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A kind of detection method of related substances in diethyl p-chlorobenzamidomalonate 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: 2022-03-04
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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  • A kind of detection method of related substances in diethyl p-chlorobenzamidomalonate sample
  • A kind of detection method of related substances in diethyl p-chlorobenzamidomalonate sample
  • A kind of detection method of related substances in diethyl p-chlorobenzamidomalonate 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 drug analysis, in particular to a method for detecting related substances in a sample of diethyl p-chlorobenzamidomalonate. The method comprises: dissolving a sample of diethyl p-chlorobenzamidomalonate in an organic solvent to obtain a sample solution; using reverse-phase high-performance liquid chromatography to detect the sample solution, and the chromatographic conditions are as follows: C18 chromatographic column; Phase A is 0.005-0.015 M potassium dihydrogen phosphate aqueous solution, pH value is 2-3; mobile phase B is acetonitrile; gradient elution. The present invention uses octadecylsilane-bonded silica gel as filler for reverse-phase chromatographic column analysis, and uses specific salt solution and organic solvent as mobile phase to carry out gradient elution to the sample solution of rebamipide raw material. The method is fast, simple, accurate and reproducible, and is suitable for the control of various related substances and the research 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 for 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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Patent Type & Authority Patents(China)
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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