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Preparation method of parecoxib sodium

A technology of parecoxib sodium and valdecoxib, which is applied in the field of medicinal chemistry, can solve the problems of low purity, high cost, and low yield, and achieve the effect of simple operation, low price, and good repeatability

Inactive Publication Date: 2014-12-31
SICHUAN WEITUO BIOLOGICAL PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] Therefore, the method for preparing parecoxib sodium in the above-mentioned prior art is more complicated, the yield is low, the purity is not high, the quality does not reach the pharmaceutical standard, and the cost is high, and individual routes involve large doses of acidic reagents, which are unfavorable for safe production , and are difficult to industrialized production, for this reason, the present inventor improved the synthetic method of EP1550658 through a large amount of research, obtained a kind of improved method of preparing parecoxib sodium, and this method saves multi-step cumbersome The advanced post-treatment process makes the whole synthesis method simple to operate, good in repeatability, high in yield, low in cost, and less than 0.1% of a single impurity, suitable for industrial production, and the obtained product is also suitable for medicinal use

Method used

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  • Preparation method of parecoxib sodium

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Dissolve 50g of 3,4-diphenyl-5-methylisoxazole in 50mL of dichloromethane, add 100g of chlorosulfonic acid, and heat to 50-60°C for reaction; liquid, the aqueous phase was extracted with dichloromethane, the aqueous layer was discarded, and the organic phases were combined to obtain a dichloromethane solution of 4-(5-methyl-3-phenyl-4-isoxazole) benzenesulfonyl chloride without passing through processing, proceed directly to the next step.

[0045] Add the dichloromethane solution of 4-(5-methyl-3-phenyl-4-isoxazole)benzenesulfonyl chloride directly into 100mL of ammonia water, react at 20-30°C, after the reaction is complete, directly concentrate under reduced pressure Remove dichloromethane, then add water to dilute, crystallize, filter, and dry, that is, about 58g of daldecoxib, which is directly carried out to the next step without further treatment.

[0046] Add 58g of valdecoxib, 58ml of propionic anhydride, and 3ml of hydrochloric acid into the reaction kettle, ...

Embodiment 2

[0051] Dissolve 50g of 3,4-diphenyl-5-methylisoxazole in 300mL of toluene, add 300g of chlorosulfonic acid, and heat to 30-40°C to react; after the reaction is complete, quench with ice water, separate the liquid, The aqueous phase was extracted with toluene, the aqueous layer was discarded, and the organic phases were combined to obtain a toluene solution of 4-(5-methyl-3-phenyl-4-isoxazole)benzenesulfonyl chloride, which was directly carried out to the next step without treatment. .

[0052] Add the toluene solution of 4-(5-methyl-3-phenyl-4-isoxazole)benzenesulfonyl chloride directly into 300mL ammonia water and react at 0-10°C. After the reaction is complete, directly concentrate the toluene under reduced pressure, Add water to dilute, precipitate solid, filter, dry, that is about 60g of daldecoxib, without further treatment, directly proceed to the next step.

[0053] Add 60g of valdecoxib and 180ml of propionic anhydride into the reaction kettle, heat to 130-140°C to re...

Embodiment 3

[0057] Dissolve 50g of 3,4-diphenyl-5-methylisoxazole in 400mL of dichloromethane, add 350g of chlorosulfonic acid, and heat to 50-60°C for reaction; liquid, the aqueous phase was extracted with dichloromethane, the aqueous layer was discarded, and the organic phases were combined to obtain a dichloromethane solution of 4-(5-methyl-3-phenyl-4-isoxazole) benzenesulfonyl chloride without passing through processing, proceed directly to the next step.

[0058] Add the dichloromethane solution of 4-(5-methyl-3-phenyl-4-isoxazole)benzenesulfonyl chloride directly into 100mL ammonia water, heat to 45-60°C to react, after the reaction is completed, directly concentrate under reduced pressure Dichloromethane was added for dilution with water, and a solid was precipitated, filtered, and dried, that is, about 62 g of devaldecoxib, which was directly carried out to the next step without further treatment.

[0059] Add 62g of valdecoxib and 124ml of methyl propionate into the reaction ket...

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Abstract

The invention discloses a preparation method of parecoxib sodium. The method comprises the following steps: sulfonating 3,4-diphenyl-5-methylisoxazole as a raw material, ammonolyzing, acylating, salifying, and re-crystallizing to obtain parecoxib sodium. The method has the advantages of simple operation, good repeatability, high yield and low cost, and is suitable for industrialized production, and the parecoxib sodium finished product obtained in the invention has a content of a separate impurity of below 0.1%, and is suitable for preparing medicinal parecoxib sodium preparations.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of parecoxib sodium and a pharmaceutical composition containing the parecoxib sodium directly obtained by the method. Background technique [0002] Parecoxib sodium is a specific COX-2 inhibitor, mainly used for the treatment of postoperative pain. Its chemical structure is as follows. [0003] [0004] Parecoxib sodium (trade name: Dynastat) has been marketed in Europe and is mainly used for short-term treatment of postoperative pain. It can be used clinically for the treatment of moderate or severe postoperative acute pain. [0005] At present, the preparation methods of parecoxib sodium all need to first synthesize valdecoxib, and then undergo propionylation and salt formation to prepare parecoxib sodium. [0006] Chinese patent application CN102329277A discloses a method for synthesizing parecoxib, the reaction formula is as follows, th...

Claims

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Application Information

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IPC IPC(8): C07D261/08A61K31/42A61P29/00
CPCC07D261/08A61K31/42
Inventor 刘超叶子峥彭显峰戴萍
Owner SICHUAN WEITUO BIOLOGICAL PHARMA
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