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Synthetic method of celecoxib

A synthetic method, celecoxib technology, applied in the field of medicinal chemistry, can solve the problems of multiple recrystallization times, complex solvent system, and difficult solvent recovery, and achieve the effects of high purity, simple operation, and shortened reaction time

Inactive Publication Date: 2014-07-16
SUZHOU TIANMA SPECIALTY CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The object of the present invention is to provide a kind of synthetic method of celecoxib, to overcome the two-step synthetic route method in the above-mentioned prior art brings recrystallization times many, long production cycle, solvent system is complicated, solvent recovery is more difficult, production cost High deficiencies, the production cost and environmental hazards of the celecoxib products are minimized

Method used

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  • Synthetic method of celecoxib

Examples

Experimental program
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Effect test

Embodiment 1

[0030] Embodiment one: a kind of synthetic method of celecoxib

[0031] 1L four-necked reaction flask, equipped with mechanical stirring, water bath. Under nitrogen protection, 12.8g of sodium methylate and 200ml of industrial toluene were first added thereto. Control the internal temperature not to exceed 40°C, and add 30 g of ethyl trifluoroacetate dropwise. After dropping, cool to about 30°C, add 25g of p-methylacetophenone dropwise, no heat release at this time. Stir at room temperature for 1 hour, then gradually raise the temperature to 110°C and react for about 5 hours. The central control checks that the content of p-methylacetophenone is less than 1%, and the reaction is stopped. After the reaction, add 100ml of 3N hydrochloric acid solution to the reaction solution to adjust the pH to 2, stir for 10 minutes until the organic layer is clear, and let stand to separate layers; the aqueous layer is extracted with 50ml of toluene, and the combined organic layers are wash...

Embodiment 2

[0035] Embodiment two: a kind of synthetic method of celecoxib

[0036] 1L four-necked reaction flask, equipped with mechanical stirring, water bath. Under nitrogen protection, 12.5 g of sodium methoxide and 200 ml of industrial toluene were added. Control the internal temperature not to exceed 40°C, and add 30 g of ethyl trifluoroacetate dropwise. After dropping, cool to about 30°C, add 25g of p-methylacetophenone dropwise, and stir at room temperature for 1 hour after adding. Gradually raise the temperature to 110°C and react for about 3 hours. The central control checks that the content of p-methylacetophenone is less than 1%, and the reaction is stopped. After the reaction, add 100ml of 3N hydrochloric acid solution to the reaction solution to adjust the pH to 2, stir for 10 minutes until the organic layer is clear, and let stand to separate layers; the aqueous layer is extracted with 50ml of toluene, and the combined organic layers are washed once with 60ml of water.

...

Embodiment 3

[0040] Embodiment three: a kind of synthetic method of celecoxib

[0041] 1L four-necked reaction flask, equipped with mechanical stirring, water bath. Under nitrogen protection, 12.5 g of sodium methoxide and 200 ml of industrial toluene were added. Control the internal temperature not to exceed 40°C, and add 31 g of ethyl trifluoroacetate dropwise. After dropping, cool to about 30°C, add 25g of p-methylacetophenone dropwise, and stir at room temperature for 1 hour after adding. Gradually raise the temperature to 110°C and react for about 3 hours. The central control checks that the content of p-methylacetophenone is less than 1%, and the reaction is stopped. After the reaction, add 100ml of 3N hydrochloric acid solution to the reaction solution to adjust the pH to 2, stir for 10 minutes until the organic layer is clear, and let stand to separate layers; the aqueous layer is extracted with 50ml of toluene, and the combined organic layers are washed once with 60ml of water. ...

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Abstract

The invention discloses a synthetic method of celecoxib. The synthetic method is characterized by comprising the following steps: firstly, adding sodium methylate as an aldol condensation catalyst and methylbenzene as a reaction solvent into a reaction container, adding p-methylacetophenone and trifluoroacetic acid ethyl ester, fully reacting, adding diluted hydrochloric acid, and separating out a water layer to obtain a methylbenzene solution of an intermediate-diketone; secondly, adding water, a phase transfer catalyst and 4-aminosulfophenyl hydrazine hydrochloride into the methylbenzene solution of the intermediate-diketone, and performing dehydration cyclization reaction to obtain a celecoxib reaction solution; thirdly, replenishing methylbenzene, standing, separating out the water layer and remaining an organic layer; cooling the organic layer, preserving heat and crystallizing to obtain a crystal product, and performing suction filtration, methylbenzene washing and water washing in sequence to obtain a celecoxib crude product; drying the crude product in vacuum, decolorizing and re-crystallizing to obtain a celecoxib raw material. According to the synthetic method, the celecoxib yield is increased, the reaction time is shortened, the celecoxib purity is high, the three-waste discharge in the whole production process is reduced, and the production cost is low.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a synthesis method of celecoxib. Background technique [0002] Celecoxib was launched by Pfizer in December 1998. It is the world's first cyclooxygenase-2 (COX-2) inhibitor. This type of drug can relieve pain while avoiding the previous non- Severe gastrointestinal side effects caused by steroidal anti-inflammatory drugs, the molecular formula of celecoxib is C 17 h 14 f 3 N 3 o 2 S, molecular weight is 381.37, its chemical structure formula is shown in formula 1: [0003] [0004] At present, there is only one route for industrially synthesizing celecoxib, all of which use p-methylacetophenone and ethyl trifluoroacetate as raw materials to condense in different alkalis and organic solvents to produce the intermediate diketone. Then it is dehydrated and cyclized with 4-aminosulfophenylhydrazine hydrochloride in different solvent systems to produce...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D231/12
CPCC07D231/12
Inventor 孙光福徐敏
Owner SUZHOU TIANMA SPECIALTY CHEM
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