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Parecoxib sodium degradation impurity and preparation, detection method and application thereof

A parecoxib sodium and impurity technology, which is applied in the field of drug synthesis, can solve the problem of parecoxib sodium degrading less impurities, and achieve the effect of accurate results and easy operation

Active Publication Date: 2018-06-15
CHENGDU SINO STRONG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] At present, there are few research materials on the degradation impurities of parecoxib sodium, and only the oxidation impurities and hydrolysis impurities of parecoxib sodium are introduced in the literature Current Pharmaceutical Analysis, 2017, 13, 271-278

Method used

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  • Parecoxib sodium degradation impurity and preparation, detection method and application thereof
  • Parecoxib sodium degradation impurity and preparation, detection method and application thereof
  • Parecoxib sodium degradation impurity and preparation, detection method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] This embodiment provides the preparation of the compound of formula I, and its reaction formula is as follows:

[0039]

[0040] The specific operation is: sequentially add 2.5g of the compound of formula II and 30mL of dry tetrahydrofuran into the round bottom flask, slowly add 11mL of n-butyllithium (1.6M) into the reaction solution under the protection of nitrogen and at a low temperature of -78°C, after the addition is complete, , continue to stir the reaction for 2h; the reaction solution was slowly warmed to room temperature and reacted overnight. Slowly add saturated ammonium chloride solution to the reaction solution to quench the reaction, extract with ethyl acetate, dry and concentrate the organic layer, and obtain the compound of formula I (R=H) by column chromatography as a white solid, about 0.56 g, and obtain Yield: 24%; HPLC purity: 96.3%.

[0041] Formula I compound: 1 H-NMR (CD 3 COCD 3 ,400MHz): δ=8.04(d, J=8.0Hz, 1H), 7.90(s, 1H), 7.72(d, J=4.0...

Embodiment 2

[0044] The present embodiment provides the preparation of the compound of formula III, and its reaction formula is as follows:

[0045]

[0046] The specific operation is: sequentially add 4.5g of 4-bromo-2-methoxycarbonylbenzenesulfonamide (preparation method reference Bioorganic & Medicinal Chemistry Letters 19 (2009) 6855-6861), 40mL of dry tetrahydrofuran into the round bottom flask, nitrogen protection conditions Lower the temperature to 0°C, slowly drop 45mL of ethylmagnesium bromide solution (1.0M, tetrahydrofuran solution) into the reaction solution, after the drop is completed, continue stirring for 30 minutes, then slowly warm the reaction solution to room temperature, and stir the reaction overnight . 20 mL of water was added to the reaction solution to quench the reaction, extracted with ethyl acetate, the organic layer was dried and concentrated, and the residue was purified by column chromatography to obtain 1.5 g of the compound of formula III.

Embodiment 3

[0048] This embodiment provides the preparation of the compound of formula I, and its reaction formula is as follows:

[0049]

[0050] In Example 2, 1.5g of the compound of formula III, 1.7g of pinacol diborate, 0.3g of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, 1.2g of potassium acetate, 20ml Add 1,4-dioxane into a round bottom flask, under nitrogen protection, slowly raise the temperature of the reaction solution to 100°C for 5 hours, cool the reaction solution to room temperature, filter, concentrate the filtrate, and purify the residue by column chromatography followed by subsequent reactions.

[0051] The above product, 1.2g of compound of formula IV, 0.2g of tetrakis(triphenylphosphine)palladium, 10mL of ethanol, and 5mL of 2M sodium carbonate solution were successively added into a round bottom flask, and the temperature was slowly raised to reflux under stirring. The progress of the reaction was monitored by TLC. The reaction solution was cooled to...

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Abstract

The invention discloses a parecoxib sodium degradation impurity shown in a formula I and a preparation method thereof and aims at solving the problem of no parecoxib sodium degradation impurity research in the prior art. The invention further discloses application of the degradation impurity and a high performance liquid chromatography detection method of the degradation impurity. The parecoxib sodium degradation impurity disclosed by the invention provides basis for quality researches, standard researches, stability researches, adverse drug reaction mechanism researches on the parecoxib sodium and provides basis for production, package, storage, transportation and application condition selection of the parecoxib sodium at the same time. (The formula is shown in the description.).

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a parecoxib sodium degraded impurity and its preparation, detection method and application. Background technique [0002] Trina is the first water-soluble prodrug of valdecoxib (valdecoxib), a specific cyclooxygenase-2 (COX-2) inhibitor developed by Pharmacia, which can be administered intravenously and intramuscularly. The coxib analgesics in the drug can be used clinically for the treatment of moderate or severe postoperative acute pain. The active ingredient of Terai is Parecoxib Sodium (Parecoxib Sodium), N-[[4-(5-methyl-3-phenyl-4-isoxazolyl)phenyl]sulfonyl]propionamide sodium salt . [0003] There are many synthetic routes of parecoxib sodium reported in the literature, and the difference of each process route is mainly reflected in the difference in the preparation process of the intermediate 3,4-diphenyl-5-methylisoxazole. Comprehensive analysis of factors suc...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/04G01N30/02
CPCC07D417/04G01N30/02
Inventor 匡建明张善军冯强李敏刘力超许娟
Owner CHENGDU SINO STRONG PHARMA
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