Preparation method of 5-chloro-3-fluoro-2-pyridinecarboxylic acid_Industrial additives

Overview of the preparation method of 5-chloro-3-fluoro-2-pyridinecarboxylic acid

5-Chloro-3-fluoro-2-pyridinecarboxylic acid is an organic intermediate, and its synthesis method is rarely reported. It can be prepared from 5-chloro-3-fluoro-2-iodopyridine in two steps.

Preparation method of 5-chloro-3-fluoro-2-pyridinecarboxylic acid Preparation method

Method 1: In a dry ice/methanol bath, add 5-chloro-3-fluoro-2-iodopyridine (1c; 3.9g, 15mmol) to butyllithium (15mmol) in toluene (20mL) and hexane ( 10mL) solution. After 1 hour at -75°C, the reaction mixture was poured onto an excess of freshly crushed solid carbon dioxide. After evaporating the volatiles, add water (50 mL) to the residue, wash with ethyl acetate (2-15 mL) and acidify to Ph=1, collect the precipitate formed, dry and recrystallize with ethanol to obtain colorless prismatic crystals of 5-chloro -3-Fluoro-2-pyridinecarboxylic acid; melting point 172-174°C; obtained 2.5 g (94%).

¹HNMR(D₃CCOCD₃): δ8.57(dd, J1.9, 0.9Hz, 1H), 8.05 (dd, J9.9, 1.9Hz, 1H)ppm.¹³CNMR (D₃CCOCD₃): δ162.8(d, J6Hz), 159.7 (d, J275Hz), 144.8 (d, J5 aminophenylboronic acid pinacol ester Hz), 136.5 (d, J4Hz), 136.0 (d, J9Hz), 127.0 (d, J23Hz) ppm.C6H3ClFNO2 (175.55 ): calcd.C41.05, H1.72; foundC40.91, H2.08.

Method 2:

1) Place 423g of ethyl 3-chloro-5-trifluoromethyl-2-pyridinecarboxylate (embodiment P2) in a mixture of 800ml of water and 160ml of ethanol. Add 800ml 2N sodium hydroxide solution dropwise below 35°C. After 3 hours, the mixture was washed twice with methylene chloride and then acidified with an excess of concentrated hydrochloric acid while cooling in an ice bath. The resulting slurry was filtered, washed with water, and dried under vacuum. 318 g of the desired product were obtained as a white solid with a melting point of 135°C (decomposition). Barium carbonate

2) Add 70g ethyl 3-fluoro-5-chloro-2-pyridinecarboxylate to 105ml dimethyl sulfoxide (DMSO). Add 230 ml of 2N sodium hydroxide solution dropwise within 30 minutes at 40°C. The resulting yellow suspension was introduced into a mixture of 2 liters of ice water and ml of 2N hydrochloric acid. After stirring for 20 minutes, the mixture was filtered and the filtration residue was washed twice with water. 56.4 g of the desired target compound 5-chloro-3-fluoro-2-pyridinecarboxylic acid were obtained as a white solid. ¹H-NMR (DMSO-d₆): 13.79ppm (wide signal, 1H); 8.60ppm (d, 1H); 8.27ppm (dxd, 1H).