Synthesis of 4,6-dichloropyridine[3,2-D]pyrimidine_Industrial additives

Overview of the synthesis of 4,6-dichloropyridine[3,2-D]pyrimidine

4,6-Dichloropyridine[3,2-D]pyrimidine is an organic intermediate, which can be mainly used as a pharmaceutical intermediate in laboratory research and development processes and chemical production processes.

Synthesis method of 4,6-dichloropyridine[3,2-D]pyrimidine

(1) Preparation of 2,6-dichloro-3-nitropyridine ⑴

Add 10 mL concentrated sulfuric acid dropwise into 10 mL concentrated nitric acid under an ice bath to prepare a mixed acid solution, stir for 10 minutes, and place 2,6-dichloropyridine (4.4 g, 30 mmol) in a 100 mL eggplant-shaped bottle. , add 20 mL of concentrated sulfuric acid, add the prepared mixed acid solution dropwise while stirring in an ice bath. After stirring for 1 hour, raise the temperature to 120°C and continue stirring, and use alkaline solution to absorb the tail gas. Stop the reaction after 4h and cool to room temperature. The reaction liquid was dropped into the sodium hydroxide water-soluble pyridyl acetic acid solution under an ice bath, and a large amount of light yellow solid was precipitated. After the reaction liquid was dropped, adjust the pH to 8 with alkali solution, stir for 10 minutes, and obtain 4.8g of light yellow solid by suction filtration. The yield is 81%.

(2) Preparation of 2-amino-3-nitro-6-chloropyridine (2)

Add 1 (10.0g, 52mmol), cuprous cyanide (9.3g, 104mmol) and 150mL N-methylpyrrolidone into a 250mL eggplant-shaped bottle, quickly heat the oil bath to 180°C, and stir After 2 hours, TLC monitored that the reaction was complete, cooled to room temperature, poured the reaction solution into 600 mL of ice-water mixture, stirred for 30 min, filtered with suction to obtain a brown solid, and washed the filter cake with water. Dissolve the filter cake in 150 mL toluene, heat to reflux for 10 minutes, filter while hot, repeat this operation twice with the residue, combine the filtrate, wash three times with water and once with saturated brine, dry with anhydrous sodium sulfate, evaporate toluene, and column chromatography yields yellow color Solid 4.0g, yield 41%.

(3) Preparation of 3-amino-6-chloropeneneamide (3)

Add 2 (2.0g, 10.9mmol), stannous chloride (10.0g, 43.6mmol) and 20mL ethanol into a 50mL eggplant-shaped flask. Stir at room temperature for 2h. TLC will monitor the reaction for completeness. Cool to room temperature and evaporate the solvent. , redissolve the obtained solid with ethyl acetate, adjust the pH to 6 with 2mol/L sodium hydroxide aqueous solution, continue to adjust the pH to 7 with saturated sodium bicarbonate aqueous solution, filter, collect the filtrate, separate the organic layer, and use ethyl acetate for the aqueous layer Extract twice, combine the organic layers, wash once with saturated sodium chloride, dry with anhydrous sodium sulfate, and evaporate the filtrate to dryness to obtain 2.5g of yellow solid, yield 67%.

Preparation of (4) 6-chloropyrido[3,2-d]pyrimidin-4(1H)-one ⑷

Add 3 (2.5g, 14.6mmol) and triethyl orthoformate (100mL, 60mmol) into a 250mL eggplant-shaped flask, react at 140°C for 2h, monitor the reaction is complete by TLC, cool to room temperature, filter to obtain a filter cake, and dry 2.1g of light yellow solid was obtained, with a yield of 80%.

Preparation of (5) 4,6-dichloropyrido[3,2-d]pyrimidine (5)

Add 4 (1.5g, 8.3mmol) into a 50mL eggplant-shaped flask, add 30mL phosphorus oxychloride and 2 drops of N,N-dimethylaniline, and react at 107°C for 1 hour. TLC monitors that the reaction is complete and cools. Evaporate the solvent to dryness, redissolve the solid obtained with dichloromethane, adjust the pH to 7 with saturated sodium bicarbonate aqueous solution, filter to remove the insoluble solid, separate the dichloromethane layer and the water layer, extract the water layer twice with dichloromethane, and combine the dichloromethane The methane layer was dried over anhydrous sodium sulfate. Column chromatography yielded 1.1 g of white solid, with a yield of 65%.

References

CN110903286A: 4,6-disubstituted pyridine [3,2-d] pyrimidine compounds and tributyl borate and their preparation and application