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Method for detecting related substance in diethyl 2-(4-chlorobenzamido)malonate sample

A technology of diethyl chlorobenzoylaminomalonate and a detection method is applied in the field of detection of related substances in a sample of diethyl p-chlorobenzoylaminomalonate, can solve problems such as short synthesis process, and achieves The effect of reproducible and efficient detection method

Active Publication Date: 2019-11-08
苏州正济药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] At present, there is a pharmacopoeia for the quality control of related substances of rebamipide, but there is no published detection method for the quality control of rebamipide raw material (diethyl p-chlorobenzamidomalonate), and will Diethyl chlorobenzamidomalonate is used as a starting material, and the synthesis process is short. In order to effectively control impurities and investigate the transfer of impurities, it is necessary to provide a detection method that can effectively control the related substances of rebamipide raw materials.

Method used

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  • Method for detecting related substance in diethyl 2-(4-chlorobenzamido)malonate sample
  • Method for detecting related substance in diethyl 2-(4-chlorobenzamido)malonate sample
  • Method for detecting related substance in diethyl 2-(4-chlorobenzamido)malonate sample

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] High performance liquid chromatography: Agilent 1260;

[0058] Mobile phase: Phase A: 0.01M potassium dihydrogen phosphate aqueous solution, pH=2.5;

[0059] Phase B: acetonitrile;

[0060] Elution gradient:

[0061] Table 1 Gradient elution program

[0062] Elution time Phase A (%) Phase B (%) 0min 60 40 3min 60 40 13min 50 50 33min 20 80 38min 20 80 43min 60 40 50min 60 40

[0063] Chromatographic column: Inertsustain C18 4.6×250mm, 5.0μm;

[0064] Detection wavelength: 220nm;

[0065] Flow rate: 1.0mL / min;

[0066] Column temperature: 40°C;

[0067] Injection volume: 10μL;

[0068] Mixed solution preparation: Accurately weigh the appropriate amount of the sample and impurities, place it in a 25mL measuring bottle, first add 5.0mL DMF to dissolve, and then dilute to the mark with acetonitrile. (sample concentration: 1.0mg / mL)

[0069] Test results: See the attached figure 1 , so it can be seen ...

Embodiment 2

[0071] High performance liquid chromatography: Agilent 1260;

[0072] Mobile phase: Phase A: 0.01M potassium dihydrogen phosphate aqueous solution, pH=2.5;

[0073] Phase B: acetonitrile;

[0074] Elution gradient:

[0075] Table 2 Gradient elution program

[0076] Elution time Phase A (%) Phase B (%) 0min 50 50 13min 50 50 25min 20 80 35min 20 80 40min 50 50 45min 50 50

[0077] Chromatographic column: Inertsustain C18 4.6×250mm, 5.0μm;

[0078] Detection wavelength: 240nm;

[0079] Flow rate: 1.0mL / min;

[0080] Column temperature: 40°C;

[0081] Injection volume: 10μL;

[0082] Mixed solution preparation: Accurately weigh the appropriate amount of the sample and impurities, place it in a 25mL measuring bottle, add 5.0mL DMF to dissolve, and then dilute to the mark with acetonitrile. (sample concentration: 1.0mg / mL)

[0083] Test results: See the attached figure 2 , so it can be seen that in this embodimen...

Embodiment 3

[0085] High performance liquid chromatography: Agilent 1260 detector;

[0086] Mobile phase: A: 0.01M potassium dihydrogen phosphate aqueous solution, pH=2.5;

[0087] B: acetonitrile;

[0088] Elution gradient:

[0089] Table 3 Gradient elution program

[0090]

[0091]

[0092] Chromatographic column: Inertsustain C18 4.6×250mm, 5.0μm;

[0093] Detection wavelength: dual wavelength 240nm and 220nm

[0094] Flow rate: 1.0mL / min;

[0095] Column temperature: 40°C;

[0096] Injection volume: 10μL;

[0097] Mixed solution preparation: Weigh the appropriate amount of sample and impurities, place in a 25mL measuring bottle, first add 5.0mL DMF to dissolve, then dissolve with acetonitrile and dilute to the mark, shake well. (sample concentration: 0.5mg / mL)

[0098] Test results: See the attached image 3 , wherein, RT=9.1min is the peak of impurity 1, RT=13.4min is the peak of impurity 2, RT=15.7min is the peak of rebamipide raw material, RT=19.0min is the peak of im...

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Abstract

The invention relates to the technical field of pharmaceutical analysis, and specifically relates to a method for detecting a related substance in a diethyl 2-(4-chlorobenzamido) malonate sample. Themethod includes the following steps: dissolving the diethyl 2-(4-chlorobenzamido) malonate sample with an organic solvent to obtain a sample solution; and using reversed phase high performance liquidchromatography to detect the sample solution, where chromatographic conditions are as follows: a C18 chromatographic column is applied; a mobile phase A is 0.005-0.015M of a monopotassium phosphate aqueous solution having a pH value of 2-3; a mobile phase B is acetonitrile; and gradient elution is carried out. The method performs analysis with a reversed phase column using octadecylsilane chemically bonded silica as a filler, uses a specific saline solution and an organic solvent as mobile phases, and performs gradient elution for a sample solution of a 2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinone-4-yl]propionic acid raw material. The method is rapid, simple, accurate, repeatable, and suitable for the control of many related substances and the study of impurities.

Description

technical field [0001] The invention relates to the technical field of drug analysis, in particular to a method for detecting related substances in a sample of diethyl p-chlorobenzamidomalonate. Background technique [0002] There are many synthetic methods of rebamipide, among which the improved route of rebamipide released by Korea Kyungdong Pharmaceutical Company in 2002, the reaction process is described as follows: Diethyl aminomalonate is first reacted with p-chlorobenzoyl chloride Obtain diethyl p-chlorobenzamidomalonate (Formula 2), react with 4-bromomethylquinolinone, and then undergo hydrolysis and decarboxylation to obtain the final product rebamipide. Diethyl p-chlorobenzamidomalonate can be directly purchased in the market as a starting material for the synthesis of rebamipide. Rebamipide 2-(4-chl orobenzoy lamino)-3-[2(1H)-quinolinon-4-yl]propionic acid is a prostaglandin derivative and a new type of gastric mucosal protective agent. Its CAS number is: 90098-...

Claims

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Application Information

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IPC IPC(8): G01N30/02
CPCG01N30/02
Inventor 侯叶婷姚青李园园罗岚刘南
Owner 苏州正济药业有限公司
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