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Method for synthesizing 2-[4-(4-chlorobutyryl)phenyl]-2-methylpropanoic acid

A technology of chlorobutyryl and methylpropionic acid, applied in the fields of amide preparation, organic chemistry, etc., can solve the problems of low yield, low yield, many reaction steps, etc., and achieves less environmental pollution, simple process, and high productivity. high rate effect

Inactive Publication Date: 2009-11-25
NINGBO INST OF TECH ZHEJIANG UNIV ZHEJIANG
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Problems solved by technology

[0003] The Indian patent application document with the application number 2004CH00206 discloses a method for synthesizing 2-[4-(4-chlorobutyryl)phenyl]-2-methylpropionic acid with α,α-dimethylphenylacetic acid as a raw material. The method requires the reaction of 2-(4-cyclopropoxycarbonylphenyl)-2-methylpropionic acid and 2-(3-cyclopropoxycarbonylphenyl)-2-methylpropionic acid with dicyclohexylamine to form a salt , and then separate 2-[4-(4-chlorobutyryl) phenyl]-2-methylpropionic acid through crystallization, acidification and ring opening, the reaction steps are many, the resolution efficiency is low, and the productive rate is not very high (about 40%); publication number is that the application document of WO2005019175 (A1) also discloses with α, α-dimethylphenylacetic acid is raw material synthesis 2-[4-(4-chlorobutyryl) phenyl]-2-methyl The method of propionic acid, this method needs to go through the steps such as esterification, reduction, the protection of alcoholic hydroxyl group, para-acylation, cyclopropanation, oxidation, not only yield is low (about 38%), and the potassium permanganate in the reaction Use will cause greater environmental pollution

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  • Method for synthesizing 2-[4-(4-chlorobutyryl)phenyl]-2-methylpropanoic acid

Examples

Experimental program
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Effect test

Embodiment 1

[0027] Add 16.00 grams (0.40mol) of sodium hydroxide and 150 milliliters of anhydrous methanol to a 250 milliliter three-necked flask and stir evenly, then, while stirring, 15.50 grams (0.05mol) of N-methyl-N-methoxy-2- [4-(4-Chlorobutanoyl)phenyl]-2-methylpropanamide is dissolved in 50 ml of anhydrous methanol to form a uniformly stirred solution dropwise into a three-necked flask, and after the dropwise addition is completed, stir and react at 30°C 18 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 sulfate, filtered, and the dichloromethane was distilled off under reduced pressure to obtain the product N-methyl-N-methoxy-2-(4-cyclopropoxycarbonylb...

Embodiment 2

[0034] Add 20.50 grams (82%, 0.30mol) of potassium hydroxide and 150 milliliters of anhydrous methanol in a 250 milliliter three-necked flask and stir evenly, then, while stirring, 15.50 grams (0.05mol) of N-methyl-N-methoxy -2-[4-(4-chlorobutyryl) phenyl]-2-methylpropanamide was dissolved in 50 milliliters of anhydrous methanol to form a stirred solution that was added dropwise to the there-necked flask, after the dropwise addition, at 20 The reaction was stirred at °C 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 sulfate, filtered, and the dichloromethane was distilled off under reduced pressure to obtain the product N-methyl-N-methoxy-2-...

Embodiment 3

[0038] Add 20.00 grams (0.50mol) of sodium hydroxide and 150 milliliters of absolute ethanol to a 250 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 dissolved in 50 ml of absolute ethanol 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, 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, distill off the dichloromethane under reduced pressure to obtain the product N-methyl-N-methoxy-2-(4-cyclopropoxycarbonylphenyl) - 12.65 g (0.046 mol) of 2-methylpropanamide, yield 92%. ...

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Abstract

The invention discloses a method for synthesizing 2-[4-(4-chlorobutyryl)phenyl]-2-methylpropanoic acid, comprising the steps of adding an alkali metal hydroxide in an alcohol solvent, dripping the alcohol solvent of N-methyl-N-methoxyl-2-[4-(4-chlorobutyryl)phenyl]-2-methacrylamide in the alcohol solvent, agitating and reacting for 10-30h at 20-50 DEG C, extracting, drying and filtering to obtain N-methyl-N-methoxyl-2-(4-cyclopropoxycarbonylphenyl)-2-methacrylamide; adding the N-methyl-N-methoxyl-2-(4-cyclopropoxycarbonylphenyl)-2-methacrylamide in the alcohol solvent of the alkali metal hydroxide, refluxing for 20-40h, and adjusting pH to be 3 by hydrochloric acid, extracting, drying and filtering to obtain 2-(4-cyclopropoxycarbonylphenyl)-2-methylpropanoic acid, and adding the 2-(4-cyclopropoxycarbonylphenyl)-2-methylpropanoic acid in an inorganic acid, reacting for 20-30h at 60-100 DEG C, extracting, drying, filtering and crystallizing by ethanol to obtain the product target. The invention has a simple technology, high yield and little pollution.

Description

technical field [0001] The invention relates to a method for synthesizing 2-[4-(4-chlorobutyryl)phenyl]-2-methylpropionic acid. 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, it has the advantages of fast action, high curative effect, and less toxic and side effects. 2-[4-(4-chlorobutyryl)phenyl]-2-methylpropionic acid is an important intermediate in the synthesis of fexofenadine hydrochloride. [0003] The Indian patent application document with the application number 2004CH00206 discloses a method for synthesizing 2-[4-(4-chlorobutyryl)phenyl]-2-methylpropionic acid with α,α-dimethylphenylacetic acid as a raw material. The method requi...

Claims

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Application Information

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IPC IPC(8): C07C59/88C07C51/06
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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