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Method for preparing 2-(4-Chloromethylphenyl) propionic acid as loxoprofen key intermediate

A technology of chloromethylphenylpropionic acid and tolylpropionic acid is applied in the field of synthesis of cloxoprofen, which can solve the problems of not providing a preparation method for 2-p-chloromethylphenylpropionic acid, and achieve a short production process. , cost saving, cheap raw materials

Active Publication Date: 2013-07-10
ANHUI HERYI CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method does not provide the preparation method of 2-p-chloromethylphenylpropionic acid

Method used

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  • Method for preparing 2-(4-Chloromethylphenyl) propionic acid as loxoprofen key intermediate
  • Method for preparing 2-(4-Chloromethylphenyl) propionic acid as loxoprofen key intermediate

Examples

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Embodiment 1

[0053] Put 92g of toluene into a clean and dry reaction flask, put in 160g of aluminum trichloride when cooled to 10°C, stir for 20 minutes below 10°C, cool to 0-2°C, add 100g of propionyl chloride dropwise, and control the temperature not to exceed 5°C; After the dropwise addition, react at 0-2°C for 2 h, pour into 500 ml of ice water, filter out the solid, wash with water until neutral, and dry to obtain 110 g of p-methylpropiophenone.

[0054] Put 74g of p-methylpropiophenone into the reaction bottle, put in 300ml of methanol, add 93g of bromine dropwise at 10°C during the stirring process, raise the temperature to 60°C to react for 1h after dropping, start to heat up and distill methanol to 100°C at the same time. Cool to 70°C, add 94g of trimethyl orthoformate, stir and cool to 30°C, throw in 200ml of dichloromethane, reflux reaction at 40°C for 2h, then add 300ml of 20wt% sodium hydroxide solution, stir to heat up and evaporate at the same time Organic solvent, heat up t...

Embodiment 2

[0057] Put 92g of toluene into a clean and dry reaction flask, put in 160g of aluminum trichloride when cooled to 8°C, stir for 25 minutes below 8°C, cool to 0-2°C, add 100g of propionyl chloride dropwise, and control the temperature not to exceed 5°C; After the dropwise addition, react at 0-2°C for 2.3 h, pour into 500 ml of ice water, filter out the solid, wash with water until neutral, and dry to obtain 110 g of p-methylpropiophenone.

[0058] Put 74g of p-methylpropiophenone into the reaction bottle, put in 300ml of methanol, add 93g of bromine dropwise at 5°C during the stirring process, raise the temperature to 50°C and react for 1.3h after dropping, start to heat up and simultaneously distill methanol to 100°C . Cool to 60°C, put in 94g of trimethyl orthoformate, stir and cool to 25°C, throw in 200ml of dichloromethane, reflux at 25°C for 2.2h, then add 300ml of 20wt% sodium hydroxide solution, stir and heat up while evaporating Remove the organic solvent and heat it u...

Embodiment 3

[0061] Put 92g of toluene into a clean and dry reaction flask, put in 160g of aluminum trichloride when cooled to 15°C, stir for 13 minutes below 10°C, cool to 0-2°C, add 100g of propionyl chloride dropwise, and control the temperature not to exceed 5°C; After the dropwise addition, react at 0-2°C for 1.5 h, pour into 500 ml of ice water, filter out the solid, wash with water until neutral, and dry to obtain 110 g of p-methylpropiophenone.

[0062] Put 74g of p-methylpropiophenone into the reaction bottle, put in 300ml of methanol, drop 93g of bromine at 15°C during the stirring process, raise the temperature to 75°C and react for 0.6h after dropping, start to heat up and distill methanol to 100°C at the same time . Cool to 73°C, add 94g of trimethyl orthoformate, stir and cool to 35°C, throw in 200ml of dichloromethane, reflux reaction at 45°C for 1.6h, then add 300ml of 20wt% sodium hydroxide solution, stir and heat up while evaporating Remove the organic solvent and heat i...

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Abstract

The invention relates to a method for preparing 2-(4-Chloromethylphenyl) propionic acid as a loxoprofen key intermediate. The method comprises the following steps of: condensing methyl benzene as a starting raw material with propionyl chloride to obtain methyl propiophenone, carrying out bromination and methoxycarbonylation through a one-step method on the obtained methyl propiophenone, hydrolyzing to obtain 2-(p-tolyl)propionic acid, and finally carrying out chlorination on the 2-(p-tolyl)propionic acid to obtain the 2-(4-Chloromethylphenyl) propionic acid. According to the method disclosed by the invention, the methyl propiophenone can be prepared from methyl; the key intermediate 2-(p-tolyl)propionic acid can be obtained directly through a one-step one-pot method; the intermediate is chlorinated under the conditions of quantitatively illuminating and charging chlorine in petroleum ether so that the loxoprofen is finally synthesized; and in addition, the production process is very short and the wastewater amount is small.

Description

technical field [0001] The present invention relates to the technical field of the synthesis method of cloxoprofen, in particular to a method for preparing cloxoprofen key intermediate 2-p-chloromethylphenylpropionic acid. Background technique [0002] Cloxoprofen is a non-steroidal anti-inflammatory analgesic drug (NSAIDS) launched by Sankyo Company in Japan in 1986. It is used to treat rheumatoid arthritis, frozen shoulder and other analgesic and anti-inflammatory drugs. It is widely used clinically. Cloxoprofen has significant analgesic, anti-inflammatory and antipyretic effects, especially the analgesic effect is significantly better than other propionic acid drugs; at the same time, Cloxoprofen is a prodrug, which is converted into an active metabolite after being absorbed by the digestive tract Compared with other NSAIDS, it has less damage to the gastrointestinal mucosa. [0003] 2-p-Chloromethylphenylpropionic acid is a key intermediate in the synthesis of cloxoprof...

Claims

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Application Information

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IPC IPC(8): C07C57/58C07C51/363
Inventor 董来山
Owner ANHUI HERYI CHEM
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