Several preparation methods of 2-chloro-3-cyanopyridine_Industrial additives

Background and overview of several preparation methods of 2-chloro-3-cyanopyridine

2-Chloro-3-cyanopyridine is a common and important intermediate in the pharmaceutical industry. According to literature reports, it may be reddish brown, red or light yellow. It has a wide range of uses. It can be used as a raw material to synthesize many drugs with excellent properties, such as the antidepressant mirtazapine and the anti-AIDS drug nevirapine. It also has anti-inflammatory and analgesic effects, treating wasting syndrome, etc. It can also be used as a raw material to synthesize agricultural chemicals. , used to improve feed protein utilization, and can also be used as pesticides and herbicides.

Several preparation methods of 2-chloro-3-cyanopyridine

Report on several preparation methods of 2-chloro-3-cyanopyridine 1.

The steps of synthesizing 2-chloro-3-cyanopyridine from 3-cyanopyridine are achieved by the following method: 1. Put 100~250g 3-cyanopyridine into 200~500g H2O2 with a molar concentration of 28~31% In the solution, let it stand for 2 to 3 hours, and then evaporate the water of the mixed solution at a temperature of 80 to 100°C for 3 to 5 hours to obtain dry nicotinamide-N-oxide; 2. Take 95 to 240g of dried nicotinamide-N-oxide. Put the N-oxide into the three-necked flask, add POCl3 that is 1.5 to 10 times the mass of nicotinamide-N-oxide into the three-necked flask, and then stir the mixed material in the three-necked flask at 35 to 80°C 2 ~10 hours, then take POCl3 which is 0.2~2 times the mass of nicotinamide-N-oxide and add it dropwise into the three-necked flask. The dripping needs to be completed within 0.25~0.3 hours, and then put the three-necked flask containing the mixed solution into the three-necked flask. Let it stand for 5 to 15 hours at 35 to 90°C to obtain the chlorination reaction liquid; 3. Distill the chlorination reaction liquid under reduced pressure at a temperature of 20 to 80°C and a pressure of 0.8 to 12.5kPa. until the yellow condensed liquid flows out; 4. Cool the chlorination reaction liquid after vacuum distillation to room temperature, and then add it to the chlorination reaction liquid at 5 to 80°C to obtain a cooled chlorination reaction liquid with a mass of 10~ 100 times of cold water with a temperature of 0 to 5°C, and then let it stand for 1 to 10 hours at room temperature. Then filter the mixture to obtain a solid phase; 5. Use a mass ratio of 1 to 15:3 Fully dissolve the solid phase in the methanol-water system, then add 2 to 30% of the solid phase mass of activated carbon to the methanol-water system with the solid phase dissolved in it, and then stir the methanol at 30 to 80°C. – Filter out the activated carbon after 0.5 to 5 hours from the water system; 6. Evaporate the methanol-water system with solid phase content at a temperature of 80 to 100°C. If crystals precipitate, stop heating and evaporate within 20 to 30 minutes. The system is cooled to -5~-10°C to obtain the cooled recrystallization. The recrystallization is dried in a vacuum drying oven at a temperature of 20~80°C for 24-48 hours to obtain 2-chloro-3-cyanopyridine.

Report on several preparation methods of 2-chloro-3-cyanopyridine 2.

Weigh 50g of chloroform and add it to a 250ml three-necked flask. Weigh 10g of N-oxonicotinamide and add it to the three-necked flask. Cool the temperature to 15±5°C. Weigh 20g of thionyl chloride and control the dropping time to 0.5h. Add to the three-necked flask, complete the dropwise addition, then cool down to 10±5°C, weigh 2g of triethylamine and control the dropping time to 1 hour and add dropwise to the three-necked flask. After the dropwise addition is completed, keep the temperature at 10°C and continue stirring for 20min. Then raise the temperature to 25°C, keep stirring for 30 minutes, then raise the temperature to 50°C, keep stirring for 30 minutes, then raise the temperature to 95°C, keep stirring for 3 hours. After the insulation is completed, the chloride reaction solution is obtained, and the chloride reaction solution is transferred to a rotary evaporation bottle. Control the temperature at 30°C and the pressure at 10Kpa for rotary evaporation until no obvious liquid flows out. Measure 20ml of water and add it to the rotary evaporator. Raise the temperature to 60°C. Transfer the solution in the rotary evaporator to a 250ml three-necked flask and keep it warm with hydrogen carbonate. Calcium was stirred for 1.5 hours, cooled to 15°C, stirred for 20 minutes, and filtered with suction to obtain 2-chloro-3-cyanopyridine wet product.

Report 3 on several preparation methods of 2-chloro-3-cyanopyridine.

Take a dry four-necked flask, set up an exhaust gas absorption device, add 15g (125mmol) 3-cyanopyridine N-oxide and 110mL 1,2-dichloroethane, and stir at a low temperature of 0°C. Homogeneous solution, when T=-5~0℃, add 25.30g (250mmol) triethylamine, continue to cool down, add 3.50g (62.5mmol) sodium chloride, 0.78g (6.25mmol) sodium sulfite, 1.13g (5mmol) ) benzyltriethylammonium chloride, continue to cool to -15°C, and begin to slowly add 60 mL of 1,2-dichloroethane solution containing 18.52g (62.5mmol) bis(trichloromethyl) carbonate dropwise. After the addition is completed, the reaction was maintained at this temperature for 16 hours. When the reaction was completed, 40 mL of deionized water was added dropwise to stir and quench. Separate layers, wash the organic phase with 60 mL of 10% sodium hydroxide solution, then 60 mL of deionized water, and finally extract the aqueous phase with (60 mL*2) 1,2-dichloroethane, combine the organic layers, add activated carbon, and Reflux and decolorize at 60°C for one hour. After decolorization is completed, filter, dry the organic phase with anhydrous magnesium sulfate, remove the solvent, beat the crude product, and dry it to obtain 16.30g of reddish-brown product with a yield of 94.15%.

References

[1] [China invention, China invention authorization] CN200710072672.3 Method for synthesizing 2-chloro-3-cyanopyridine using 3-cyanopyridine

[2] [Chinese invention] CN201811256988.2 Preparation method of 2-chloro-3-cyanopyridine

[3] [Chinese invention] CN201811240.8 A green preparation method of 2-chloro-3-cyanopyridine

[4] Liu Zhenxiang, Cai Chun. Synthesis of 2-chloro-3-cyanopyridine[J]. Fine Chemical Intermediates, 2005(03):28-30.