4,6-Dichloronicotinic acid

White solid

Sodium hydroxide (40 mL, 6.25 M solution) was added to a stirred solution of 4, 6-dichloronicotinic acid ethyl ester (22) (25.95 g, 118 mmol) in 4:1:1 THF:MeOH:water (600 mL). After 30 minutes, the reaction mixture was acidified to pH 2 with concentrated HCl, diluted with 1:1 EtOAc:Et2O and washed with water and brine. The organic layer was dried (Na2SO4) and concentrated. The resulting off-white solid was twice concentrated from toluene to give the desired product (23) as a white solid (21.73 g, 96percent).Step B: Scheme 30 compound 1 and LiOH were dissolved in THF/HIntermediate 521A: 4, 6-Dichloronicotinic acid [0610] ethyl 4, 6-dichloronicotinate (8 g, 36.4 mmol) in THF (50 mL), ethanol (25 mL) and water (25 mL) was added LiOH (2.61 g, 109 mmol). The mixture was stirred at 25° C. for 2 hours. The reaction mixture was concentrated to remove solvent. The residue was dissolved in water and acidified to neutral pH with 1.5 N HCl. The precipitated solid was filtered and washed with water (2×30 mL). The solid was dried to afford 4, 6-dichloronicotinic acid (6.5 g, 83percent yield). LCMS 194.1 (M+2); To a solution of ethyl 4, 6-dichloronicotinate (8 g, 36.4 mmol) in THF (50 mL), ethanol (25 mL) and water (25 mL) was added LiOH (2.61 g, 109 mmol). The mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated in vacuo. Theresidue was dissolved in water and acidified to neutral pH with 1.5 N HC1. The precipitated solid was filtered and washed with water (2 x 30 mL). The solid was dried under vacuum to afford 4, 6-dichloronicotinic acid (6.5 g, 83percent yield). LCMS m/z 194.1 (M+2); ‘H NMR (400 MHz, DMSO-d6) 8.80 (s, 1H), 7.93 (s, 1H).Dichloropyridine X.1 (prepared using the procedure described in Brunette, S. R.; Kim, J. M.; Lemieux, R. M.; Aaron, M. US2006/0217417.) (164 mmol based on the theoretical yield of the previous step) was diluted with 100 mL of 1, 4-dioxane followed by 1 M LiOH (197 mL, 197 mmol). The resulting cloudy solution was then stirred at rt until all starting material was consumed. The crude mixture was then acidified to pH=2 with 6 M HCl, then diluted with water until ppt formation ceased. The solids were then isolated by filtration affording the desired product as a light beige powder (22.14 g, 70percent). MS found for C6H3Cl2NO2 as (M+H)(1) 2, 4-dichloro-nicotinic acid ethyl (6.0g), It was added 1N aqueous sodium hydroxide solution (41 mL) in a mixture of methanol (5 mL) and THF (5mL). After stirring for 30 minutes at 20-25 , it was pH4 by the addition of 1 N hydrochloric acid. The precipitated crystals were collected by filtration, washed with water to give 4.79g of the dried 4, 6-dichloro-pyridine-3-carboxylic acid4, 6-Dichloro-nicotinic acid methyl ester (27.3 g, 133 mmol) was dissolved in THF (150 mL). LiOH (3.53 g, 147 mmol), dissolved in H[00217] Step B; 4.6-Dichloronicotinic acid:[00218] To a solution of methyl 4, 6-dichloronicotinate in a mixture of THF (400 ml), MeOH ( 100 ml) andHTo a stirred solution of methyl 4, 6-dichloropyridine-3-carboxylate (3.5 g, 16.990 mmol) in THF (30 mL) was added a solution of lithium hydroxide monohydrate (3.56 g, 84.951 mmol) in water (15 mL). The reaction mixture was stirred at RT for 1.5 h. The progress of reaction was monitored by TLC. After completion of reaction, the pH of the aqueous layer was adjusted to 2 by the addition of 2 N HC1 (aq.) and the product was extracted with EtOAc (2x50 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 4, 6- dichloropyridine-3-carboxylic acid (3.2 g) as a white solid.Lithium hydroxide monohydrate (665 mg) was added to a solution of methyl 4, 6-dichloronicotinate (2.97 g) in THF (60 mL) and water (15 mL) at room temperature, and the mixture was stirred at room temperature for 1 hr. To the reaction solution was added 6N hydrochloric acid at room temperature, and the solvent was evaporated under reduced pressure. The residual solid was washed with water to give a white solid. The filtrate was extracted with ethyl acetate. The extract was washed with water and saturated brine, combined with an ethyl acetate solution of the solid obtained earlier, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (2.60 g) as a pale-yellow solid. (1378)

Molecular Weight:192.00
XLogP3:2
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:190.9540837
Monoisotopic Mass:190.9540837
Topological Polar Surface Area:50.2
Heavy Atom Count:11
Complexity:165
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes