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Synthetic method of fexofenadine hydrochloride

A technology of fexofenadine hydrochloride and its synthesis method, which is applied in the field of synthesis of fexofenadine hydrochloride, can solve the problems of difficult amide separation, reduced purity and yield, and low purity of fexofenadine hydrochloride, and achieves The effect of simple process route, low production cost and high yield

Inactive Publication Date: 2010-03-17
NINGBO INST OF TECH ZHEJIANG UNIV ZHEJIANG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

2-[3-(4-chlorobutyryl)phenyl]-2-methylpropanoic acid ethyl ester can also react with 4-piperidine benzylmethanol, and the generated product undergoes three stages of reduction, hydrolysis and salt formation. After the step, the meta-fexofenadine impurity that is difficult to separate is formed, and the separation of this impurity causes the production cost of fexofenadine hydrochloride to increase greatly
[0012] In this method, the obtained product of the Friedel-Crafts acylation reaction cannot be purified, and the impurities in the product can react with 4-piperidine diphenylcarbinol, which not only reduces the purity and the yield of the condensation reaction product in the latter step, but also increases the final product hydrochloric acid. Production cost of fexofenadine
In addition, the hydrolysis yield of the amide in the hydrolysis step is only about 85%, and the unhydrolyzed amide is difficult to separate from the product, resulting in a low purity of the final product fexofenadine hydrochloride

Method used

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  • Synthetic method of fexofenadine hydrochloride
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Examples

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Embodiment 1

[0030]The present invention starts with N-methyl-N-methoxy-2-[4-(4-chlorobutyryl)phenyl]-2-methylpropanamide (III) as the starting material. The synthetic method of N-methyl-N-methoxy-2-[4-(4-chlorobutyryl) phenyl]-2-methylpropionamide is prepared by prior art: 98.4 grams (0.6mol) α , α-dimethylphenylacetic acid was dissolved in 400 milliliters of toluene, 131 milliliters of thionyl chloride was added dropwise at 0°C, stirred at room temperature for 15 hours and then refluxed for 2 hours, and 100 milliliters of toluene and toluene were removed by vacuum distillation after the reaction was completed. Excess thionyl chloride, add 184.6 grams (1.34mol) of potassium carbonate, 58.5 grams (0.6mol) of N, O-dimethylhydroxylamine hydrochloride and 300 milliliters of water, stir and react at room temperature for 4 hours, after the completion of the reaction, the reaction 200 ml of 2N hydrochloric acid was added dropwise to the mixture, and the liquid was separated. The organic phase wa...

Embodiment 2

[0038] Using the N-methyl-N-methoxy-2-[4-(4-chlorobutyryl)phenyl]-2-methylpropanamide prepared by the method of the above-mentioned Example 1 as the starting material, in 250 ml three Add 140 ml of anhydrous methanol to the flask, bubble dry hydrogen chloride gas at 0°C until saturated, and then add N-methyl-N-methoxy-2-[4-(4-chlorobutyryl)benzene Base]-2-methyl propionamide 20 grams (0.064mol), reflux reaction 24 hours after adding. After the reaction was completed, anhydrous methanol and hydrogen chloride were distilled off under reduced pressure, 200 ml of water and 200 ml of dichloromethane were added to the residue, the layers were separated, and the aqueous layer was extracted twice with 100 ml of dichloromethane respectively. The extracts containing the dichloromethane layer were combined, dried with anhydrous sodium sulfate, filtered, and the dichloromethane was distilled off under reduced pressure to obtain the product 2-[4-(4-chlorobutyryl)phenyl]-2-methylpropane 16...

Embodiment 3

[0041] Using the N-methyl-N-methoxy-2-[4-(4-chlorobutyryl)phenyl]-2-methylpropanamide prepared by the method of the above-mentioned Example 1 as the starting material, in 250 ml three Add 140 ml of anhydrous n-propanol to the flask, bubble dry hydrogen chloride gas at 0°C until saturated, then add N-methyl-N-methoxy-2-[4-(4-chlorobutyryl ) phenyl]-2-methyl propionamide 17.47 grams (0.056 mol), reflux reaction for 30 hours after adding. After the reaction was completed, anhydrous n-propanol and hydrogen chloride were evaporated under reduced pressure, 200 ml of water and 200 ml of dichloromethane were added to the residue, the layers were separated, and the aqueous layer was extracted twice with 100 ml of dichloromethane respectively. The extracts containing the dichloromethane layer were combined, dried with anhydrous sodium sulfate, filtered, and the dichloromethane was distilled off under reduced pressure to obtain the product 2-[4-(4-chlorobutyryl)phenyl]-2-methylpropane 1...

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Abstract

The invention discloses a synthetic method of fexofenadine hydrochloride. N-methyl-N-methoxyl-2-[4-(4-chlorine butyryl)]-2-methacrylamide which is prepared through the prior art is taken as the raw material, which is reacted in saturated hydrogen chloride absolute ethyl alcohol dissolvent, then 2-[4-(4-chlorine butyryl)]-2-propyl methacrylate is obtained, and finally the object product is preparedthrough a series of reactions. The synthetic method of fexofenadine hydrochloride has the advantages of having high yield, no meta-isomer and amide impurities existence, little pollution, simple processing procedure, low production cost and being suitable for the industrial production.

Description

technical field [0001] The invention relates to a synthesis method of fexofenadine hydrochloride. Background technique [0002] Allergic diseases are common diseases in humans, such as allergic rhinitis, chronic sudden urticaria, and hay fever. Fexofenadine hydrochloride is a new generation of anti-allergic drugs, compared with similar products astemizole (astemizole, withdrawn from the U.S. market in 1999 due to easy cardiotoxicity), cetirizine, loratadine, etc. , Fexofenadine hydrochloride has the advantages of quick action, high curative effect, and less toxic and side effects. [0003] Fexofenadine hydrochloride chemical name: 4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α,,α-dimethylphenethyl Hydrochloride; [0004] Chemical Structure: [0005] [0006] U.S. Patent No. 4,254,129 discloses a method for synthesizing fexofenadine hydrochloride with α, α-dimethylphenylacetic acid as a raw material. In the method, α-dimethylphenylacetic acid ethyl es...

Claims

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Application Information

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IPC IPC(8): C07D211/22
Inventor 骆成才张华星杨志杰郑志利柴胜利
Owner NINGBO INST OF TECH ZHEJIANG UNIV ZHEJIANG
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