Methyl 4-chloro-3-fluoropicolinate

67-56-1

1034921-07-7

1034921-05-5

A. The synthesis of methyl 4-chloro-3-fluoropyridinecarboxylate was carried out according to the literature method (see: Proc. Int., 29(1), 117-122 (1997)). The procedure was as follows: lithium 4-chloro-3-fluoropyridinecarboxylate (20.0 g, 136 mmol) and sodium bromide (28.0 g, 272 mmol, 2 eq.) were suspended in thionyl chloride (99 mL, 1.36 mol, 10 eq.), and the system was replaced by argon and heated to reflux (95°C). The reaction mixture was refluxed for 2 days, then thionyl chloride (50 mL, 680 mmol, 5 eq.) was added and refluxing was continued for 3 days. Upon completion of the reaction, the solvent was removed by evaporation and the residue was cooled to 0°C. Subsequently, methanol (300 mL) was added carefully in batches and the mixture was stirred overnight at 23°C. The reaction solution was diluted with ethyl acetate. The reaction solution was diluted with ethyl acetate and washed sequentially with saturated aqueous sodium carbonate solution and water, and the aqueous phase was then back-extracted with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was dissolved in boiling hexane and decanted to remove residual tar. The filtrate was evaporated to afford the target product methyl 4-chloro-3-fluoropyridinecarboxylate (24.36 g, 94% yield) as a solid. The product was confirmed by 1H NMR (400 MHz, DMSO-d6): δ 3.92 (3H, s), 8.01 (1H, t, J = 5.1 Hz), 8.50 (1H, d, J = 5.1 Hz). lC/MS (M + H)+: 190.