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Preparation method of cyclooxygenase-2 inhibitor parecoxib

A technology of parecoxib and cyclooxygenase, which is applied in the field of drug synthesis, can solve problems such as the safety impact of waste discharge operators, corrosiveness of compounds, and difficulty in reaction treatment, so as to reduce reaction time, increase reaction yield, and Effects in simple steps

Active Publication Date: 2016-08-17
无锡德方生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] CN105418528A discloses a preparation method of parecoxib sodium, which innovatively adopts a dipolar cycloaddition reaction to synthesize an isoxazole ring with benzaldoxime and 1-phenyl-1-propyne in the presence of a catalyst, The yield has also reached a relatively high level, but the catalyst chlorosuccinimide used in large quantities in this method is even up to 3 times the amount, which makes the reaction treatment more difficult, and the compound is corrosive, requires high equipment, and a large amount of Emission of waste and impact on operator safety

Method used

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

Examples

Experimental program
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Embodiment 1

[0025] Preparation of 5-methyl-3,4-diphenylisoxazole

[0026] Mix 12.1 g (100 mmol) of benzaldoxime with 12.8 g (110 mmol) of 1-phenylpropyne, 3.9 g (6 mmol) of tris(2-phenylpyridine) iridium (III), 8.1 g (80 mmol) of triethylamine and Magnesium oxide 0.4g (10mmol) was added to a flask containing 30ml THF, and the light reaction was carried out at 25°C for 35min. The light was emitted by a blue light-emitting diode with a wavelength of 460nm. The reaction solution was concentrated, washed with water, recrystallized from ethanol, and dried to obtain 23.0 g of 5-methyl-3,4-diphenylisoxazole with a yield of 97.8% and a purity of 99.64%.

Embodiment 2

[0028] Preparation of 5-methyl-3,4-diphenylisoxazole

[0029] Mix 12.1 g (100 mmol) of benzaldoxime with 13.9 g (120 mmol) of 1-phenylpropyne, 5.2 g (8 mmol) of tris(2-phenylpyridine) iridium (III), 7.1 g (70 mmol) of triethylamine and Magnesium oxide 0.8g (20mmol) was added to a flask containing 30ml THF, and the light reaction was carried out at 25°C for 30min. The light was emitted by a blue light-emitting diode with a wavelength of 460nm. The reaction solution was concentrated, washed with water, recrystallized from ethanol, and dried to obtain 23.2 g of 5-methyl-3,4-diphenylisoxazole with a yield of 98.5% and a purity of 99.47%.

Embodiment 3

[0031] Preparation of 5-methyl-3,4-diphenylisoxazole

[0032] Mix 12.1 g (100 mmol) of benzaldoxime with 15.1 g (130 mmol) of 1-phenylpropyne, 3.2 g (5 mmol) of tris(2-phenylpyridine) iridium (III), 6 g (60 mmol) of triethylamine and Magnesium 0.6g (15mmol) was added into a flask filled with 30ml THF, and the light reaction was carried out at 30°C for 40min. The light was emitted by a blue light-emitting diode, and the light wavelength was 470nm. The reaction solution was concentrated, washed with water, recrystallized from ethanol, and dried to obtain 22.9 g of 5-methyl-3,4-diphenylisoxazole with a yield of 97.2% and a purity of 99.36%.

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Abstract

The invention discloses a preparation method of a cyclooxygenase-2 inhibitor parecoxib. The method comprises the following steps that 1, benzaldoxime reacts with 1-phenylpropyne in the presence of tris(2-phenylpyridine)iridium (III), triethylamine and magnesium oxide under the illumination condition to obtain 5-methyl-3,4-diphenylisoxazole; 2, a stirring reaction is conducted on 5-methyl-3,4-diphenylisoxazole obtained in the first step and chlorosulfonic acid, dichloromethane extraction is conducted after the reaction is completed, a dichloromethane phase is directly added into ammonium hydroxide, an organic phase is separated, water washing, concentrating and ethanol recrystallization are conducted, and valdecoxib is obtained; 3, valdecoxib obtained in the second step reacts with propionic anhydride in the presence of triethylamine, and parecoxib is obtained. The preparation method of parecoxib is simple in step, high in yield and simple in posttreatment.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a preparation method of cyclooxygenase-2 inhibitor parecoxib. 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 dehydration to obtai...

Claims

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Application Information

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IPC IPC(8): C07D261/08
CPCC07D261/08
Inventor 王晓岳
Owner 无锡德方生物科技有限公司
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