Preparation background and overview of 2-p-chlorobenzylpyridine calcium carbonate
2-p-Chlorobenzylpyridine is an important intermediate for the preparation of chlorpheniramine drugs. Chlorpheniramine, alias: chlorpheniramine. It is an antihistamine drug, mainly used for various allergic diseases, such as insect bites, urticaria, vasodilatory rhinitis, asthma, contact dermatitis, etc. It can also be combined with other Chinese and Western medicine to treat colds, etc. Chlorpheniramine has always occupied an important position among anti-allergic drugs due to its strong anti-allergic activity and minor side effects.
Preparation of 2-p-chlorobenzylpyridine
Add 2.46g of 2-picolinic acid into a 100ml reaction bottle, then slowly add 10ml of thionyl chloride into the constant pressure dropping funnel, slowly increase the temperature to reflux, and react for 3 hours. Stop heating, recover the remaining thionyl chloride under reduced pressure, and obtain a dark red solid as 2-pyridylcarbonyl chloride hydrochloride. Add 20ml of chlorobenzene under ice bath conditions, and slowly add 5.34g of aluminum trichloride while stirring. After the addition is completed, continue stirring. After half an hour, transfer the reaction bottle to the oil bath and slowly heat it to about 100°C, and react for 3 hours. , stop reacting. Recover the remaining chlorobenzene under reduced pressure, and then slowly add ice cubes under ice bath conditions (made by adding 2 ml concentrated hydrochloric acid to 20 ml water). The reaction is very violent, so ice cubes should be added carefully. Then slowly add concentrated NaOH solution until the pH is about 12, and filter to obtain a red solid of 1-(4-chlorophenyl)-1-(2-pyridyl)methanone and impurities. Add 60 ml n-hexane and 3 g activated carbon and heat to reflux for 1 hour. Filter activated carbon to obtain n-hexane solution. Finally, the n-hexane solution is cooled and crystallized to obtain a white solid of 1-(4-chlorophenyl)-1-(2-pyridyl)methanone. Filter, wash with water, drain, and dry in a vacuum drying oven at 50°C to obtain a white solid. Powder solid 1-(4-chlorophenyl)-1-(2-pyridyl)methanone 0.61g. The residue after recovering n-hexane was separated by column chromatography (silica gel 200-300 mesh, eluent: V ethyl acetate: V petroleum ether = 1:3) to obtain 0.11g of the product, and a total of 1-(4-chloro Phenyl)-1-(2-pyridyl)methanone 0.72g, yield 16.7%, melting point: 60-61°C. GC-MS: 98%.
Take 2.18g of 1-(4-chlorophenyl)-1-(2-pyridyl)methanone prepared by the above method, add 6ml of diethylene glycol, 12ml of 85% hydrazine hydrate, and potassium hydroxide 1.3g, reflux heavy calcium carbonate for 1 hour, and then evaporate the water in the reaction bottle while raising the reaction temperature. The temperature was raised to 190°C and the reaction was carried out for 3 hours. After cooling, add 100 ml of water, extract with 10 ml × 3 toluene, recover the toluene and distill under reduced pressure to obtain 1.52 g of colorless oily liquid 2-p-chlorobenzylpyridine, yield 75%; GC-MS: 99%.
References
[1] [Chinese invention] CN201010045622.8 Preparation method of 2-p-chlorobenzylpyridine
