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Preparation method for high purity etofenamate

An etofenamate, high-purity technology, applied in the field of drug synthesis, can solve the problems of poor product appearance, difficult separation, low content, etc., and achieve the effect of good appearance, simple separation and purification, and high product purity

Active Publication Date: 2012-07-04
SHANGHAI RIGHTHAND PHARMTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0015] The present invention aims to provide a method for preparing high-purity etofenamate, which solves the shortcomings of low yield, difficult separation, special high-vacuum high-temperature rectification equipment, poor product appearance and low content in the prior art. Produce high-purity products that meet the European Pharmacopoeia, ensuring clinical application and safety requirements

Method used

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  • Preparation method for high purity etofenamate
  • Preparation method for high purity etofenamate
  • Preparation method for high purity etofenamate

Examples

Experimental program
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Effect test

Embodiment 1

[0036] Embodiment 1: the preparation of etofenamate.

[0037] Add 281.5 g of flufenamic acid into 1000 g of toluene, stir and cool to 10°C, add 217.5 g of trimethylchlorosilane (R*=TMS), and stir at this temperature for 1 hour. Then 1062 grams of diethylene glycol was added, and the temperature was raised to 30° C. to continue the reaction for 5 hours. The reaction process was tracked and detected by TLC or HPLC until the raw materials and intermediates of flufenamic acid disappeared, then 800 g of 10% dilute hydrochloric acid was added and stirred and hydrolyzed at 30-40°C for 1 hour, and it was tracked and detected by HPLC until it was completely converted into etofenamate. The reaction liquid was cooled to about 10°C, and then the pH of the reaction system was adjusted to about 9 with sodium carbonate, and the layers were separated after standing. The organic layer was washed five times with 1000 g of pure water, then decolorized by adding an appropriate amount of activate...

Embodiment 2

[0038] Embodiment 2: the preparation of etofenamate.

[0039] Add 281.5 g of flufenamic acid into 1000 g of toluene, stir and cool to 10°C, add 331.6 g of tert-butyldimethylsilyl chloride (R*=TBDMS), and keep stirring at 20°C for 1 hour. Then add 1592 grams of diethylene glycol and heat up to 40°C to continue the reaction for 5 hours. The reaction process was tracked and detected by TLC or HPLC until the raw materials and intermediates of flufenamic acid disappeared, then 900 g of 10% dilute hydrochloric acid was added and stirred and hydrolyzed at 30-40°C for 1 hour, and it was tracked and detected by HPLC until it was completely converted into etofenamate. The reaction solution was cooled to about 10°C, and then the pH of the reaction system was adjusted to about 9 with potassium carbonate, and the mixture was allowed to stand for stratification. The organic layer was washed six times with 1200 g of pure water, then added an appropriate amount of active carbon for decolori...

Embodiment 3

[0040] Embodiment 3: the preparation of etofenamate.

[0041] Add 281.5 g of flufenamic acid into 1200 g of DMF, stir and cool to 10°C, add 381.5 g of p-toluenesulfonyl chloride (R*=Ts), and keep stirring at 20°C for 1 hour. Then add 1062 grams of diethylene glycol, and heat up to 40°C to continue the reaction for 5 hours. Use TLC or HPLC to track and detect the disappearance of flufenamic acid raw materials and intermediates. Concentrate the reaction solution under reduced pressure at 50~60°C to about 1700ml, then add 800g of 10% dilute hydrochloric acid, stir and hydrolyze at 30~40°C for 2 hours , HPLC tracking detection to all converted to etofenamate. The reaction solution was cooled to about 10°C, and then the pH of the reaction system was adjusted to about 10 with sodium carbonate, and the reaction solution was extracted twice with 1000 grams of toluene. The organic layers were combined, washed five times with 1000 g of pure water, then decolorized by adding an approp...

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Abstract

The invention relates to a preparation method for high purity etofenamate. Flufenamic acid reacts with diethylene glycol in non-protic organic solvent in the presence of an organic carboxylic acid activating agent (R*-Cl) such as chlorosilane and sulfonyl chloride, reactant is hydrolyzed under the acidic condition and then extracted and separated simply to obtain high purity etofenamate. Compared with the prior art, the preparation method for the high purity etofenamate has the advantages of being less in equipment investment and reaction steps, easy to operate, high in productivity and product purity and the like and has wide application prospects.

Description

technical field [0001] The invention relates to a preparation method of etofenamate compound, which belongs to the technical field of medicine synthesis. Background technique [0002] Etofenamate, its English name is Etofenamate, its chemical name is 2-(2-hydroxyethoxy)-ethyl-2-[3-(trifluoromethyl)anilino]benzoate, CAS number: [30544-47-9], molecular formula: C 18 h 18 f 3 NO 4 , molecular weight: 369.33. Structural formula: [0003] (I). [0004] Etofenamate is an anacid-type non-steroidal anti-inflammatory drug, which was developed by Bayer and launched in Germany in 1977, and then in Australia, Switzerland, Spain, Taiwan and other countries and regions. Bayer launched cream in my country in 1999, sold cream in 2002, and sold spray and raw materials in 2005. Bayer (China) was approved to produce cream in 2002, and the registered product name is "Traumon". The API of this product has been recorded in the European Pharmacopoeia. [0005] Etofenamate has analges...

Claims

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Application Information

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IPC IPC(8): C07C229/58C07C227/18
Inventor 王海平池骋池正明许关煜
Owner SHANGHAI RIGHTHAND PHARMTECH
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