Preparation method of 3-amino-4,6-dichloro-2-pyridinecarboxylic acid_Industrial additives

Background and overview of the preparation method of 3-amino-4,6-dichloro-2-pyridinecarboxylic acid

3-Amino-4,6-dichloro-2-pyridinecarboxylic acid is an organic intermediate that can be prepared from 3-aminopyridine through a four-step reaction.

Preparation method of 3-amino-4,6-dichloro-2-pyridinecarboxylic acid

Preparation method of 3-amino-4,6-dichloro-2-pyridinecarboxylic acid Step 1: Preparation of 2-chloro-3-aminopyridine

Dissolve 3-aminopyridine (25.0g) in concentrated hydrochloric acid (250mL, 37%) at 30-35°C and cool in an ice bath after the raw materials are completely dissolved. Maintaining below 10 °C, slowly add hydrogen peroxide (28.5 mL, 30% aqueous solution) to the solution using a dropping funnel. The orange solution was slowly warmed to room temperature over 2 hours and stirred at room temperature for a further 2 hours. Cool the solution in an ice bath, and slowly add 160 mL of aqueous sodium hydroxide solution (50%) with dimethoxypyridine. For acidic aqueous solution. Wash with 30 mL of toluene, and extract the organic washings once again with 5N aqueous hydrochloric acid solution. Aqueous sodium hydroxide solution (50%) was added to the combined acidic aqueous solution and the pH was adjusted to ~8-10. The aqueous solution was extracted three times with 200 mL of toluene, and the organic layer of pyridinium chlorochromate was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (silica 60, chloroform/ethyl acetate 20:1) to give 17.6 g of the title compound of formula as an orange solid. Rf = 0.25. ¹H-NMR (CDCl₃, TMS) δ (ppm): 4.12 (2H, br s), 7.04-7.05 (2H, m), 7.78-7.81 (1H, m).

Preparation method of 3-amino-4,6-dichloro-2-pyridinecarboxylic acid Step 2: Preparation of 3-aminopyridine-2-carbonitrile

Dissolve 2-chloro-3-aminopyridine (2.0g) in DMF (24mL) and add zinc cyanide (1.83g) to the solution. The solution was degassed 5 times in vacuum, tetrakis(triphenylphosphine)palladium(0) (901 mg) was added, and the reaction mixture was stirred at 90 °C for 7 h. After the reaction mixture was cooled to room temperature, the solid was removed by filtration, and the filter cake was washed with ethyl acetate. Water was added to the filtrate, the layers were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed 3 times with water, washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica 60, chloroform/ethyl acetate 3:1) to give 755 mg of the title compound of formula as a white solid. Rf = 0.25. ¹H-NMR (CDCl₃ TMS) δ (ppm): 4.43 (2H, br s), 7.10 (1H, dd, 10 J= 9 Hz, 1 Hz), 7.25-7.29 (1H, m), 8.07 (1H, dd, J= 4 Hz, 1 Hz).

Preparation method of 3-amino-4,6-dichloro-2-pyridinecarboxylic acid Step 3: Preparation of 3-amino-4,6-dichloropyridine-2-carbonitrile

Dissolve 3-aminopyridine-2-carbonitrile (100 mg) in DMF (2 mL) and add N-succinimide (246 mg). The solution was stirred at room temperature for 20 hours, then water was added. The mixture was extracted twice with ethyl acetate, the combined organic layers were washed three times with water, brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica 60, hexane/ethyl acetate = 3:1) to obtain 121 mg of the title compound of formula as an orange solid. R_f = 0.30. ¹H-NMR (CDCl₃, TMS) δ (ppm) 4.92 (2H, br s), 7.44 ( 1H, s).

Preparation method of 3-amino-4,6-dichloro-2-pyridinecarboxylic acid Step 4: Preparation of 3-amino-4,6-dichloro-2-pyridinecarboxylic acid

Dissolve 3-amino-4,6-dichloropyridine-2-carbonitrile (121 mg) in concentrated sulfuric acid (1 mL) and stir at 100°C for 1 hour. The reaction mixture was cooled to room temperature and water (1 mL) was slowly added. The reaction mixture was warmed again to 100°C and stirred at this temperature for 2 hours. After cooling to room temperature, water was added, the pH was adjusted to ~10 by adding solid sodium bicarbonate, and the aqueous solution was washed 2 times with MTB-ether. The aqueous layer was then adjusted to pH ~2 by adding 2M hydrochloric acid and extracted 3 times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated in vacuo to afford 99 mg of the title compound of formula as a yellow solid. ¹ H-NMR (CDCl₃, TMS) δ (ppm): 6.37 (2H, brs), 7.47 (1H, s), 10.50 (1H, brs). ¹H-NMR (CDCl₃, TMS) δ (ppm): 6.37 (2H, br s), 7.47 (1H, s), 10.50 (1H, br s) ).

References

[1] From PCT Int. Appl., 2008130021, 30 Oct 2008