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

A technology of methyl propionate and chlorobutyryl is applied in the field of synthesizing 2-[4-phenyl]-2-methyl propionate, and can solve the problems of low yield, difficult separation, and many steps, and achieves High yield and low pollution effect

Inactive Publication Date: 2012-01-04
NINGBO INST OF TECH ZHEJIANG UNIV ZHEJIANG
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  • Abstract
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Problems solved by technology

[0003] U.S. Patent No. 6,242,606B1 discloses the synthesis of 2-[4-(4 The method of -chlorobutyryl) phenyl]-2-methylpropionic acid methyl ester or 2-[4-(4-chlorobutyryl)phenyl]-2-methylpropionic acid ethyl ester, the method gains two There are a large number of meta-isomer impurities in the product, and these impurities are difficult to separate, which greatly reduces the purity of the product
The Indian patent application document with the application number 2004CH00206 discloses that the mixture of meta-position and para-position products prepared by the above method is hydrolyzed and cyclopropanated and then resolved to obtain pure 2-(4-cyclopropylcarbonylphenyl) Ring-opening and esterification of 2-methylpropionic acid to prepare 2-[4-(4-chlorobutyryl)phenyl]-2-methylpropanoic acid ethyl ester, the method has many steps and resolution Low efficiency, about 40% yield
[0004] U.S. patent application document US2002007068 (A1) also discloses a similar splitting method, which has many steps and low splitting efficiency, with a yield of about 28%.
[0005] The patent application document with the publication number WO2005019175 (A1) discloses the synthesis of 2-[4-(4-chlorobutyryl)phenyl]-2-methylpropionic acid from α,α-dimethylphenylacetic acid methyl ester The method of methyl ester, this method needs to go through the steps such as esterification, reduction, the protection of alcoholic hydroxyl group, para-acylation, cyclopropanation, oxidation, ring-opening of cyclopropane, esterification, not only productive rate is lower (about 30% ), and the use of potassium permanganate in the reaction will bring greater environmental pollution
[0006] Giacomo B.D. etc. [Giacomo, B.D.; Coletta, D.; Natalini B.; Ni, M.H.; The method of synthesizing 2-[4-(4-chlorobutyryl) phenyl]-2-methyl propionate as raw material not only has many steps, but the yield is low (about 27%), and lithium aluminum hydride, lithium aluminum hydride, The use of compounds such as diazomethane increases the risk of operation, making this method unsuitable for industrial production

Method used

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

Examples

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Embodiment 1

[0033] 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

[0038] 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

[0041] 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-methacrylate, 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, 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 an inorganic acid, reacting for 20-30h at 60 DEG C, extracting, drying, filtering, crystallizing by ethanol to obtain 2-[4-(4-chlorobutyryl)phenyl]-2-methylpropanoic acid; infusing HCl gas in the alcohol solvent, then adding the 2-[4-(4-chlorobutyryl)phenyl]-2-methylpropanoic acid, washing by water, drying and filtering to obtain the target product. The synthetic method of the invention has high yield, little pollution and applicable industrial production.

Description

technical field [0001] The invention relates to a method for synthesizing 2-[4-(4-chlorobutyryl)phenyl]-2-methyl propionate. 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 antiallergic drug, and similar products astemizole (astemizole, withdrawn from the U.S. market in 1999 due to easy cardiotoxicity), cetirizine, and loratadine Compared with other drugs, fexofenadine hydrochloride has the advantages of fast action, high curative effect, and less toxic and side effects. 2-[4-(4-Chlorobutyryl)phenyl]-2-methylpropionate is a key intermediate in the synthesis of fexofenadine hydrochloride. [0003] U.S. Patent No. 6,242,606B1 discloses the synthesis of 2-[4-(4 The method of -chlorobutyryl) phenyl]-2-methylpropionic acid methyl ester or 2-[4-(4-chlorobutyryl)phenyl]-2-methylpropionic acid ethyl ester, the method gains two There ar...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C67/08C07C69/738
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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