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Method for preparing 2-(1-methylethyl)-5-[(E)-2-phenylethenyl]benzene-1,3-diol

A technology of phenylene mode and cumene, applied in the preparation of organic compounds, chemical instruments and methods, organic chemistry, etc., can solve the problems of difficult to control impurities, strong corrosiveness, explosion, etc., and achieve easy operation. Effect

Inactive Publication Date: 2016-08-24
SHANGHAI FOSUN PHARMA DEV CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The above-mentioned synthetic method has obvious disadvantages in poor reaction conditions and difficult to control impurities. For example, in the first step of the Friedel-Crafts reaction of the isopropyl group on the benzene ring, it is easy to connect the isopropyl group to the 2-position, resulting in the risk of forming positional isomers; Potassium borohydride in the second step reaction is easy to cause explosion, the use of thionyl chloride in the third step reaction is highly corrosive to the equipment, and environmentally unfriendly second-class solvents such as toluene and pyridine are used in the last step of demethylation. There are too many times of refining, and the solvent residues of raw materials are difficult to control, etc.

Method used

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  • Method for preparing 2-(1-methylethyl)-5-[(E)-2-phenylethenyl]benzene-1,3-diol
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  • Method for preparing 2-(1-methylethyl)-5-[(E)-2-phenylethenyl]benzene-1,3-diol

Examples

Experimental program
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Effect test

Embodiment 1

[0028] Example 1: Preparation of 3,5-dibromo-4-isopropylbenzaldehyde

[0029] Add 20.0kg of 4-isopropylbenzaldehyde (commercially available, 134.95mol) into a 100L reactor, start stirring, control the reaction temperature to about 10°C in an ice-salt bath, and slowly add 53.91kg (337.37mol) of liquid bromine dropwise. After the dropwise addition was completed, the reaction temperature was kept at 5-10° C. for 2 hours. The solution was released, and 50 L of distilled water was added to precipitate a large amount of light yellow solid, which was centrifugally filtered, washed with distilled water several times, and dried in vacuum to obtain 33.69 kg of light yellow solid with a molar yield of 81.6%.

Embodiment 2

[0030] Embodiment two: the preparation of 3,5-dimethoxy-4-isopropylbenzaldehyde

[0031] Add DMF20L, 3,5-dibromo-4-isopropylbenzaldehyde 20.0kg (65.36mol) and cuprous iodide 1kg in the 100L reactor, start stirring to dissolve, add 40% methanol solution of sodium methoxide 35kg, react Vacuum the inside of the kettle and fill it with nitrogen, replace it three times continuously to make it complete, react at 90°C for 3 hours, and stop the reaction after the reaction is complete. Evaporate methanol, cool to room temperature, release the reaction solution into an ice-water bath, and precipitate a large amount of yellow solid, adjust the pH to 4-5 with 6N hydrochloric acid, shake off the filter, dissolve the filter cake with ethyl acetate, filter, and extract the filtrate with distilled water. Ethyl acetate was distilled off to obtain a yellow solid, which was dried in vacuum to obtain 12.63 kg of 3,5-dimethoxy-4-isopropylbenzaldehyde with a molar yield of 92.8%.

Embodiment 3

[0032] Embodiment three: the preparation of 3,5-dihydroxy-4-isopropyl benzaldehyde

[0033] Add 20kg of anhydrous pyridine and 10kg (55.49mol) of 3,5-dimethoxy-4-isopropylbenzaldehyde into the 100L reactor, start stirring, and react at 150°C for 5 hours, and evaporate the pyridine after the reaction is complete. Cool down to room temperature, add 50L of ethyl acetate, add 20L of distilled water, adjust the pH to 4-5 with 2N hydrochloric acid, extract and separate, extract twice more with distilled water, dry, evaporate the ethyl acetate to obtain a light yellow solid, and vacuum dry to obtain a light yellow 8.61kg, molar yield 86.2%.

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Abstract

The invention provides a method for preparing 2-(1-methylethyl)-5-[(E)-2-phenylethenyl]benzene-1,3-diol, belongs to the technical field of medicine preparation and particularly provides a simple method for preparing 2-(1-methylethyl)-5-[(E)-2-phenylethenyl]benzene-1,3-diol. The method includes the following steps that 4-isopropylbenzaldehyde serves as the starting material, 3,5-dibromo-4-isopropylbenzaldehyde is obtained through 3,5 position bromination, 3,5-dimethoxy-4-isopropylbenzaldehyde is synthesized with sodium methoxide, then 3,5-dyhydroxy-4-isopropylbenzaldehyde is obtained through demethylation with pyridine, 3,5-dialkyl ester-4-isopropylbenzaldehyde is obtained through esterification, 2-(1-methylethyl)-5-[(E)-2-phenylethenyl]benzene-1,3-diol protected by carbethoxy is obtained through wittig reaction, and the target compound, namely 2-(1-methylethyl)-5-[(E)-2-phenylethenyl]benzene-1,3-diol, is obtained through hydrolysis reaction. The method has the advantages that the number of reaction steps is small, reaction conditions are mild and industrialization is easy, and can meet the synthesis requirement of 2-(1-methylethyl)-5-[(E)-2-phenylethenyl]benzene-1,3-diol raw materials.

Description

technical field [0001] The invention belongs to the technical field of medicine preparation, and in particular relates to a simple and convenient preparation method of an anti-psoriasis drug, phenylene modad. Background technique [0002] Styrenimod is a new generation of stilbene anti-inflammatory drugs, which can be used in the treatment of several major autoimmune diseases, such as psoriasis, pyogenic colitis and various allergic diseases. The dosage form of phenymod is a cream, the specification is 0.1g / 10g. As a new drug project that has been listed as a "National Science and Technology Major Project" by the Ministry of Science and Technology, it has obtained the new drug clinical approval document on September 8, 2009, and is currently in phase III clinical trials. It is expected that the drug will be declared for production in the near future. The production approval has become a unique anti-psoriasis drug with independent intellectual property rights. [0003] Benz...

Claims

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Application Information

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IPC IPC(8): C07C39/21C07C37/055
Inventor 张亚
Owner SHANGHAI FOSUN PHARMA DEV CO LTD
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