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Method for synthesizing intermediate of fexofenadine

A synthetic method and intermediate technology, which is applied in the field of synthesis of fexofenadine intermediates, can solve the problems of lower yield, higher cost, longer overall route, etc., and achieve the effect of solving the problem of product purity

Inactive Publication Date: 2008-05-21
CHONGQING UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0019] The purpose of the present invention is exactly in order to solve the synthetic fexofenadine in the technology of above-mentioned US6242606, (±)-4-[1-hydroxyl-4-[4-(hydroxyl benzhydryl)-1-piperidinyl]- Butyl]-α,α-dimethylphenylacetic acid hydrochloride process, must be 2-(4-(4-chloro-1-oxo-butyl))phenyl-2-methylpropionic acid (iv) Condensation reaction can only be carried out after esterification, and then hydrolysis will be carried out, and the increase of two-step reaction will make the total route longer, and the yield will decrease and the cost will increase.

Method used

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  • Method for synthesizing intermediate of fexofenadine
  • Method for synthesizing intermediate of fexofenadine
  • Method for synthesizing intermediate of fexofenadine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] The synthesis of embodiment one intermediate 2-phenyl-2-methyl propanol acetate (i)

[0039] After adding methacryl acetate (228 g, 2.0 mol) and 1200 ml of benzene into the three-necked flask, the temperature was lowered to 5°C. And keeping the temperature below 5°C, add anhydrous aluminum trichloride (399g, 3.0mol), keep the reaction at this temperature for 1 hour, pour into the ice-water mixture, and add 100ml of hydrochloric acid, separate the organic phase, and wash the organic phase with water. phase to neutral, dried over sodium sulfate, and after recovering benzene, distilled under reduced pressure to obtain the intermediate 2-phenyl-2-methacryl alcohol acetate, whose content was detected by GC.

Embodiment 2

[0040] Example two Synthesis of 2-(4-(4-chloro-1-oxo-butyl))phenyl-2-methylpropanol acetate (ii)

[0041] Intermediate i (150g, 0.78mol) was dissolved in 500ml of dichloromethane, cooled to below 5°C, anhydrous aluminum trichloride (208g, 1.56mol) was added, and 4-chlorobutyryl chloride was added dropwise at this temperature, React at 0-5°C for 15h. The reaction solution was slowly poured into a mixture of ice and water, 150ml of hydrochloric acid was added, the organic phase was separated, the organic phase was washed with aqueous sodium bicarbonate solution and water respectively, dried, and the solvent was evaporated to dryness to obtain intermediate ii as an oil (221.1g, 95.6% ). It was directly used in the next reaction without purification.

[0042] 1 H NMR (300MHz, CDCl 3 ( 2H each, d).

Embodiment 3

[0043] Synthesis of Example Three 2-(4-(4-chloro-1-oxo-butyl))phenyl-2-methyl propanol (iii)

[0044] Add 2-(4-(4-chloro-1-oxo-butyl))phenyl-2-methylpropenol acetate, 600ml of 25% hydrochloric acid, and 1500ml of ethanol into the reaction flask, and reflux for 3 hours. After ethanol was evaporated to dryness, dichloromethane was added to the residue, and the organic phase was washed with aqueous sodium bicarbonate and water, dried, and the solvent was evaporated to give intermediate iii as an oil (211 g, 95%). It was directly used in the next reaction without purification.

[0045] 1 H NMR (300MHz, CDCl 3 )δ1.35 (6H, s), 2.21 (2H, quent.) 3.15, (2H, t), 3.64 (2H, s), 3.66 (2H, 5), 7.48, 7.93 (2Heach, d).

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Abstract

The present invention provides a synthesis method of the intermediates of fexofenadine. The intermediates are 4-[4-[4-(hydroxyl diphenyl methyl)-1-piperidyl]-1-butyryl]-alpha and alpha-dimethyl phenyl acetic acid (v). The method considers methyl allyl alcohol acetic ester and benzene as raw materials to be synthesized as the intermediate (i) by the Friedel-Crafts alkylation reaction, the ortho-para-orientation effect of phenylethyl alcohol and two methyl are used to increase steric hindrance; the intermediate (ii) with the comparatively pure intermediate is obtained by the Friedel-Crafts alkylation reaction; the intermediate (iii) is obtained by alkaline hydrolysis; then the intermediate (iv) is obtained by potassium permanganate oxidation; the intermediate (v) is generated by the condensation under the alkaline condition by the phase transfer catalysis; the v is deoxidized by sodium borohydride as slat to obtain the fexofenadine. The method has smooth technology, short route, high yield, low cost and friendly environment and is a feasible route for the industrialization.

Description

technical field [0001] The present invention relates to a kind of intermediate 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-butyryl]-α,α-dimethyl of fexofenadine The synthetic method of phenylacetic acid. Background technique [0002] (±)-4-[1-Hydroxy-4-[4-(hydroxybenzhydryl)-1-piperidinyl]-butyl]-α,α-dimethylphenylacetic acid hydrochloride, drug The name is Fexofenadine (Fexofenadine), which is specially used for the treatment of seasonal allergic rhinitis and chronic sudden urticaria. The drug is an active metabolite of terfenadine, and its main advantage is that it removes the cardiotoxicity of its parent drug terfenadine. Fexofenadine is an antihistamine that selectively antagonizes peripheral H1 receptors, and its enantiomers all show approximately equal antihistamine effects. It is salified by reduction of key intermediate 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-butyryl]-α,α-dimethylphenylacetic acid and hydrochloric acid And get. [0003] At present,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/34
Inventor 马利甘孟瑜陈奉强陈超卢苇
Owner CHONGQING UNIV
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