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Synthetic method of a fexofenadine hydrochloride

A fexofenadine and synthetic method technology, applied in the direction of active ingredients of heterocyclic compounds, drug combination, organic chemistry, etc., can solve the problem of reducing purity and yield, difficult separation of amides, and production of fexofenadine hydrochloride Cost increase and other issues, to achieve the effect of low pollution and high yield

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

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 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 a low purity of the final product fexofenadine hydrochloride

Method used

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  • Synthetic method of a fexofenadine hydrochloride
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  • Synthetic method of a fexofenadine hydrochloride

Examples

Experimental program
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Effect test

Embodiment 1

[0042] 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-methoxyl-2-[4-(4-chlorobutyryl) phenyl]-2-methylpropionamide is prepared by prior art: (1) 98.4 grams (0.6 mol) 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 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, and the reaction is complete Afterwards, 200 ml of 2N hydrochloric acid was added dropwise to the reaction mixture, and the liquids were separated. The organic phase was washed with 2N hydrochloric acid, saturated sodium bicarbonate, and s...

Embodiment 2

[0053] 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 20.50 grams (82%, 0.30mol) potassium hydroxide and 150 milliliters of anhydrous methanol in the flask and stir evenly, then, 15.50 grams (0.05mol) N-methyl-N-methoxy-2-[ 4-(4-Chlorobutyryl)phenyl]-2-methylpropanamide was dissolved in 50 ml of anhydrous methanol 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 20°C 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 anhydr...

Embodiment 3

[0059] 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 20.00 grams (0.50mol) of sodium hydroxide and 150 milliliters of absolute ethanol in the flask, stir evenly, then, while stirring, 15.50 grams (0.05mol) of N-methyl-N-methoxy-2-[4- (4-Chlorobutyryl)phenyl]-2-methylpropanamide is dissolved in 50 ml of absolute ethanol to form a uniformly stirred solution, which is added dropwise to a three-necked flask. After the dropwise addition, stir and react at 50°C for 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 layer, dry over anhydrous sodium sulfate, filter...

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Abstract

The invention discloses a synthetic method of a 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 to obtain N-methyl-N-methoxyl-2-(4-cyclopropoxycarbonylphenyl)-2-methacrylamide; refluxing the N-methyl-N-methoxyl-2-(4-cyclopropoxycarbonylphenyl)-2-methacrylamide in an alkaline alcohol solvent and adjusting pH to obtain 2-(4-cyclopropoxycarbonylphenyl)-2-methylpropanoic acid; reacting the 2-(4-cyclopropoxycarbonylphenyl)-2-methylpropanoic acid in HCl for 20-30h at 60-100 DEG C and recrystallizing to obtain 2-[4-(4-chlorobutyryl)phenyl]-2-methylpropanoic acid; adding the 2-[4-(4-chlorobutyryl)phenyl]-2-methylpropanoic acid in the hydrochloric acid solution of absolute alcohol to prepare the 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 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, 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 α, ethyl α-dimethylphe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
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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