Preparation method of 2-chloro-5-nitropyridine_Industrial additives

Background and overview of the preparation method of 2-chloro-5-nitropyridine

2-Chloro-5-nitropyridine is an important fine chemical intermediate that can be used to prepare a variety of drugs and pesticides such as the antimalarial drug pyronaridine, the fungicide cyclostrobin and some antibiotics. It has a wide range of uses in medicine and pesticide production and has great production value.

Preparation method of 2-chloro-5-nitropyridine

Preparation method report 1 of 2-chloro-5-nitropyridine,

A method for preparing 2-chloro-5-nitropyridine using dichlorine monoxide is to combine 3-nitropyridine with 1-3 times the amount of alkali and 1-2 times the amount of chlorine based on the molar ratio. Mix the chemical salt and the solvent evenly, and cool it to -15°C to -10°C. Dissolve dichlorine monoxide with a molar ratio of 2-3 times in the solvent, then drop it into the reaction mixture with full stirring, and keep it at -10 ℃ to 0 ℃, complete the dropwise addition in 2 hours, raise the temperature to room temperature and continue stirring for 2 hours until the raw material 3-nitropyridine reacts completely. Pour the reactant into ice water, separate the organic layer, collect the organic layer, and use the mass of the organic layer Wash once with 5% hydrochloric acid and once with water, dry with anhydrous magnesium sulfate, and evaporate the organic solvent under reduced pressure to obtain 2-chloro-5-nitropyridine.

Preparation method report 2 of 2-chloro-5-nitropyridine,

Step 1, synthesis of 2-amino-5-nitropyridine

Add 2-aminopyridine (60.2g, 0.639mol) into concentrated sulfuric acid (150mL) while stirring and controlling the temperature to <10°C. After 2-aminopyridine is completely dissolved, keep the temperature <30°C and add it dropwise. After adding the mixed acid of concentrated sulfuric acid (95mL) and fuming nitric acid (95mL, 2.37mol), keep the temperature at 25~30℃ and stir for 40min, then raise the temperature to 55~65℃ and keep it for 11h. TLC detects the reaction of the raw material 2-aminopyridine. Complete, the reaction is over, pour the reaction solution into crushed ice (1000g), use 50wt.% sodium hydroxide aqueous solution to adjust pH=5.5~6.0, filter the precipitate, rinse the filter cake with ice water (100mL×2), and filter Dissolve the cake in 10wt.% hydrochloric acid aqueous solution (200mL), filter with suction to remove the oil on the surface, use 50wt.% sodium hydroxide aqueous solution for the filtrate, adjust pH=4.0~5.0, filter and precipitate, ice water (50mL× 2) Rinse the filter cake and dry it to constant weight to obtain 2-amino-5-nitropyridine, yield: 85.7%.

Step 2, synthesis of 2-hydroxy-5-nitropyridine

Dissolve 2-amino-5-nitropyridine (138.1g, 1.000mol) in 15wt.% hydrochloric acid aqueous solution (913mL, 4.500mol), filter, and cool the filtrate to -5~0°C with stirring. Control the temperature to -5~0°C, add sodium nitrite (103.5g, 1.500mol) water (100mL) solution dropwise. After the dropwise addition is completed, keep the temperature at 0~5°C and continue stirring for 45 minutes. TLC detects that the reaction is complete. Filter and remove the filtrate. Distill under reduced pressure, and the residue is recrystallized with a mixed solution of water and ethanol with a volume ratio of 2:1 to obtain 2-hydroxy-5-nitropyridine, with a final yield of 81.3%.

Step 3, synthesis of 2-chloro-5-nitropyridine

Put the raw materials 2-hydroxy-5-nitropyridine (321.7g, 2.296mol), N,N-diethylaniline (361.8g, 2.985mol) and tetraethylammonium chloride (95.1g, 0.574mol) ) into phosphorus oxychloride (350mL), react at 120-125°C for 5-8 hours, TLC detects that the raw material 2-hydroxy-5-nitropyridine has reacted completely, cool the reaction to <50°C, and evaporate excess trichloride under reduced pressure Oxygen phosphorus, pour the residue into crushed ice (5000g), stir until the ice is completely melted, filter with suction, rinse the filter cake with ice water (100mL×3), and dry to constant weight to obtain the target product 2-chloro-5 -Nitropyridine, yield: 76.9%.

Preparation method report 3 of 2-chloro-5-nitropyridine

Step 1,

Into a 500 ml four-necked flask connected to a stirrer, thermometer, and reflux condenser, add 30.5 g (0.5 mol) nitromethane, 60.5 g (0.5 mol) methyl 2-chloroacrylate, 1.5 g DBU, 50- Stir and react at 55°C for 5 hours, then add 110.5g (0.75 mol) triethyl orthoformate and 8.0g of zinc chloride, stir and react at 95-100°C for 4 hours, then cool to 50°C, add 200.0g of 10% ammonia water, 50 grams of methanol, 10.0 grams of ammonium chloride, stir and react at 50-55°C for 6 hours, cool to 20°C, filter, use 120 grams of isopropyl alcohol and 1.0 grams of activated carbon to recrystallize the filter cake to obtain 61.5 grams of yellow needle-shaped solid 2- Hydroxy-5-nitropyridine, the difluoropyridine recovery rate is 87.8%, and the liquid phase purity is 99.8%.

Step 2,

Add 380 grams of phosphorus oxychloride, 50.0 grams (0.36mol) 2-hydroxy-5-nitropyridine, and 110.1 grams (0.54mol) into a 500mL four-necked flask equipped with a thermometer, mechanical stirring, and reflux condenser. Phosphorus pentachloride, stir and react at 60°C for 16 hours, then distill under reduced pressure to recover excess phosphorus oxychloride. Pour the residue into 300 grams of ice water, stir thoroughly, and then extract three times with ethyl acetate, 80 grams each time, and combine the organic phases , and washed with 50 grams of saturated brine, then dried with 10 grams of anhydrous sodium sulfate, and the ethyl acetate was removed by rotary evaporation to obtain 51.0 grams of yellow needle-like solid 2-chloro-5-nitropyridine, yield 89.5%, liquid phase purity 99.5%. Melting point: 109–111°C; NMR data of the product are as follows: ¹HNMR (CDCl₃, δ, ppm): 9.25 (d, 1H), 8.47 (d methoxy phenylboronic acid d,1H), 7.57(d,1H); ¹³CNMR (CDCl₃, δ, ppm): 157.1, 145.4, 143.4, 133.6, 124.8. .

References

[1][Chinese invention] CN201810712826.9 A preparation method for preparing 2-chloro-5-nitropyridine using dichlorine monoxide

[2][Chinese invention] CN201010576082.6 A preparation method of 2-chloro-5-nitropyridine

[3][China invention, China invention authorization] CN201710795679.1 A preparation method of 2-chloro-5-nitropyridine with high yield