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

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 splitting efficiency, complicated process, increased risk and the like , to achieve the effect of shortening the production cycle, simple process steps, and reducing operational risks

Inactive Publication Date: 2012-10-10
NINGBO INST OF TECH ZHEJIANG UNIV ZHEJIANG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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
[0004] The application number is the Indian patent application document of 2004CH00206, which discloses that the mixture of meta-position and para-position products prepared by the disclosed method of the above-mentioned U.S. Patent US6242606B1 is hydrolyzed and cyclopropanated to obtain pure 2-(4-ring Propoxycarbonylphenyl)-2-methylpropionic acid and then ring-opening and esterification to prepare the method for 2-[4-(4-chlorobutyryl)phenyl]-2-methylpropionic acid ethyl ester, the The method has many steps, the resolution efficiency is low, and the yield is about 40%.
[0005] 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%.
[0006] 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, which needs to go through steps such as esterification, reduction, protection of alcoholic hydroxyl group, para-acylation, cyclopropanation, oxidation, cyclopropane ring opening, esterification, etc., has many reaction steps, long reaction cycle, and relatively long process. Complicated, the productive rate is relatively low (about 30%), and the use of potassium permanganate in the reaction will also bring greater environmental pollution
[0007] Giacomo B.D. etc. [Giacomo, B.D.; Coletta, D.; Natalini B.; Ni, M.H.; For raw material synthesis 2-[4-(4-chlorobutyryl) phenyl]-2-methyl propionate method reaction step is more, and productive rate is also relatively low (about 27%), and in the reaction The use of compounds such as lithium aluminum hydride and diazomethane increases the risk of operation, making this method unsuitable for industrial production

Method used

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

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Embodiment 1

[0024] Add 140 ml of anhydrous methanol to a 250 ml three-necked flask, bubble dry hydrogen chloride gas at 0°C until saturated, and then add N-methyl-N-methoxy-2-[4-(4-chloro Butyryl) phenyl] -2-methyl propionamide 20 g (0.064 mol), reflux reaction for 24 hours after addition. After the reaction was completed, anhydrous methanol and hydrogen chloride were evaporated under reduced pressure, and 200 ml of water and 200 ml of dichloromethane were added to the residue, stirred evenly, left to stand, separated, and the separated aqueous layer was extracted twice with 100 ml of dichloromethane . The extracts of all dichloromethane layers were combined, dried with anhydrous sodium sulfate, filtered, and the dichloromethane in the filtrate was evaporated under reduced pressure to obtain the product 2-[4-(4-chlorobutyryl)phenyl]-2- 16.63 grams (0.059 mol) of methyl propionate, yield 92%.

[0025] The above raw material N-methyl-N-methoxy-2-[4-(4-chlorobutyryl)phenyl]-2-methylpropion...

Embodiment 2

[0028] Add 140 ml of absolute ethanol to a 250 ml three-necked flask, and bubble dry hydrogen chloride gas at 0°C until saturation, then add N-methyl-N-methoxy-2-[4-(4-chloro Butyryl) phenyl] -2-methyl propionamide 20.80 g (0.070 mol), reflux reaction for 30 hours after addition. After the reaction was completed, the absolute ethanol and hydrogen chloride were evaporated under reduced pressure, and 200 ml of water and 200 ml of dichloromethane were added to the residue, stirred evenly, left to stand, separated, and the separated aqueous layer was extracted twice with 100 ml of dichloromethane . The extracts of all dichloromethane layers were combined, dried with anhydrous sodium sulfate, filtered, and the dichloromethane in the filtrate was evaporated under reduced pressure to obtain the product 2-[4-(4-chlorobutyryl)phenyl]-2- 18.71 g (0.063 mol) of ethyl methpropionate, yield 90%.

Embodiment 3

[0030] Add 140 ml of anhydrous n-propanol to a 250 ml three-necked flask, bubble dry hydrogen chloride gas into it at 0°C until saturated, then add N-methyl-N-methoxy-2-[4-(4 -Chlorobutyryl)phenyl]-2-methylpropionamide 17.47g (0.056mol), reflux reaction for 30 hours after addition. After the reaction was completed, anhydrous n-propanol and hydrogen chloride were evaporated under reduced pressure, and 200 ml of water and 200 ml of dichloromethane were added to the residue, stirred evenly, left to stand for liquid separation, and the aqueous layer was extracted twice with 100 ml of dichloromethane. The extracts containing the dichloromethane layer were combined, dried with anhydrous sodium sulfate, filtered, and the dichloromethane in the filtrate was evaporated under reduced pressure to obtain the product 2-[4-(4-chlorobutyryl)phenyl]-2- 15.55 g (0.050 mol) of n-propyl methylpropionate, yield 90%.

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Abstract

The invention discloses a method for synthesizing 2-[4-(chlorobutyryl) phenyl]-2-methyl propionate, which comprises the following steps: introducing dry chlorine hydride gas into an absolute alcohol solvent in a bubbling way to the saturated state; adding N-methyl-N-methoxyl-2-[4-(chlorobutyryl) phenyl]-2-methyl propanamide, wherein the molar concentration of the N-methyl-N-methoxyl-2-[4-(chlorobutyryl) phenyl]-2-methyl propanamide in the absolute alcohol solvent is 0.40-0.50 mol / L; after carrying out the reaction in a backflow mode for 20-30 hours, removing excessive chlorine hydride and absolute alcohol solvent; dissolving the remains in methylene dichloride and water; skimming; extracting the water layer with methylene dichloride twice, and merging the methylene dichloride layer; and drying and filtering to remove methylene dichloride to obtain the product 2-[4-(chlorobutyryl) phenyl]-2-methyl propionate. The target product synthesized by the method of the invention does not contain interposition isomers; and the invention has the advantages of high yield, low pollution, environmental protection, high safety, simple technical steps and low production cost, and is suitable for 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 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-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 are ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C69/738C07C67/18
Inventor 骆成才张华星杨志杰郑志利柴胜利
Owner NINGBO INST OF TECH ZHEJIANG UNIV ZHEJIANG