An Efficient Two-step Selective Synthesis of 7-Methyl-8-nitroquinoline From m-Toluidine as a Key Starting Material in Medicinal Chemistry

Abstract

Background: A major problem in the development of required chemical compounds in a variety of industries such as pharmaceutical, agricultural, paint and polymer industries is to easily access the chemical starting materials. One class of these materials is quinoline derivatives. Synthesis of these compounds, despite their simple chemical structures is relatively complicated and their synthesis design and purification are challenging. Quinoline derivatives were synthesized and explored for their anticancer, antitinephritic, antitumor, anti-inflammatory and analgesic activity, as antiallergetic agents for treating Alzheimer’s disease (AD). Possible formation of 5- and 7-substituted quinolines during the Skraup reaction using m-substituted anilines is well understood. However, there are conflicting reports on the composition of the products from certain reactions. Objectives: As part of our research, we are interested in the development of synthetic strategies for preparation of 7-methyl-8-nitroquinoline selectively from a prepared mixture of 5- and 7-methyl quinoline as a key material to study its biological activities as well as to develop other corresponding quinoline derivatives for our research purpose. Materials and Methods: Synthesis and characterization of 7-methylquinoline using the Skraup methodology was reported. A subsequent nitration reaction was also carried out using a mixture of 5- and 7-methylquinoline to obtain pure 7-methyl-8-nitroquinoline selectively. In this project, in the first step, a mixture of 7-methylquinolin and 5-methylquinolin was prepared from the reaction of m-toluidine and glycerol. In the next step, 7-methyl-8-nitroquinoline was selectively synthesized and subsequently characterized using conventional methods such as NMR, IR, GC-MS and elemental analysis. Results: The compound 7-methyl-8-nitroquinolin was selectively synthesized in a two-step reaction with an excellent yield. Conclusions: 7-methyl-8-nitroquinolin as a key starting material was obtained through a two-step synthesis from m-toluidine. Skraup synthesis was employed to produce a mixture of 7- and 5-methylquinoline in a 2:1 ratio, which was then used for a nitration reaction using nitric acid and sulfuric acid without further purification. The final reaction selectively produced 7-methyl-8-nitroquinolin with an excellent yield.