New Anticancer Drugs Intermediates 3 - Amino - 2 - Halogen Benzoic Acid Methyl Ester And Its Derivatives,

Anti-cancer drugs have attracted great attention during the last several decades. In this thesis, a new anti-cancer drug intermediate methyl 3-amino-2-halobenzoate and its derivatives were synthesized, in which two major works are included:a). synthesis of methyl 3-amino-2-fluorobenzoate; b). preparation of methyl 3-amino-2-halobenzoate's derivatives.a). Synthesis of methyl 3-amino-2-fluorobenzoate(1) In consideration of its economic benefits, environment issues and feasibility of the reported synthesis protcols of methyl 3-amino-2-halobenzoate, an optimized three-step synthetic route was proposed. By using 2-fluoro-l-methyl-3-nitrobenzene, an inexpensive and commercially available precursor, the target compound was obtained after oxidation, esterification and reduction, in which expensive regents were excluded.(2) During oxidation of methyl, chromic anhydride as an oxidation regent better than other oxidation regents, in which consistency of chromic acid and reaction temperature were also optimized. In esterification of carboxylic acid, filtration was applied instead of extraction in work-up represented more convenient purification. Several reduction regents, solvent and temperature were also included in investigation to study the effect on the reduction step in order to improve the yield. By combination the aforementioned improvements, the overall yield of the new three steps synthetic route was increased from 12% to 41% with a lower cost. In addition, with a simple work-up process, the new methodology is also suitable for scale-up in industry.(3) When 2-chloro-l-methyl-3-nitrobenzene was applied instead of 2-fluoro-l-methy 1-3-nitrobenzene, up to 37% overall yield was obtained for the desired product.b). Synthesis of methyl 3-amino-2-halobenzoate's derivatives.Methyl 3-amino-2-halobenzoate's derivatives could be obtained in two different synthetic routes. The first one is a preferred synthetic for of the drug lead compounds. The other one is ideal route for bioactive compounds, which successfully avoided protection and de-protection steps, was and presented highly effective and showed excellent atomic economy.