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Preparation method of 4-methylthio phenylacetic acid

A technology of methylthiophenylacetic acid and methylthiobenzene is applied in the field of synthesizing 4-methylthiophenylacetic acid, which can solve the problems of large environmental pollution and achieve the effects of small environmental pollution, wide sources, and easy industrialization

Active Publication Date: 2016-06-08
RAFFLES PHAMRMATECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The present invention aims to provide a new synthetic route for the problem of large environmental pollution in the current industrial production of 4-methylthiophenylacetic acid

Method used

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  • Preparation method of 4-methylthio phenylacetic acid
  • Preparation method of 4-methylthio phenylacetic acid
  • Preparation method of 4-methylthio phenylacetic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0016] 4-bromophenylacetic acid as the starting material to prepare the target compound

[0017] Take 10g of 4-bromophenylacetic acid in a 100mL three-necked flask, add 20mL of DMF, add 5.0g of sodium methyl mercaptide, add 0.1g of cuprous bromide, after nitrogen replacement, raise the reaction temperature to 130°C under stirring, and stir under nitrogen protection Reacted for 4 hours, cooled the reaction liquid, added 40% NaOH 5mL, and stirred for 10 minutes. Cool the reaction solution, add 25 mL of ethyl acetate to extract twice, add 50 mL of ethyl acetate to the water layer, add 10% dilute sulfuric acid to adjust the pH to 2-4, collect the ethyl acetate, wash the ethyl acetate with 10 mL of water, and distill out the acetic acid Ethyl ester to about 20mL, add 20mL of n-hexane, increase the reaction temperature to reflux, after all the solids are dissolved, slowly cool to room temperature, filter to obtain light yellow scaly crystals, and obtain 6.38g of the target product a...

Embodiment 2

[0019] Synthesis of target compound from ethyl 4-bromophenylacetate

[0020] Take 10g of ethyl 4-bromophenylacetate in a 100mL three-necked flask, add 20mL of DMF, add 5.0g of sodium methyl mercaptide, add 0.1g of cuprous bromide, and replace with nitrogen, raise the reaction temperature to 130°C under stirring, and protect with nitrogen Down to the end of the reaction, cool the reaction solution, add 20mL of 40% sodium hydroxide to reflux for 2 hours, cool the reaction solution, add 25mL of ethyl acetate to extract twice, add 50mL of ethyl acetate to the water layer, add 10% dilute sulfuric acid to adjust the pH to 2-4. Collect ethyl acetate, wash ethyl acetate with 10mL of water, distill off ethyl acetate to about 20mL, add 20mL of n-hexane, raise the reaction temperature to reflux, after all solids are dissolved, slowly cool to room temperature, filter, Light yellow scaly crystals were obtained, and after drying, 5.17g of the target product was obtained, yield: 65.6%

Embodiment 3

[0022] Synthesis of target compound from 4-bromophenylacetonitrile

[0023] Take 10g of 4-bromophenylacetonitrile in a 100mL three-necked flask, add 20mL of DMF, add 5.0g of sodium methyl mercaptide, add 0.1g of cuprous bromide, and replace with nitrogen, raise the reaction temperature to 130°C under stirring, and under the protection of nitrogen to After the reaction, cool the reaction liquid to room temperature, add 20 mL of 50% sulfuric acid, reflux for 5 h, cool the reaction liquid, add 25 mL of ethyl acetate to extract three times, combine the ethyl acetate layer, add 100 mL of 5% sodium hydroxide to the ethyl acetate layer, and stir After 5 minutes, the aqueous layer was collected. Add 100 mL of ethyl acetate to the water layer, add 10% dilute sulfuric acid to adjust the pH to 2-4, separate the ethyl acetate layer, wash with 10 mL of water, distill off the ethyl acetate to about 20 mL, add 20 mL of n-hexane, and increase the reaction temperature To reflux, after all the...

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Abstract

The invention provides a preparation method of 4-methylthio phenylacetic acid. According to the preparation method, p-halogenated phenylacetic acid and phenylacetic acid derivatives thereof are taken as the primary raw materials. The preparation method is characterized in that p-halogenated phenylacetic acid and phenylacetic acid derivatives thereof and sodium methyl mercaptide carry out catalytic reactions in the presence of cuprous ions and DMF, and 4-methylthio phenylacetic acid is obtained after the post treatment. The Willgerodt-kindler reactions will generate hydrogen sulfide, which is pollutant to the environment, the provided method does not have Willgerodt-kindler reactions, and thus the environmental pollution is avoided. Moreover, the operation is simple, and the method is environment-friendly and is suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to a method for synthesizing 4-methylthiophenylacetic acid, which belongs to the field of chemical pharmacy. Background technique [0002] Etoricoxib is a selective cyclooxygenase inhibitor developed by Merck, which has anti-inflammatory, analgesic and antipyretic effects. This product is currently on the market in more than 80 countries around the world. The global API demand is about 100 tons. [0003] 4-Methylthiophenylacetic acid is the key intermediate for the preparation of etoricoxib. The traditional method is to prepare 4-methylthiophenylacetic acid by hydrolysis after Willgerodt-kindler rearrangement of 4-methylthioacetophenone. In the preparation of the present compound, the Willgerodt-kindler rearrangement reaction is to sublimate sulfur and use morpholine as a reagent to prepare a thioamide intermediate, which is hydrolyzed to obtain 4-methylthiophenylacetic acid. The synthetic route of the 4-methylthiophenylacetic...

Claims

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Application Information

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IPC IPC(8): C07C323/62C07C319/14
CPCC07C319/14C07C323/62
Inventor 孙家强费安杰叶伟平徐俊烨
Owner RAFFLES PHAMRMATECH CO LTD
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