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

A technology of methyl methanesulfonate and dichlorophenyl, applied in the field of pharmaceutical synthesis, can solve problems such as easy to cause combustion or explosion, unavoidable deep bromination, complicated post-processing, etc., and achieve the effect of avoiding column chromatography

Inactive Publication Date: 2012-07-25
SHOUGUANG FUKANG PHARMA
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  • Abstract
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  • Claims
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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

Method used

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

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Embodiment Construction

[0019] The following examples describe the invention in detail. However, these examples are by no means limiting the protection scope of the present invention.

[0020] (1) Synthesis of 2-bromo-1-(2,4-dichlorophenyl)ethanone

[0021] Put 150g (1.12mol) of anhydrous aluminum trichloride into a 500mL three-necked flask, add 147g (1.00mol) of m-dichlorobenzene, stir at room temperature, and slowly add 201g (1.00mol) of bromoacetyl bromide dropwise Continue to stir at room temperature for 30 minutes, slowly raise the temperature to 50-55°C, and stir at this temperature for 5 hours, pour the reaction solution into ice water to freeze, cool to room temperature, and extract twice with 500mL dichloromethane, The dichloromethane extracts were combined, washed with water until neutral, dried over anhydrous sodium sulfate, the solvent was recovered by filtration, and the residue was reconstituted to obtain 240 g of a white irritating solid with a yield of 90.0%.

[0022] (2) Synthesis ...

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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...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D407/06
Inventor 杨磊宋伟国董良军董向生刘彬张福建
Owner SHOUGUANG FUKANG PHARMA
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