Preparation of cis-2-(2,4- dichlorophenyl)-2-([1,2,4]- triazole-1-methyl )-[1,3] dioxolane -4-Methyl methanesulfonate

Abstract

The invention relates to a preparation method for pharmaceutical intermediate cis-2-(2,4- dichlorophenyl)-2-([1,2,4]triazole-1-methyl)-[1,3] dioxolane-4-methyl methanesulfonate. The preparation method adopts a process route that m-dichlorobenzene is used as a raw material which is condensed with glycerin under the catalysis of heteropoly acid TiSiW12O40 / SiO2 after friedel-crafts reaction, and is esterified with benzoyl chloride, and the product is obtained by condensing the reaction product with 1,2,4-triazole, hydrolyzing, recrystallizing and esterifying with the methylsulfonyl chloride. The invention is characterized by (1) adopting a creative process route that the m-dichlorobenzene is used as the raw material; (2) adopting the heteropoly acid TiSiW12O40 / SiO2 for catalysis in the production of ketal, the heteropoly acid being repeated and having environmental and economical performances; (3) adopting sodium carbonate as an acid binding agent, avoiding the expensive and dangerous sodium hydride catalysis; and (4) adopting a recrystallization method and avoiding column chromatography, lowering the production cost and being useful for industrialization.

Description

technical field [0001] The invention belongs to the field of drug synthesis. It specifically relates to a pharmaceutical intermediate cis-2-(2,4-dichlorophenyl)-2-([1,2,4]-triazole-1-methyl)-[1,3]dioxo Preparation method of pentane-4-methyl methanesulfonate. Background technique [0002] At present, anti-infective drugs have become the third largest class of drugs in the world after cardiovascular system drugs and central nervous system drugs, occupying an important share in the world market. Itraconazole, as a representative variety of anti-infective drugs, has become the best-selling variety in the world in 2006, and with its unique mode of action and excellent curative effect, its market share has a tendency to increase greatly. cis-2-(2,4-dichlorophenyl)-2-([1,2,4]-triazole-1-methyl)-[1,3]dioxolane-4-methyl Mesylate (hereinafter referred to as mesylate active ester) is an important intermediate in the synthesis of antifungal drugs, and also a necessary intermediate in...

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Problems solved by technology

[0006] Process route 1. has the following disadvantages: at first 2,4-dichloroacetophenone is carried out free radical bromination, because there are three hydrogen atoms on the methyl group of acetophenone, deep bromination is inevitable, not economical and environmentally friendly; When condensing with glycerin, concentrated sulfuric acid is used as a catalyst for condensation, which inevitably produces a large amount of waste acid, and the post-treatment is relatively cumbersome; at the same time, the cis-alcohol and its isomers are subjected to column chromatography after hydrolysis. Separation and purification, high cost is not conducive to large-scale production;

[0007] Process route ② use sodium hydride to catalyze the condensation of bromoester and 1,2,4-triazole, and separate and purify cis-alcohol by column chromatography. Because sodium hydride is expensive and can spontaneously ignite in humid air, it will encounter acids, water, Halogen and oxidants can have strong chemical reactions, which can easily cause combustion or explosion, so the industrial production cost is high and the risk is high. At the same time, column chromatography is not conducive to industrial production

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