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Preparation method of cyclooxygenase-2 inhibitor parecoxib intermediate

A technology of parecoxib and cyclooxygenase, which is applied in the field of drug synthesis, can solve problems such as complex reaction steps, high equipment requirements, and environmental pollution by fluoride, and achieves a high reaction yield, simple reaction steps, and mild conditions Effect

Inactive Publication Date: 2016-09-28
周喜燕 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] In the above method, the intermediate 5-methyl-3,4-diphenylisoxazole has complicated reaction steps, which can be obtained through the cyclization step first, and then dehydration, and in the cyclization step, the acetyl oxygen is also It will participate in the hydroxylamine reaction to generate by-products; in addition, the elimination step uses trifluoroacetic acid system for dehydration, which requires high equipment, and fluoride will also cause environmental pollution

Method used

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  • Preparation method of cyclooxygenase-2 inhibitor parecoxib intermediate
  • Preparation method of cyclooxygenase-2 inhibitor parecoxib intermediate
  • Preparation method of cyclooxygenase-2 inhibitor parecoxib intermediate

Examples

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Embodiment 1

[0021] A method for preparing a parecoxib intermediate, the method comprising: 29.1 g (100 mmol) of 1-phenyl-2-(4-sulfonic acid phenyl)-2-acetyl ethyl ketone, 30.8 g of ammonium acetate (400mmol), iodobenzene diacetate 19.3g (60mmol), potassium iodide 6.6g (40mmol) join in the flask that 150ml dichloromethane is housed, 75 ℃ carry out contact reaction 1 hour, after reaction finishes, organic phase concentration, washing, Wash with saturated brine, dry over anhydrous sodium sulfate, then recrystallize from ethanol, and dry to obtain 27.5 g of the parecoxib intermediate 5-methyl-3,4-diphenylisoxazole with a yield of 87.3% and a purity of 99.60 %.

Embodiment 2

[0023] A method for preparing parecoxib intermediate, the method comprising: 29.1g (100mmol) of 1-phenyl-2-(4-sulfonic acid phenyl)-2-acetyl ethyl ketone, 38.5g of ammonium acetate (500mmol), iodobenzene diacetate 22.5g (70mmol), potassium iodide 9.9g (60mmol) join in the flask that 150ml dichloromethane is housed, 80 ℃ carry out contact reaction 1 hour, after reaction finishes, organic phase is concentrated, washed, Washed with saturated brine, dried over anhydrous sodium sulfate, recrystallized from ethanol, and dried to obtain 27.4 g of the parecoxib intermediate 5-methyl-3,4-diphenylisoxazole with a yield of 86.8% and a purity of 99.71 %.

Embodiment 3

[0025] A method for preparing parecoxib intermediate, the method comprising: 29.1g (100mmol) of 1-phenyl-2-(4-sulfonic acid phenyl)-2-acetyl ethyl ketone, 38.5g of ammonium acetate (500mmol), iodobenzene diacetate 19.3g (60mmol), potassium iodide 6.6g (40mmol) join in the flask that 150ml dichloromethane is housed, 85 ℃ carry out contact reaction 0.5 hour, after reaction finishes, organic phase is concentrated, washed, Washed with saturated brine, dried over anhydrous sodium sulfate, then recrystallized from ethanol, and dried to obtain 26.5 g of the parecoxib intermediate 5-methyl-3,4-diphenylisoxazole with a yield of 84.5% and a purity of 99.33 %.

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Abstract

The invention discloses a preparation method of a cyclooxygenase-2 inhibitor parecoxib intermediate. The preparation method comprises the following steps: in the presence of iodobenzene diacetate and potassium iodide, carrying out contact reaction on 1-phenyl-2-(4-sulfophenyl)-2-acetylethylketone and ammonium acetate; and after the reaction finishes, concentrating the organic phase, washing with water, recrystallizing with ethanol, and drying to obtain the 5-methyl-3-phenyl-4-(4-sulfophenyl)isoxazole. The method for preparing the parecoxib intermediate has the advantages of simple steps, mild conditions and high yield.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a preparation method of a cyclooxygenase-2 inhibitor parecoxib intermediate. Background technique [0002] Parecoxib Sodium (Parecoxib Sodium) is a specific cyclooxygenase-2 inhibitor that can be given intravenously and intramuscularly. . The chemical name of parecoxib sodium is N-[[4-(5-methyl-3-phenyl-4-isoxazolyl)phenyl]sulfonyl]propionamide sodium salt, and the specific structure is as follows: [0003] [0004] At present, there are many studies on the synthesis method of parecoxib (sodium), but basically all of them use 5-methyl-3,4-diphenylisoxazole as the key intermediate to prepare parecoxib. For example, WO2005123701A1 discloses a preparation method of parecoxib, which uses diacetophenone as a starting material, first reacts with tetrahydropyrrole, and then undergoes acetylation, ring-closure reaction with hydroxylamine hydrochloride, elimination and dehyd...

Claims

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Application Information

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IPC IPC(8): C07D261/08
CPCC07D261/08
Inventor 王晓岳
Owner 周喜燕
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