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A kind of synthetic method of parecoxib sodium

A technology of parecoxib sodium and its synthesis method, which is applied in the field of pharmaceutical production, can solve problems such as troublesome handling of crude reaction products, little advantages in production, unfavorable production scale-up, etc., and achieves the effect of short route steps, low cost and easy operation

Active Publication Date: 2018-10-30
HONGGUAN BIO PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The problems of this route are: the starting material 1-phenylacetone is a precursor drug and is not easy to obtain; the second step reaction crude product is more troublesome to deal with, and column chromatography is required for separation, so it is not conducive to production scale-up
The advantage of this route is that it reduces the amount of sulfonyl chloride and generates sulfonic acid, but it still needs to be converted into sulfonyl chloride with thionyl chloride in the later stage. In fact, a two-step reaction is used to make sulfonyl chloride. In addition, the first When the first step reaction generates sulfonic acid, the reaction takes a long time, therefore, this route has little advantage in production

Method used

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  • A kind of synthetic method of parecoxib sodium
  • A kind of synthetic method of parecoxib sodium
  • A kind of synthetic method of parecoxib sodium

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Step 1: Chlorosulfonation reaction

[0046]

[0047] Dissolve 98 g of chlorosulfonic acid in 75 mL of dichloromethane, cool to 5°C and add 5-methyl-3,4-diphenyl-isoxazole (25 g, from Shanghai Farmer Biotechnology Co., Ltd. purchased) in dichloromethane (50 mL); after the dropwise addition was completed, the system was heated up to reflux, and kept warm for reflux reaction for 8 hours. After the reaction was completed, it was cooled to room temperature, and the reaction system was slowly poured into 175 mL of ice water to quench the reaction, and the system was kept at 5°C. After the quenching reaction was complete, the liquids were left to separate, the aqueous phase was extracted with dichloromethane (62 mL X 2), the organic phases were combined, washed with water (190 mL X 3), and then concentrated to remove dichloromethane to obtain a concentrate. Add 250 mL of cyclohexane to the concentrate, heat to reflux for 30 minutes, add 75 mL of water, and continue to refl...

Embodiment 2

[0055] The difference with embodiment 1 is:

[0056] In Step 1, dissolve 75 g of chlorosulfonic acid in 60 mL of dichloromethane, cool to 3°C and add dropwise a solution of 5-methyl-3,4-diphenyl-isoxazole (25 g) in dichloromethane (50 mL); after the dropwise addition, the system was heated up to reflux, kept warm for reflux reaction for 7 hours; after the reaction was completed, cooled to room temperature, the reaction system was slowly poured into ice water to quench the reaction, and the system was kept at 3°C After the quenching reaction is complete, separate liquid, extract, wash, and concentrate to obtain a concentrate; add cyclohexane to the concentrate, heat and reflux for 20 minutes, add water, and continue to reflux for 20 minutes; separate liquid, remove the water phase, and leave the organic phase at room temperature Stir and crystallize for 30 minutes; obtain 20.2 g of intermediate 1 pure product, the purity is greater than 95%, and the yield is 58.7%, and its nucl...

Embodiment 3

[0060] The difference with embodiment 1 is:

[0061] In Step 1, dissolve 125 g of chlorosulfonic acid in 100 mL of dichloromethane, cool to 8°C and add dropwise a solution of 5-methyl-3,4-diphenyl-isoxazole (25 g) in dichloromethane ( 50 mL); after the dropwise addition, the system was heated up to reflux, and kept at reflux for 9 hours; after the reaction was completed, it was cooled to room temperature, and the reaction system was slowly poured into ice water to quench the reaction, and the system was maintained at 8°C; After the quenching reaction is complete, separate liquid, extract, wash, and concentrate to obtain a concentrate; add cyclohexane to the concentrate, heat to reflux for 50 minutes, add water, and continue to reflux for 50 minutes; separate liquid, remove the water phase, and stir the organic phase at room temperature Crystallization for 60 minutes; 20.8 g of intermediate 1 pure product was obtained, the purity was greater than 95%, and the yield was 59.2%. I...

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Abstract

The invention belongs to the technical field of medical production, and particularly relates to a preparation method of parecoxib sodium. The invention aims to provide a synthesis method of parecoxib sodium, which has the advantages of short synthesis route, mild and controllable conditions and low cost and is simple to operate. By using 5-methyl-3,4-diphenylisooxazole as the initial raw material, chlorosulfonation, acylation and salification are carried out to synthesize the target product parecoxib sodium. The synthesis method provided by the invention has the characteristics of short route steps, mild and controllable conditions, small environmental pollution, higher yield and the like, and is simple to operate and suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical production, and in particular relates to a preparation method of a parecoxib sodium compound. Background technique [0002] The English name of Parecoxib sodium is Parecixib Sodium, and its chemical name is N-[[4-(5-methyl-3-phenyl-4-isoxazolyl)phenyl]sulfonyl]propionamide sodium salt. Molecular formula is C 19 h 17 N 2 o 4 SNa, the molecular weight is 392.41, the CAS number is 198470-84-8, and the structural formula is as follows: [0003] [0004] Parecoxib sodium is the world's first intravenously administered selective cyclooxygenase-2 (COX-2) inhibitor Valdecoxib (Valdecoxib) prodrug, mainly used for short-term treatment of postoperative pain , can effectively overcome the shortcomings of traditional oral administration of non-steroidal anti-inflammatory drugs. [0005] At present, the synthetic routes of parecoxib sodium can be classified into the following five categories. ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D261/08
CPCC07D261/08
Inventor 程宜兴朱金龙于学彬王佳明费炜栋徐磊杨继斌
Owner HONGGUAN BIO PHARMA CO LTD
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