Study On New Synthetic Approach To Substituted Alkoxy Benzoic Acids

Alkoxy benzoic acids are important intermediates in organic synthesis,applied in various areas of the fine chemical industry,such as herb antibacterial,pharmaceutical, pesticide,dye.This paper aimed to design a new synthetic route:starting from phenols,via acylation,Fries rearrangement,O-methylation,oxidation,getting corresponding alkoxy benzodic acids.The effect of temperature,time,the ratio of reactants and other factors were investigated and the improved reaction conditions were obtained as follows:1)In acylation reaction,the mole ratio of phenol and acetic anhydride was 1:2 with refluxing at 142℃,lasting 3～4 hours.2)In Fries rearrangement reaction,if the products were p-isomers,the mole ratio of phenol ester and aluminium chloride was 1:1.2 using nitrobenzene as co-solvent or without co-solvent at 30～40℃for about 10～12 hours(using co-solvent)or 1～2 hours(without solvent);If the products were o-isomers,the mole ratio of phenol ester and aluminium chloride was 1:1.5 using NaCl as co-solvent at 130～160℃for about 1.5～2 hours.3)In O-methylation reaction, the mole ratio of dimethyl sulfate and hydroxyl acetophenone was 1:3,with dimethyl sulfate dropping 20ml/h at 50～60℃,keeping pH 9～10.After dropping,kept temperature at 70～80℃for 1～2 hours.4)In oxidation reaction,using water as solvent refluxed at 80℃for 8～12 hours.The mole ratio of sodium hypochlorite and methoxyl acetophenone was 5:1.This route giving following advantages:1)it could apply to a series of alkoxyl benzoic acids of similar structures.2)In acylation reaction,by increasing the amount of acetic anhydride to replace the use of catalysts,the reaction yield was more than 98%.3)In Fries rearrangement reaction,the hydrolysis treatment for using nitrobenzene as co-solvent was putting strong base to become alkaline salts,then separated from organic phase,acidizing.It avoided the high-temperature steam distillation,and the product was of high purity;The hydrolysis treatment for using sodium chloride as co-solvent,put water first keeping 110℃for 1 hour,then cooling to 80℃,adding small amount of 36%hydrochloric acid.It greatly reduced the amount of hydrochloric acid.4)In oxidation reaction,using water as solvent,through appropriate extension of reaction time and intense agitation replaced the use of organic solvent and phase transfer catalyst to simplify operations and lower costs,and it was also favorable to the environment.The most overall yield was more than 50%,and the finally product was identified by melt point and ~1H NMR.This route is much of industrial value in cheap and easily gained material,the mild reaction conditions,convenient operation and environment benign.