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Preparation method of an antiallergic agent fexofenadine hydrochloride

A technology for fexofenadine and hydrochloride, which is applied in the field of preparation of antiallergic drug fexofenadine hydrochloride, can solve the problem of reducing purity and yield, difficult separation of amide, and fexofenadine hydrochloride Solve problems such as low salt purity, achieve high yield and low pollution

Inactive Publication Date: 2009-11-25
NINGBO INST OF TECH ZHEJIANG UNIV ZHEJIANG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] In this method, the product obtained by the 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 fexofena. Determine the production cost of hydrochloride
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 the low purity of the final product fexofenadine hydrochloride, which contains amide impurities

Method used

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  • Preparation method of an antiallergic agent fexofenadine hydrochloride
  • Preparation method of an antiallergic agent fexofenadine hydrochloride
  • Preparation method of an antiallergic agent fexofenadine hydrochloride

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Embodiment 1

[0041] The present invention starts with N-methyl-N-methoxy-2-[4-(4-chlorobutyryl)phenyl]-2-methylpropanamide (III) as the starting material. N-methyl-N-methoxy-2-[4-(4-chlorobutyryl) phenyl]-2-methylpropionamide is prepared by prior art: (1) 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 was washed with 2N hy...

Embodiment 2

[0051] The N-methyl-N-methoxy-2-[4-(4-chlorobutyryl) phenyl]-2-methylpropionamide prepared by the method described in the above-mentioned Example 1 was used as starting material at 250 Add 20.50 grams (82%, 0.30mol) potassium hydroxide and 150 milliliters of anhydrous methanol in the milliliter three-necked flask and stir evenly, then, while stirring, 15.50 grams (0.05mol) N-methyl-N-methoxy-2 -[4-(4-Chlorobutyryl)phenyl]-2-methylpropanamide dissolved in 50 ml of anhydrous methanol to form a uniformly stirred solution was added dropwise to the three-necked flask. The reaction was stirred for 30 hours. After the reaction was completed, anhydrous methanol was distilled off under reduced pressure, 100 ml of water and 100 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 sulfat...

Embodiment 3

[0056] The N-methyl-N-methoxy-2-[4-(4-chlorobutyryl) phenyl]-2-methylpropionamide prepared by the method described in the above-mentioned Example 1 was used as starting material at 250 Add 20.00 grams (0.50mol) of sodium hydroxide and 150 milliliters of dehydrated ethanol in the milliliter three-necked flask, stir well, then, while stirring, 15.50 grams (0.05mol) of N-methyl-N-methoxy-2-[ 4-(4-Chlorobutyryl)phenyl]-2-methylpropanamide was dissolved in 50 ml of absolute ethanol to form a uniformly stirred solution, which was added dropwise to the three-necked flask. After the dropwise addition was completed, the reaction was stirred at 50°C 30 hours. After the reaction was completed, absolute ethanol was distilled off under reduced pressure, 100 ml of water and 100 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. Combine the extracts containing the dichloromethane ...

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Abstract

The invention discloses a preparation method of an antiallergic agent fexofenadine hydrochloride, comprising the steps of adding an alkali metal hydroxide in an alcohol solvent, dripping N-methyl-N-methoxyl-2-[4-(4-chlorobutyryl)phenyl]-2-methacrylamide alcohol solvent in the solvent, reacting for 10-30h at 20-50 DEG C, conventionally processing to obtain N-methyl-N-methoxyl-2-(4-cyclopropoxycarbonylphenyl)-2-methacrylamide; adding the N-methyl-N-methoxyl-2-(4-cyclopropoxycarbonylphenyl)-2-methacrylamide in an inorganic acid, reacting for 20-30h at 60 DEG C, conventionally processing and crystallizing by ethanol to obtain 2-[4-(4-chlorobutyryl)phenyl]-2-methylpropanoic acid; adding the 2-[4-(4-chlorobutyryl)phenyl]-2-methylpropanoic acid in the alcohol solvent in which HCl gas is infused, conventionally processing to obtain 2-[4-(4-chlorobutyryl)phenyl]-2-methacrylate, and finally obtaining the target product of the invention through routine techniques. The invention has the advantages of high yield, freeness of meta-isomers and amide impurities, little pollution and applicable industrial production.

Description

technical field [0001] The invention relates to a preparation method of an antiallergic drug 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, and similar products astemizole (astemizole, withdrawn from the U.S. market in 1999 due to easy cardiotoxicity), cetirizine, loratadine, etc. Compared with fexofenadine hydrochloride, it has the advantages of fast 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-dimethyl Phenylacetic acid 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 raw material, in the method by...

Claims

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Application Information

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IPC IPC(8): C07D211/22A61K31/445A61P37/08
Inventor 骆成才郑志利张华星杨志杰柴胜利
Owner NINGBO INST OF TECH ZHEJIANG UNIV ZHEJIANG
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