Study On The Synthesis Of2-methyl-4-nitrobenzoic Acid

2-Methyl-4-nitrobenzoic acid is an important pharmaceutical intermediate, which can be used for the preparation of a series of novel antitumor drugs. To investigate the synthesis of2-methyl-4-nitrobenzoic acid, using o-xylene as starting material, through selective nitration giving4-nitro-o-xylene, and the obtained4-nitro-o-xylene was then selectively oxidized, ultimately leading to the formation of2-methyl-4-nitrobenzoic acid.The selective nitration of o-xylene with nitrogen dioxide was effectively processed to improve the yield of4-nitro-o-xylene isomer. A preferable4-nitro-o-xylene was obtained up to an isomer ratio of4-nitro-o-xylene to3-nitro-o-xylene of3above by nitration of o-xylene with nitrogen dioxide of3-4equivalent amounts under mild conditions. Non protonic acids presented better catalytic behaviors than protonic acids on nitration of o-xylene with nitrogen dioxide.4-Nitro-o-xylene of63.4%yield was high selectively obtained in a ratio of4-nitro-o-xylene to3-nitro-o-xylene of3.72in the presence of zinc chloride.Moreover,4-nitro-o-xylene was selectively oxidized to form2-methyl-4-nitrobenzoic acid by using dilute nitric acid as oxidizing agent. It was found that the oxidation of4-nitro-o-xylene was effectively promoted by the addition of radical initiators. Under reflux conditions,2-methyl-4-nitrobenzoic acid in yield of86.3%was prepared by using8equivalent amounts of nitric acid in the synergistic effect of N-hydroxyphthalimide, cobalt dichloride, manganese acetate, and benzyltriethylammonium chloride. The target compounds were characterized by1H NMR analyses.