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The preparation method of tofisopam intermediate

A technology of tofisopam and intermediates, applied in the field of drug synthesis, can solve the problems of serious pollution and restriction of tofisopam production, and achieve the effect of protecting the environment and reducing the content of heavy metals

Active Publication Date: 2016-04-13
SHANDONG JINCHENG PHARMACEUTICAL GROUP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] Invention patents WO2004054952A1, WO2003050092A2, CN200910047120, CN201310488767 use chromium trioxide, sodium dichromate, potassium dichromate, and potassium permanganate as oxidants in the oxidation process, and the dosage is compound 3-[2-(3,4-dimethoxy Benzoyl)-4,5-dimethoxyphenyl]-pentan-2-one molar weight of 2-5eq generates a large amount of heavy metal wastewater, which is seriously polluted and restricts the output of Tofisopam

Method used

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  • The preparation method of tofisopam intermediate
  • The preparation method of tofisopam intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0031] Add 35.7g (0.10mol) of 1-(3,4-dimethoxy-phenyl)-3-ethyl-5,6-dimethoxy-2-methyl-indane and 357g of water to 500ml In the four-neck flask, add 50.0g (0.5mol) of 98wt% concentrated sulfuric acid, stir; add 0.48g (0.003mol) of copper sulfate, cool down to 3±2°C, add dropwise 17.0g (0.20mol) of 40wt% hydrogen peroxide, and control the temperature At 20±5°C, the dropwise addition is completed, and the temperature is raised to 50±5°C for 1 hour; 200ml of dichloromethane is added for extraction, and the dichloromethane is evaporated to dryness; 150ml of isopropanol is added for recrystallization to obtain 3-[2-(3, 31.7 g of 4-dimethoxybenzoyl)-4,5-dimethoxyphenyl]-pentan-2-one (purity 99.1%), yield 85.6%.

Embodiment 2

[0033] 35.7 g (0.10 mol) of 1-(3,4-dimethoxy-phenyl)-3-ethyl-5,6-dimethoxy-2-methyl-indane and 178.5 g of water were added to In a 500ml four-necked bottle, add 9.7g (0.1mol) of 65wt% concentrated nitric acid, stir; add 0.27g (0.002mol) of copper chloride, cool to 3±2°C, add dropwise 102.0g (0.30mol) of 10wt% hydrogen peroxide, Control the temperature at 25±5°C, after the dropwise addition, raise the temperature to 40±5°C for 5 hours; add 200ml of dichloromethane for extraction, evaporate the methylene chloride to dryness; add 150ml of isopropanol for recrystallization to obtain 3-[2-( 27.8 g of 3,4-dimethoxybenzoyl)-4,5-dimethoxyphenyl]-pentan-2-one (purity 98.9%), yield 75.1%.

Embodiment 3

[0035] Add 35.7g (0.10mol) 1-(3,4-dimethoxy-phenyl)-3-ethyl-5,6-dimethoxy-2-methyl-indane and 215g water to 500ml In the four-neck flask, add 19.8g (0.2mol) of 36.8wt% concentrated hydrochloric acid, 12g (0.2mol) of glacial acetic acid, and stir; add 0.4g (0.005mol) of copper oxide, cool down to 3±2°C, and dropwise add 30wt% hydrogen peroxide 56.7g (0.50mol), control the temperature at 15±5°C, after the dropwise addition is complete, raise the temperature to 25±5°C for 10 hours; add 200ml of dichloromethane for extraction, evaporate the dichloromethane to dryness; add 150ml of ethanol for recrystallization, and obtain 3 -[2-(3,4-Dimethoxybenzoyl)-4,5-dimethoxyphenyl]-pentan-2-one 32.7g (purity 99.4%), yield 88.2%.

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Abstract

The invention relates to a preparation method of a tofisopam intermediate 3-[2-(3,4-dimethoxy benzoic acyl)-4,5-dimethoxyphenyl]-penta-2-ketone, and belongs to the technical field of pharmaceutical synthesis. The method comprises the following step: carrying out reaction on 1-(3,4-dimethoxy-phenyl)-3-ethyl-5,6-dimethoxy-2-methyl-indan as an initial material, copper compounds as catalysts, and hydrogen peroxide as an oxidant under an acid condition, so as to prepare the tofisopam intermediate 3-[2-(3,4-dimethoxy benzoic acyl)-4,5-dimethoxyphenyl]-penta-2-ketone. According to the preparation method, the content of heavy metals in the wastewater is greatly lowered, chromium compounds with carcinogenesis are avoided, the production capacity of tofisopam is released, and the environment is protected.

Description

technical field [0001] The present invention relates to a preparation method of tofisopam intermediate 3-[2-(3,4-dimethoxybenzoyl)-4,5-dimethoxyphenyl]-pentan-2-one , belongs to the technical field of drug synthesis. Background technique [0002] Tofisopam, chemical name: (RS)-7,8-dimethoxy-1-(3,4-dimethoxyphenyl)-5-ethyl-4-methyl-5 Hydrogen-2,3-benzodiazepine is a new type of antidepressant drug developed by Servier Company and first launched in Hungary in 1974 for the treatment of anxiety and other diseases. As a new type of benzodiazepine Nitrogen drugs have few side effects, are stable, economical and applicable, and are widely used clinically. Therefore the improvement of tofisopam synthetic technique is particularly important, and intermediate 3-[2-(3,4-dimethoxybenzoyl)-4,5-dimethoxyphenyl]-penta-2- Ketone, as a key step restricting the preparation of tofisopam, requires us to conduct in-depth research. [0003] Invention patents WO2004054952A1, WO2003050092A2, CN...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C49/84C07C45/28C07C43/21C07C41/18C07C41/01
CPCC07C41/01C07C41/16C07C45/28C07C2602/08C07C49/84C07C43/21C07C43/253
Inventor 孟宾孙滨张彤南红燕
Owner SHANDONG JINCHENG PHARMACEUTICAL GROUP CO LTD
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