Method for synthesizing 2-(4-cyclopropoxycarbonylphenyl)-2-methylpropanoic acid

A technology of cyclopropylcarbonylphenyl and methylpropionic acid, which is applied in the field of synthesizing 2-(4-cyclopropylcarbonylphenyl)-2-methylpropionic acid, can solve the problem of many steps, high cost and high production cost. The efficiency is not very high, and the effect of simple preparation process, low production cost and few reaction steps is achieved.

Inactive Publication Date: 2012-12-19
NINGBO INST OF TECH ZHEJIANG UNIV ZHEJIANG
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  • Abstract
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  • Application Information

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Problems solved by technology

The methods in the above two patent applications have many steps, the resolution efficiency is low, and the yield is not very high (the product yield in US2002007068 (A1) is about 28%, and the product yield in the Indian patent is about 40%)
[0004] U.S. Patent No. 6,242,606 (B1) discloses that 2-(4-(1-oxo-1-cyclopropyl))-phenyl-2-methylpropanol or 2-(4-(1-oxo-1 - Process for the oxidation of cyclopropyl))-phenyl-2-methylpropanol acetate to prepare 2-(4-cyclopropylcarbonylphenyl)-2-methylpropanoic acid which requires minimal preparation of starting materials Five-step reaction, the cost is high, and the oxidation method that uses precious metal compound ruthenium trichloride as catalyst in the oxidation method will greatly increase the product preparation cost, and the oxidation method that uses acidic potassium permanganate or acidic sodium nitrite as oxidant will bring relatively high Large environmental pollution, low yield of oxidation method using fuming nitric acid as oxidant

Method used

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  • Method for synthesizing 2-(4-cyclopropoxycarbonylphenyl)-2-methylpropanoic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Add 16.00 g (0.40 mol) of sodium hydroxide and 150 ml of anhydrous methanol to a 250 ml three-necked flask and stir evenly, then, while stirring, 15.50 g (0.05 mol) 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, which is added dropwise to a three-necked flask, and stirred at 30°C for reaction after the dropwise addition 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-cyclopropylcarbonylbenzene Base)-2-me...

Embodiment 2

[0029] Add 20.50 g (82%, 0.30 mol) of potassium hydroxide and 150 ml of anhydrous methanol into a 250 ml three-necked flask and stir evenly, then, while stirring, add 15.50 g (0.05 mol) of N-methyl-N-methoxy -2-[4-(4-Chlorobutanoyl)phenyl]-2-methylpropanamide was dissolved in 50 ml of anhydrous methanol to form a uniformly stirred solution that was added dropwise to the three-necked flask. 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-(4-cyclopropylcarbonylbenzene base)-2-methylpropan...

Embodiment 3

[0032] Add 20.00 g (0.50 mol) of sodium hydroxide and 150 ml of absolute ethanol to a 250 ml three-necked flask, stir well, then, while stirring, add 15.50 g (0.05 mol) 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, melting range 82-83°C, yield 92...

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Abstract

The invention discloses a method for synthesizing 2-(4-cyclopropoxycarbonylphenyl)-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 and reacting for 20-40h, and adjusting the pH of the reaction mixture to be 3 by hydrochloric acid, extracting, drying, filtering and removing methylene dichloride to obtain 2-(4-cyclopropoxycarbonylphenyl)-2-methylpropanoic acid. The synthetic method of the invention has the advantages of a few reaction steps, simple preparation technology, high yield, little pollution and lowproduction cost.

Description

technical field [0001] The invention relates to a method for synthesizing 2-(4-cyclopropylcarbonylphenyl)-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-Cyclopropylcarbonylphenyl)-2-methylpropionic acid is an important intermediate in the synthesis of fexofenadine hydrochloride. [0003] There are also many reports on the synthesis method of 2-(4-cyclopropylcarbonylphenyl)-2-methylpropionic acid, such as the patent application document with the publication number US2002007068 (A1) and the Indian patent ap...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C59/86C07C51/06
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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