Preparation of 3-amino-6-chloropyridine-2-carboxylic acid methyl ester_industrial additives

Preparation background and overview of methyl 3-amino-6-chloropyridine-2-carboxylate

3-Amino-6-chloropyridine-2-carboxylic acid methyl ester can be used as a pharmaceutical synthesis intermediate. If methyl 3-amino-6-chloropyridine-2-carboxylate is inhaled, move the patient to fresh air; if skin contact occurs, remove contaminated clothing and rinse skin thoroughly with soap and water. If discomfort occurs If you feel sick, seek medical attention; if eye contact occurs, separate eyelids, rinse with running water or saline, and seek medical attention immediately; if ingested, rinse mouth immediately, do not induce vomiting, and seek medical attention immediately.

Preparation of methyl 3-amino-6-chloropyridine-2-carboxylate

Step 1: Preparation of 3-amino-6-chloro-2-iodopyridine

Dissolve 5-amino-2-chloropyridine (3.0g) in DMF (40mL), add N-iodosuccinimide (5.25g), and stir the reaction mixture at room temperature for 3 hours. Water and MTB-ether were added to the reaction mixture, the layers were separated, and the organic layer was washed 3 times with water, brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel 60, hexane/ethyl acetate = 3:1) to obtain 4.80 g of the title compound of formula as an orange solid. Rf=0.30.

Step 2: Preparation of 3-amino-6-chloro-2-(2-furyl)pyridine

Suspend 3-amino-6-chloro-2-iodopyridine (1.78g), 2-furanoboronic acid (1.17g) and sodium carbonate (1.11g) in a solvent mixture of toluene (23mL), THF (23mL) middle. ) and water (7 ml). The mixture was degassed using subsequent evaporation and flushed with nitrogen (5x) and tetrakis(triphenylphosphine)palladium(0) (808 mg) was added. The reaction mixture was stirred at 90°C for 7 hours and at room temperature for 14 hours. After adding 2-furanoboric acid (783 mg), the mixture was stirred at 90 °C for a further 4 hours, then another portion of 2-furanoboronic acid (390 mg) was added and the reaction mixture was stirred at 90 °C for 5.5 hours.

After stirring at room temperature for 15 hours, the reaction mixture was quenched with water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel 60, hexane/ethyl acetate 3:1) to obtain 1.26 mg of the title compound of the following formula as a beige solid. The compound contained ~10% 3-amino-6-chloro-2-iodopyridine and was used in the next step without further purification. Rf=0.25.

Step 3: Preparation of 3-amino-6-chloro-pyridine-2-carboxylic acid

Dissolve 3-amino-6-chloro-2-(2-furyl)pyridine (1.06g) in acetone (25mL) and cool to 0°C in an ice bath. To this solution was added dropwise a solution prepared from potassium permanganate (2.57 g) in water (40 mL). After the addition is complete, the reaction mixture is warmed to room temperature and stirred for several hours. The mixture was cooled again to 0 °C, a second solution of potassium permanganate (858 mg) in water (15 mL) was added, and the cold bath was removed. After stirring for 2 hours, the reaction mixture was filtered through a pad of Celite, and the filter cake was carefully washed with water, methanol and ethyl acetate and concentrated to approximately 20 mL on a rotary evaporator.

2N sodium hydroxide solution was added to adjust the pH to ~12 and the aqueous layer was washed 2 times with MTB-ether. The aqueous layer was adjusted to pH~2 by adding 6N methyltetrahydrofuran hydrochloric acid and extracted three times with MTB-ether. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo to afford 636 mg of the title compound of formula as a brown solid. The compound still contained ~30% of unknown impurities and was used in the next step without further purification.

Step 4: Preparation of 3-amino-6-chloro-pyridine-2-carboxylic acid methyl ester

3-Amino-6-chloro-pyridine-2-carboxylic acid (636 mg) was suspended in methanol (8 mL) and toluene (22 mL) was added. A solution of (trimethylsilyl)diazomethane (2.0 M in hexanes, 2.4 mL) was slowly added to the reaction mixture. After stirring for 1 hour at room temperature, another portion of (trimethylsilyl)diazomethane (550 μl) was added and the mixture was stirred for a further 45 minutes. The reaction mixture was quenched with water and extracted three times with ethyl acetate. The combined organic layers were washed with 2N hydrochloric acid, saturated bicarbonate solution and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel 60, chloroform/ethyl acetate 50:1) to give 365 mg of the title compound of formula as a yellow solid. Rf0.30.

1H-NMR (CDCl3TMS) δ (ppm): 3.96 (3H, s), 5.82. (2H, brs), 7.05 (1H, d, J=9Hz), 7.23 (1H, d, J=9Hz)).