Improved Process For The Synthesis Of Montelukast's Intermediates

Montelukast is a leukotriene receptor antagonist (LIRA) developed by Merck mainly for the treatment of asthma and allergies, which was launched in 1998.It is now one of the three LTRAs that received wide international attention.This thesis describes the pharmacological effects of montelukast, its clinical uses, side effects and synthetic significance. The key intermediatesâ… andâ…¡in the synthesis of montelukast are studied. The chemical name for the intermediateâ… is 2-(1-(mercaptomethyl)cyclopropyl)acetic acid, and that for the intermediateâ…¡is 2-(3-(3-((E)-2-(7-chloroquinolin-2-yl)ethenyl)phenyl)-3(S)-hydroxyPropyl) benzoic acid methyl ester.The best selection of the most economical synthetic route suitable for industrial production has been made finally according to the following considerations:(â…°) the molecular structure of the target compoundsâ… andâ…¡and the technical guidelines for synthesizing process of chemical drug substances, (â…±) an overall analysis of the literature synthetic routes, the retro-synthetic analysis and the actual conditions of our laboratory, (â…²) comprehensive evaluation of the economic benefit, environmental problems and feasibility in the experiment, etc. Base on the proposed synthetic route, this thesis will focus on the following two aspects:1. Optimization of reaction conditions. Through a series of experiments, we have improved the associated experimental conditions, including solvent selection, the molar ratio of reaction materials, feeding methods, feeding sequence, reaction temperature, reaction time, catalyst and so on, and thus the optimum reaction conditions have been determined.2. Optimization of post-processing. A practicable post-processing method for industrial production has been established after improving post-processing of the reaction, including product separation and purification, unreacted reactant recycling, solvent recovery, and security and convenience in the aftertreatment, etc.By examining reaction mechanisms, we suggest a more reasonable reaction conditions and gathering and refining method of final products in this thesis, and it's synthetic route has many advantages, such as brief reaction steps, convenient manipulation, and cheap and readily available reactants. In this theis, by means of optimizing the technology conditions, the reaction operation has been therefore simplified, the production costs has been greatly cut down, and the product yield has been raised. All of the above are conducive to industrialization of this process. So far, there has not been the related report on the synthetic process of compoundsâ… andâ…¡in China, so this study has some innovation.