A kind of preparation method of parecoxib for treating postoperative pain

Abstract

The invention discloses a preparation method of parecoxib for treating postoperative pain. The method comprises the following steps: 1) conducting a contact reaction between 3-(4-sulfonylphenyl)-4-phenyl-4-(1-pyrrolidyl)-3-butene-2-one and ammonium acetate in acetic acid at 90-100 DEG C; after the reaction, diluting with dichloromethane; regulating the pH to 6-7 with saturated sodium bicarbonate; concentrating the organic phase and washing; recrystallizing with ethanol; and drying to obtain 5-methyl-3-phenyl-4-(4-sulfonylphenyl)isoxazole; 2) enabling the product obtained in the step 1) to react with ammonium chloride at 35-45 DEG C in the presence of anion exchange resin to obtain 5-methyl-3-phenyl-4-(4-sulphonylaminophenyl)isoxazole; and 3) and 3) enabling the product obtained in the step 2) to react with propionic anhydride in the presence of triethylamine to obtain parecoxib. The parecoxib preparation method disclosed by the invention 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 parecoxib for treating postoperative pain. 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 ...

Examples

Embodiment 1

[0026] Preparation of 5-methyl-3-phenyl-4-(4-sulfophenyl)isoxazole

[0027] Add 37.1 g (100 mmol) of 3-(4-sulfophenyl)-4-phenyl-4-(1-pyrrolidinyl)-3-buten-2-one and 38 g (500 mmol) of ammonium acetate to In a flask with 65ml of acetic acid, contact reaction at 95°C for 0.5 hours. After the reaction, dilute with dichloromethane, adjust the pH to 7 with saturated sodium bicarbonate, concentrate the organic phase, wash with water, then recrystallize with ethanol, and dry to obtain 5-methyl -26.8 g of 3-phenyl-4-(4-sulfophenyl)isoxazole, the yield is 85.0%, and the purity is 99.77%.

Embodiment 2

[0029] Preparation of 5-methyl-3-phenyl-4-(4-sulfophenyl)isoxazole

[0030] Add 37.1 g (100 mmol) of 3-(4-sulfonic acid phenyl)-4-phenyl-4-(1-pyrrolidinyl)-3-buten-2-one and 30 g (400 mmol) of ammonium acetate to In a flask containing 70ml of acetic acid, contact reaction at 100°C for 1 hour. After the reaction, dilute with dichloromethane, adjust the pH to 7 with saturated sodium bicarbonate, concentrate the organic phase, wash with water, then recrystallize with ethanol, and dry to obtain 5-methyl - 26.9 g of 3-phenyl-4-(4-sulfophenyl)isoxazole, the yield was 85.2%, and the purity was 99.84%.

Embodiment 3

[0032] Preparation of 5-methyl-3-phenyl-4-(4-sulfophenyl)isoxazole

[0033] Add 37.1 g (100 mmol) of 3-(4-sulfonic acid phenyl)-4-phenyl-4-(1-pyrrolidinyl)-3-buten-2-one and 30 g (400 mmol) of ammonium acetate to In a flask containing 90ml of acetic acid, contact reaction at 90°C for 1.5 hours. After the reaction, dilute with dichloromethane, adjust the pH to 6 with saturated sodium bicarbonate, concentrate the organic phase, wash with water, then recrystallize with ethanol, and dry to obtain 5-methyl - 26.8 g of 3-phenyl-4-(4-sulfophenyl)isoxazole, the yield was 84.9%, and the purity was 99.72%.

technical field

[0001] The invention belongs to the field of drug synthesis, and in particular relates to a preparation method of parecoxib for treating postoperative pain. 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 ...

Examples

Embodiment 1

[0026] Preparation of 5-methyl-3-phenyl-4-(4-sulfophenyl)isoxazole

[0027] Add 37.1 g (100 mmol) of 3-(4-sulfophenyl)-4-phenyl-4-(1-pyrrolidinyl)-3-buten-2-one and 38 g (500 mmol) of ammonium acetate to In a flask with 65ml of acetic acid, contact reaction at 95°C for 0.5 hours. After the reaction, dilute with dichloromethane, adjust the pH to 7 with saturated sodium bicarbonate, concentrate the organic phase, wash with water, then recrystallize with ethanol, and dry to obtain 5-methyl -26.8 g of 3-phenyl-4-(4-sulfophenyl)isoxazole, the yield is 85.0%, and the purity is 99.77%.

Embodiment 2

[0029] Preparation of 5-methyl-3-phenyl-4-(4-sulfophenyl)isoxazole

[0030] Add 37.1 g (100 mmol) of 3-(4-sulfonic acid phenyl)-4-phenyl-4-(1-pyrrolidinyl)-3-buten-2-one and 30 g (400 mmol) of ammonium acetate to In a flask containing 70ml of acetic acid, contact reaction at 100°C for 1 hour. After the reaction, dilute with dichloromethane, adjust the pH to 7 with saturated sodium bicarbonate, concentrate the organic phase, wash with water, then recrystallize with ethanol, and dry to obtain 5-methyl - 26.9 g of 3-phenyl-4-(4-sulfophenyl)isoxazole, the yield was 85.2%, and the purity was 99.84%.

Embodiment 3

[0032] Preparation of 5-methyl-3-phenyl-4-(4-sulfophenyl)isoxazole

[0033] Add 37.1 g (100 mmol) of 3-(4-sulfonic acid phenyl)-4-phenyl-4-(1-pyrrolidinyl)-3-buten-2-one and 30 g (400 mmol) of ammonium acetate to In a flask containing 90ml of acetic acid, contact reaction at 90°C for 1.5 hours. After the reaction, dilute with dichloromethane, adjust the pH to 6 with saturated sodium bicarbonate, concentrate the organic phase, wash with water, then recrystallize with ethanol, and dry to obtain 5-methyl - 26.8 g of 3-phenyl-4-(4-sulfophenyl)isoxazole, the yield was 84.9%, and the purity was 99.72%.

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