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Celecoxib preparation process

A celecoxib, reaction technology, applied in the field of medicine, can solve the problems of prolonging the reaction time, increasing the cost, increasing the operation process, etc.

Inactive Publication Date: 2012-10-24
TIANJIN INSTITUTE OF PHARMA RESEARCH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But in these synthetic methods, obtain celecoxib with (IV) and (V) reaction, single-step yield 46-81%; (IV) is purified, including processes such as extraction, drying and solvent removal, which undoubtedly increases the operating procedures, prolongs the reaction time, and increases the cost

Method used

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Examples

Experimental program
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Embodiment 1

[0027] Under nitrogen protection, 80 mL of dry methanol and 1.5 g (65.2 mmol) of sodium metal were added to a four-neck flask equipped with a reflux condenser and a mechanical stirrer to prepare a sodium methoxide solution. At room temperature, 20 mL of methanol solution containing 13.9 mL (96.2 mmol) of ethyl trifluoroacetate was slowly added dropwise, after stirring, 15 mL of methanol solution containing 10.5 mL (77.0 mmol) of (III) was added, and the temperature was raised to 40°C. Slowly raise the temperature to 70°C, at this temperature, continue the reaction for 2h. Heating was stopped, and 30 mL of cold water, 10% dilute hydrochloric acid and ethyl acetate were added, and the pH=2 was measured at this time. 18.5 g (77.0 mmol) of p-aminosulfonylphenylhydrazine hydrochloride was added thereto, and the temperature was raised to reflux with stirring. After the reaction was completed, the temperature was lowered to room temperature, and an off-white solid was precipitated. ...

Embodiment 2

[0029] Under nitrogen protection, 160 mL of 20% (474.1 mmol) sodium ethoxide solution was added to a four-neck flask equipped with a reflux condenser and a mechanical stirrer. Under stirring at room temperature, 60 mL of ethanol solution containing 58.4 g (447.1 mmol) of methyl trifluoroacetate was slowly added dropwise, and after stirring for 0.5 h, 60 mL of ethanol solution containing 50.9 g (372.6 mmol) of (III) was added. Slowly raise the temperature to 90°C and react for 2h. The temperature was lowered to 30° C., and 10% dilute hydrochloric acid and ethyl acetate were added to the system, and the pH=1 was measured at this time. Add 80 g (357.0 mmol) of 4-sulfanitrophenylhydrazine hydrochloride to it, stir and heat up to reflux. After the reaction was completed, the temperature was lowered to room temperature, and an off-white solid was precipitated. The white celecoxib solid was obtained by suction filtration, dried in vacuo, and weighed 114.3 g (HPLC: I 99.05%, VI 0.95...

Embodiment 3

[0031] Under nitrogen protection, 46.8 g (323.0 mmol) of ethyl trifluoroacetate and 50 mL of tetrahydrofuran were added to a four-neck flask equipped with a reflux condenser and a mechanical stirrer. Stir and cool down to below 5°C, slowly add 130g of 60% (323.0mmol) sodium hydride, and after stirring for 0.5h, add 36.9g (270.0mmol) of (III). Stop refrigeration, rise to room temperature, and then slowly heat until the system is in a reflux state. At this temperature, the reaction was 2h. Add cold water and lower the temperature to below 30°C. 10% dilute hydrochloric acid and ethyl acetate were added to the system, and the pH=1 was measured at this time. 62.0 g (260.0 mmol) of 4-aminosulfonylnitrophenylhydrazine hydrochloride was added thereto, and the temperature was raised to reflux with stirring. After the reaction was completed, the temperature was lowered to room temperature, and an off-white solid was precipitated. The white celecoxib solid was obtained by suction fil...

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Abstract

The invention provides a process for simply and efficiently preparing a selective cyclooxygenase-2 (COX-2) inhibitor 4-[3-trifluoromethyl-5-(4-methylphenyl)-1H-pyrazolyl]benzenesulfonamide (celecoxib, I). The process comprises the following steps: reacting an alkyl trifluoroacetate and 4-methylacetophenone which are initial raw materials under the action of an organic alkali solution, directly adding a dilute acid, an organic solvent and 4-aminosulfonylhydrazinobenzene or its acid salt to the resulting system, and heating to prepare the celecoxib. Above reaction adopts one kettle way, so the process has the advantages of mild condition, simple operation, high product yield and high product purity, and is suitable for industrialized production.

Description

technical field [0001] The invention belongs to the technical field of medicine, in particular to a simple and efficient preparation of selective cyclooxygenase-2 (COX-2) inhibitor 4-[3-trifluoromethyl-5-(4-methylphenyl)- 1H-pyrazolyl]benzenesulfonamide (celecoxib, Celecoxib, I) method. [0002] Background technique [0003] Non-steroidal anti-inflammatory drugs (NSAIDs) have antipyretic, analgesic, anti-inflammatory, anti-rheumatic and anti-coagulant effects, and are widely used clinically in the treatment of osteoarthritis, rheumatoid arthritis and various pain and fever Relief of symptoms. Traditional NSAIDs play a therapeutic role by inhibiting COX, but inevitably bring about adverse reactions in the gastrointestinal tract (GI). Selective COX-2 inhibitors only reduce the synthesis of inducible COX-2 without affecting the synthesis of physiological COX-1, which not only has significant anti-inflammatory activity, but also reduces gastrointestinal damage. Celecoxib, ...

Claims

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Application Information

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IPC IPC(8): C07D231/12
Inventor 梅林雨罗振福郑志超靳朝东高晶梁忠信
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH
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