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

A technology of chlorobutyryl and methylpropionic acid, which is applied in the fields of amide preparation and organic chemistry, can solve the problems of complex process, low yield, and many reaction steps, and achieve simple preparation process, low environmental pollution, and high reaction efficiency. The effect of fewer steps

Inactive Publication Date: 2012-02-15
NINGBO INST OF TECH ZHEJIANG UNIV ZHEJIANG
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Problems solved by technology

[0003] The application number is 2004CH00206 Indian patent application documents reported in α, α-dimethylphenylacetic acid as raw material synthesis of 2-[4-(4-chlorobutyryl) phenyl]-2-methyl propionic acid method, The method requires the reaction of 2-(4-cyclopropylcarbonylphenyl)-2-methylpropionic acid and 2-(3-cyclopropylcarbonylphenyl)-2-methylpropionic acid with dicyclohexylamine to form Salt, and then resolve 2-[4-(4-chlorobutyryl) phenyl]-2-methyl propionic acid by crystallization, acidification, and ring opening. There are many steps, and the resolution efficiency is low, and the yield is not very high ( about 40%)
[0004] The application document with publication number WO2005019175 (A1) also discloses a method for synthesizing 2-[4-(4-chlorobutyryl)phenyl]-2-methylpropionic acid from α,α-dimethylphenylacetic acid , this method needs to go through steps such as esterification, reduction, acylation, cyclopropanation, oxidation, not only reaction step is many, technique is complicated, and productive rate is low (about 38%), and the use of potassium permanganate in the reaction will bring greater environmental pollution

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] 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-cyclopropylcarbonylbe...

Embodiment 2

[0031] 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

[0034]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-cyclopropylcarbonylphenyl) - 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-methylpropionic acid: adding alkali metal hydroxide to an alcohol solvent, and then adding N- Alcohol solution of methyl-N-methoxy-2-[4-(4-chlorobutyryl)phenyl]-2-methylpropionamide, react at 20~50°C for 10~30h, evaporate the solvent to dryness, Extract, dry, and filter to obtain N-methyl-N-methoxy-2-(4-cyclopropoxycarbonylphenyl)-2-methylpropionamide; then N-methyl-N-methoxy -2-(4-cyclopropoxycarbonylphenyl)-2-methylpropanamide is added to the mineral acid, the weight ratio of the two is 1:2~8, react at 60°C~100°C for 20~30h, extract, Dry, filter, and recrystallize to obtain the target product. The invention has the advantages of simple preparation process, 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 hydrochloride, 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 application number is 2004CH00206 Indian patent application documents reported in α, α-dimethylphenylacetic acid as raw material synthesis of 2-[4-(4-chlorobutyryl) phenyl]-2-methyl propionic acid method, The method requ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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