| 2-Methyl-3-nitroanisole is an important pharmaceutical intermediate for the synthesis of the anti-hepatitis C drug simeprevir and indole derivatives.In this paper,2-methyl-3-nitroaniline was isolated from the waste acid used in the production of Scarlet Base G.2-methyl-3-nitroanisole was synthesized by diazotization hydrolysis and methylation to maximize the use of resources and achieve economic and environmental protection.In addition,a new route for the synthesis of 2-methyl-3-nitroanisole was designed by inverse synthesis,and experimental studies were carried out to determine the optimal reaction conditions through process optimization,aiming to find a more efficient and low-cost synthesis method.（Ⅰ）The Scarlet Base G is 2-methyl-5-nitroaniline,2-methyl-3-nitroaniline was isolated from the waste acid of the Scarlet base G and then diazotization hydrolysis and methylation to gave 2-methyl-3-nitroanisole.The preparation process conditions were explored by single-factor or orthogonal experiments and characterised by means of melting point,infrared,nuclear magnetic,gas phase and other analytical methods.（1）Nitrification of o-toluidine produces a high COD waste acid,about 5.27 tons of waste acid per ton of Scarlet Base G produced.2-Methyl-3-nitroaniline was extracted from the spent acid of the Scarlet Base G.It was determined that the best separation was by the hydrochloride method and the purity of the separated gas phase was 99.73%;（2）Better process conditions for nitration:98%sulphuric acid concentration,mixed acid composition of14%nitric acid,77%sulphuric acid,9%water,1:1.3 nitric acid molar ratio,temperature 30℃.The total yield of the synthesis product was 96.7%,the yield of 2-methyl-3-nitroaniline was increased from 20%to 26.5%and the purity was 99.94%;（3）Better process conditions for diazotization hydrolysis:35%concentration of diazotized sulphuric acid,35%concentration of sodium nitrite,60%concentration of hydrolysed sulphuric acid,the yield was 92.5%and the purity was 99.89%;（4）Better process conditions for methylation:sodium hydroxide concentration 10%,reaction temperature 20℃,feeding ratio 1:1.15,reaction time 1.5h,the yield was 96.2%and the purity was 99.84%.（Ⅱ）Using p-tert-butyltoluene as raw material,4-tert-butyl-2,6-dinitrotoluene was firstly obtained by dinitration,followed by partial reduction to 4-tert-butyl-2-nitro-6-aminotoluene,then by diazotization hydrolysis to 4-tert-butyl-2-nitro-6-hydroxytoluene,and the de-tert-butyl reaction to 2-methyl-3-nitrophenol,and finally methylated to synthesize2-methyl-3-nitroanisole.The process conditions were explored using single factor experiments and characterised by analytical means such as melting point,infrared and nuclear magnetic.（1）Better process conditions for nitrification:mixed acid composition of 11%nitric acid,87%sulphuric acid,2%water,programmed temperature rise,reaction time 12h,the yield was96.7%;（2）By comparing the three reduction processes of sodium disulfide,iron powder and thiourea dioxide,we obtained the best reduction with sodium disulfide,the better process conditions:feeding ratio 1:1.7,reflux temperature reaction 120min,the yield was 88.5%;（3）Better process conditions for diazotization hydrolysis:35%concentration of diazotized sulphuric acid,35%concentration of sodium nitrite,60%concentration of hydrolysed sulphuric acid,the yield was 86.2%.Total yield of 78%in three steps;（4）Adopting the aluminum chloride method,the p-toluenesulfonic acid method and the trifluoroacetic acid method to remove tert-butyl respectively did not obtain 2-methyl-3-nitrophenol,probably because the strong absorbing group-NO2reduced the activity of the reaction.Two separate routes were investigated to control the quality of the intermediate products as well as the target products.By treating the waste acid to obtain the valuable product2-methyl-3-nitroaniline,the waste is turned into treasure and the green economy makes it possible to reduce production costs,Optimization of process conditions to ultimately improve the product yield and purity of 2-methyl-3-nitroanisole. |
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