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Preparation method of parecoxib sodium compound as well as intermediate impurity and application of parecoxib sodium compound

A technology of parecoxib sodium and compound is applied in the field of preparation of parecoxib sodium compound, which can solve the problem of low synthesis yield and the like

Active Publication Date: 2015-03-25
JIANGSU AOSAIKANG PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, we found that its industrial synthesis yield is not high, so the research on its synthetic route and possible factors affecting the yield in the synthetic method

Method used

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  • Preparation method of parecoxib sodium compound as well as intermediate impurity and application of parecoxib sodium compound
  • Preparation method of parecoxib sodium compound as well as intermediate impurity and application of parecoxib sodium compound
  • Preparation method of parecoxib sodium compound as well as intermediate impurity and application of parecoxib sodium compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 13

[0046] The preparation of embodiment 13-methyl-4,5-diphenyl-4,5-dihydroisoxazol-5-alcohol

[0047] (1) Add 71.3g of 1,2-benzophenone, 64.6g of tetrahydropyrrole, 300mL of cyclohexane and 0.2g of glacial acetic acid into a 1L three-necked flask, heat up to reflux, and water will come out from the water separator until Anhydrous was formed to stop the reaction, and the reaction solution was concentrated under reduced pressure at 50°C until no distillate was obtained to obtain about 90 g of the compound of formula I as a yellow oil.

[0048] (2) Put the obtained oil into a 1L reaction flask, add 500mL of acetonitrile and 58g of 2,6-lutidine, dropwise add 112g of acetyl chloride below 15°C, continue the reaction until the raw materials disappear, and obtain the acylated product formula II compound solution.

[0049] (3) Slowly add the solution containing the compound of formula II dropwise to the mixed aqueous solution of hydroxylamine hydrochloride and sodium acetate (101g of hy...

Embodiment 23

[0062] The preparation of embodiment 23-methyl-4,5-diphenyl-4,5-dihydroisoxazol-5-alcohol

[0063] (1) Add 72..5g of 1,2-benzophenone, 75g of tetrahydropyrrole, 350mL of cyclohexane and 0.25g of glacial acetic acid into a 1L three-necked flask, heat up to reflux, and water will come out from the water separator. The reaction was stopped until anhydrous was formed, and the reaction solution was concentrated under reduced pressure at 50°C until no distillate was obtained to obtain about 93.5 g of the compound of formula I as a yellow oil.

[0064] (2) Put the obtained oil into a 1L reaction flask, add 525mL of acetonitrile and 55g of 2,6-lutidine, dropwise add 128g of acetyl chloride below 15°C, continue the reaction until the raw materials disappear, and obtain the acylated product formula II compound solution.

[0065] (3) Slowly add the solution containing the compound of formula II dropwise to the mixed aqueous solution of hydroxylamine hydrochloride and sodium acetate (103...

Embodiment 33

[0068] Preparation of Example 33-Methyl-4,5-diphenyl-4,5-dihydroisoxazol-5-ol

[0069] (1) Add 63.5g of 1,2-benzophenone, 70g of tetrahydropyrrole, 300mL of cyclohexane and 0.18g of glacial acetic acid into a 1L three-necked bottle, heat up to reflux, and water will come out from the water separator until there is no more Water was formed to stop the reaction, and the reaction solution was concentrated under reduced pressure at 50°C until no distillate was obtained to obtain about 82.4 g of the compound of formula I as a yellow oil.

[0070] (2) Put the obtained oil into a 1L reaction flask, add 485mL of acetonitrile and 48g of 2,6-lutidine, dropwise add 118g of acetyl chloride below 15°C, continue the reaction until the raw materials disappear, and obtain the acylated product formula II compound solution.

[0071] (3) Slowly add the solution containing the compound of formula II dropwise to the mixed aqueous solution of hydroxylamine hydrochloride and sodium acetate (98g of ...

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Abstract

The invention provides parecoxib sodium which is prepared by controlling an intermediate impurity and in particular provides a preparation method of a parecoxib sodium compound as well as the intermediate impurity and an application of the parecoxib sodium compound. According to the preparation method provided by the invention, 3-methyl-4,5-diphenyl-4,5-dihydro-isoxazole-5-alcohol is used as an isomer impurity for preparing 5-methyl-3,4-diphenyl-4,5-dihydro-isoxazole-5-alcohol as an intermediate of the parecoxib sodium, the quality of the 3-methyl-4,5-diphenyl-4,5-dihydro-isoxazole-5-alcohol is controlled in the preparation of the parecoxib sodium, specifically, the impurity content is required not to be higher than 0.5 percent, and an important significance is provided for the product quality of the parecoxib sodium; by obtaining the 3-methyl-4,5-diphenyl-4,5-dihydro-isoxazole-5-alcohol as an isomer impurity of the important 5-methyl-3,4-diphenyl-4,5-dihydro-isoxazole-5-alcohol and further studying 3-methyl-4,5-diphenyl-4,5-dihydro-isoxazole-5-alcohol in the aspects of preparation process, detection process and purification process, important quality monitoring significance is provided for the process with the 5-methyl-3,4-diphenyl-4,5-dihydro-isoxazole-5-alcohol as an industrial production raw material.

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, an intermediate impurity, a preparation method and an application thereof. Background technique [0002] Parecoxib sodium (Parecoxib sodium), developed by Pharmacia (now Pfizer), is the world's first intravenously administered selective cyclooxygenase-2 (COX-2) inhibitor, and is valdecoxib ( valdecoxib), which is mainly used for the short-term treatment of pain after surgery. The structure of parecoxib sodium is shown in formula IV. [0003] [0004] In 2002, Parecoxib Sodium was approved for marketing in 15 EU countries, Norway and Iceland. In 2008, China SFDA approved the listing of Parecoxib Sodium in China under the trade name Dynastat. Due to the parenteral route of administration, parecoxib sodium makes up for the shortcomings of coxibs in the treatment of patients who are not suitable f...

Claims

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Application Information

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IPC IPC(8): C07D261/08C07D261/04G01N1/28G01N30/02
CPCC07D261/04C07D261/08G01N30/88
Inventor 赵俊吉同琴宗在伟张艳阳
Owner JIANGSU AOSAIKANG PHARMA CO LTD
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