Synthesis Of Substituted Pyridine Carboxylic Acid Derivatives

Pyridine carboxylic acid derivatives are very im.p.ortant nitrogen organic heterocyclic com.p.ounds. Not only possesses it pharmacological activity but also it can be used as the indispensably im.p.ortant raw materials in the production of various pharmacological products, pesticide, dye, surfactant, additive and etc, and it has wide application. The com.p.osite study of pyridine carboxylic acid derivatives has great significance on the following aspects, such as new drug development, transformation of drug structure, and etc.Based on a great number of literatures and the summary of previous researches, this thesis has synthesized a series of pyridine carboxylic acid derivatives: (1) 2- methyl pyridine and 3-methyl pyridine, which are used as raw materials, are turned into methyl pyridine nitrogen oxides through hydrogen peroxide oxidation , and then by nitration, reduction, diazotization, bromination, substituted, cyano hydrolysis, they respectively synthesize 2-methyl isonicotinic acid, which yields 30.4% and 3-methyl isonicotinic acid, which yields 13.1%. The method adopted potassium ferrocyanide as the cyano substituted reagent, and the raw materials have the features of easy availability, low toxicity and mild reaction conditions.(2) Reports of the literatures, which use 2,3-dimethylpyridine, 2,4-dimethyl pyridine, 2-methyl-5-ethyl pyridine as raw materials, take the selective oxidation as the methods of pyridine carboxylic acid and mainly is potassium permanganate oxidation. This method has some disadvantages, such as low yield, big potassium permanganate dosage, a mass of byproducts and hard to deal with. This paper put forward a new synthetic route, which used 2,3-dimethylpyridine, 2,4-dimethyl pyridine, 2-methyl-5-ehtyl pyridine as raw materials, and it turned into alkyl pyridine N-oxides through hydrogen peroxide oxidation, then by selective oxidation of different concentrations of nitric acid, deoxidation by phosphorus trichloride, preparation of acid chloride, esterification, which respectively obtain the following eight Pyridine carboxylic acid derivatives: 2-methyl- niotinic acid N-oxides, 6-methylnicotinic acid N-oxides, 2-methylisonicotinic acid, 2-methylnicotinic acid, 6-methylnicotinic acid, methyl 2-mehtylisonicotinate N-oxide, methyl 2-mehtyl- isonicotinate. Discuss the affect of the concentration of the nitric acid on the reaction and obtain the best condition of reaction through doing some com.p.arative experiments systematically. Continuously im.p.rove on handling post-reaction and study the reaction mechanism. Get the best reaction conditions for obtain 2-methylisonicotinic acid, 2-methylnicotinic acid and 6-methylnicotinic acid.This method has better selection of nitric oxidation selective substituting pyridine carboxylic acid, using dialkyl pyridine as starting material. And the byproduct, which is nitrogen dioxide, has the advantages of being able to absorb and recycle and easy manipulations. And especially for the synthetize of 2-methylisonicotinic acid, which has higher yield, and it has potential application prospects on industrialized manufacture.