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Synthesis method of diclofenac sodium intermediate 1-(2,6-dichlorophenyl)indolin-2-one

A technology of diclofenac sodium and dichlorophenyl, which is applied in the field of synthesis technology of non-steroidal anti-inflammatory drugs, can solve the problems that reactants are not easily dispersed, the purity of diclofenac sodium is low, and the Friedel-Crafts reaction temperature is high, so as to avoid production burns and save energy. Energy consumption, the effect of improving the purity

Active Publication Date: 2021-06-11
TOPFOND PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But, in the existing synthesis diclofenac sodium technique, its Friedel-Crafts reaction temperature is too high, is 150-160 ℃, and reactant is difficult for dispersing, and gained diclofenac sodium purity is lower

Method used

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  • Synthesis method of diclofenac sodium intermediate 1-(2,6-dichlorophenyl)indolin-2-one
  • Synthesis method of diclofenac sodium intermediate 1-(2,6-dichlorophenyl)indolin-2-one

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Embodiment 1

[0024] Embodiment 1: the synthetic method of 1-(2,6-dichlorophenyl) indolin-2-one

[0025] The steps of the synthesis method include: 30 g (0.096 mol) of N-phenyl-N-(2,6-dichlorophenyl)-chloroacetamide, 2.5 g (0.0096 mol) of phase transfer catalyst tetrabutyl fluorination Add ammonium to the reaction flask, raise the temperature to 70°C, then slowly add 25.5g (0.19mol) of Lewis acid anhydrous aluminum trichloride (about 0.5h), and perform Friedel-Crafts reaction at 70°C, and spot plate detection Reaction, after the reaction is completed, the reactant is added dropwise to purified water for dispersion and stirring, the stirring time is 5h, and 26g of diclofenac sodium intermediate 1-(2,6-dichlorophenyl)indolin-2-one is prepared .

[0026] The yield of diclofenac sodium intermediate 1-(2,6-dichlorophenyl)indolin-2-one prepared by the above method is 86.6%, and the purity is 99.6%.

Embodiment 2

[0027] Embodiment 2: the synthetic method of 1-(2,6-dichlorophenyl) indolin-2-one

[0028] The steps of the synthesis method include: 30 g (0.096 mol) of N-phenyl-N-(2,6-dichlorophenyl)-chloroacetamide, 2.5 g (0.0096 mol) of phase transfer catalyst tetrabutyl fluorination Add ammonium to the reaction flask, raise the temperature to 60°C, then slowly add 25.5g (0.19mol) of Lewis acid anhydrous aluminum trichloride (about 0.5h), and perform Friedel-Crafts reaction at 60°C, and spot plate detection Reaction, after the reaction is completed, the reactant is added dropwise to purified water for dispersion and stirring, the stirring time is 5h, and 27g of diclofenac sodium intermediate 1-(2,6-dichlorophenyl)indolin-2-one is prepared , the yield is 90%, and the purity is 99.5%.

Embodiment 3

[0029] Embodiment 3: the synthetic method of 1-(2,6-dichlorophenyl) indolin-2-one

[0030] The steps of the synthesis method include: 30 g (0.096 mol) of N-phenyl-N-(2,6-dichlorophenyl)-chloroacetamide, 2.5 g (0.0096 mol) of phase transfer catalyst tetrabutyl fluorination Add ammonium to the reaction flask, raise the temperature to 60°C, then slowly add 25.5g (0.19mol) of Lewis acid anhydrous aluminum trichloride (about 0.5h), and perform Friedel-Crafts reaction at 60°C, and spot plate detection After the reaction is completed, the reactant is added dropwise to purified water for dispersion and stirring. The stirring time is 5 hours, and 26.1 g of diclofenac sodium intermediate 1-(2,6-dichlorophenyl)indoline-2- Ketone, its yield is 87%, and its purity is 99.3%.

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Abstract

The invention discloses a method for synthesizing diclofenac sodium intermediate 1-(2,6-dichlorophenyl)indolin-2-one, which comprises the following steps: in the presence of a phase transfer catalyst, N-phenyl ‑N‑(2,6‑dichlorophenyl)‑chloroacetamide and Lewis acid were subjected to Friedel-Crafts reaction to prepare diclofenac sodium intermediate 1‑(2,6‑dichlorophenyl)indoline‑2‑ ketone. The present invention adds a phase transfer catalyst in the Friedel-Crafts reaction, which can make N-phenyl-N-(2,6-dichlorophenyl)-chloroacetamide and Lewis acid better combined, thereby at a lower temperature The Friedel-Crafts reaction can be carried out at a lower temperature, which is reduced from the original 150-160°C to about 60°C-80°C, which saves energy consumption, reduces the danger of operation in production, and improves the temperature of 1-(2,6-dichlorobenzene base) the purity of indolin-2-one and diclofenac sodium.

Description

technical field [0001] The invention relates to a synthesis process of a non-steroidal anti-inflammatory drug, in particular to a synthesis method of a diclofenac sodium intermediate 1-(2,6-dichlorophenyl)indolin-2-one. Background technique [0002] Diclofenac Sodium (Diclofenac Sodium, DS) is the third generation of non-steroidal anti-inflammatory drugs, chemical name: 2-[(2,6-dichlorophenyl)amino]-sodium phenylacetate. Diclofenac sodium was first listed abroad in 1974, synthesized in China in 1985, and produced in many domestic pharmaceutical factories one after another. It is clinically used for anti-inflammatory, analgesic, antipyretic and anti-rheumatic. The anti-inflammatory and antipyretic effects of diclofenac sodium are 2-2.5 times stronger than indomethacin, and 26-50 times stronger than aspirin. Applied in more than 120 countries and regions, it is one of the best-selling drugs in the world. [0003] Nevertheless, diclofenac sodium still has gastrointestinal sti...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D209/34
CPCC07D209/34
Inventor 陈风王俊臣赖珅陈金春赵臻张宏周刘学威年蓓蕾薛娟王振坤吉令杨明戴维刘旭
Owner TOPFOND PHARMA CO LTD