ylinecarboxamide without further purification.

Provenance & Evidence