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Detection method for quinazoline-7-ether compound and related substances thereof

A technology for ether compounds and related substances, applied in the field of chemical analysis, can solve the problems of low chromatographic peak resolution, detection of difficult quinazoline-7-ether compounds, and high structural similarity, and achieve high system adaptability and peak shape symmetry. High-performance, high-precision effects

Active Publication Date: 2018-03-06
JIANGSU KANION PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, the most widely used method for quantitative detection of compounds is chromatography, but due to the high structural similarity of quinazoline-7-ether compounds and their related substances, quinazoline-7-ether compounds and their related The separation of chromatographic peaks in the process is low, which makes it difficult for existing chromatographic detection methods to be used for the detection of quinazoline-7-ether compounds and their related substances

Method used

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  • Detection method for quinazoline-7-ether compound and related substances thereof
  • Detection method for quinazoline-7-ether compound and related substances thereof
  • Detection method for quinazoline-7-ether compound and related substances thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0070] Detection of related substances in quinazoline-7-ether compound products

[0071] Instrument: Agilent HPLC

[0072] Chromatographic column: Gemini C18 (4.6×150mm, 5μm)

[0073] Mobile phase A: 10mM ammonium acetate buffer solution (adjust pH to 5.0 with phosphoric acid)

[0074] Mobile Phase B: Methanol

[0075] Mobile Phase C: Acetonitrile

[0076] Detection wavelength: 253nm

[0077] Flow rate: 1.0ml / min

[0078] Injection volume: 20μl

[0079] Column temperature: 30°C

[0080] Dilution solvent: 10 mM ammonium acetate buffer solution (adjust the pH value to 5.0 with phosphoric acid), methanol and acetonitrile are mixed according to the volume ratio of 55:30:15.

[0081] The elution program is shown in Table 1:

[0082] Table 1 Elution program

[0083] time (min)

Mobile phase A(%)

Mobile phase B(%)

Mobile phase C(%)

0

55

30

15

15

44

56

0

20

35

65

0

25

10

90

0

[0084] Need t...

Embodiment 2

[0093] System suitability test of detection method

[0094] 1. Prepare the solution

[0095] 1) Dilute solution: mix 10mM ammonium acetate buffer solution (adjust the pH value to 5.0 with phosphoric acid), methanol and acetonitrile according to the volume ratio of 55:30:15;

[0096] 2), blank solution: diluted solution;

[0097]3) Impurity stock solution: take 5 mg each of impurity A (compound of formula (II) structure), impurity B (compound of formula (III) structure), impurity C (compound of structure of formula (IV)) each 5 mg, accurately weigh and place in the same In a 20ml measuring bottle, dissolve and dilute to the mark with the blank solution, and shake well;

[0098] 4) Separation solution: Take about 25 mg of quinazoline-7-ether compound, put it in a 25 ml measuring bottle, add 0.1 ml of impurity stock solution, dissolve it with diluent solution and dilute to the mark, and shake well.

[0099] 2. Chromatographic detection:

[0100] Inject the above-mentioned bla...

Embodiment 3

[0106] Specific detection of detection method

[0107] The strong degradation test is to accelerate the destruction of quinazoline-7-ether compounds under strong conditions, such as strong acid, strong alkali, strong oxidation, high temperature, and strong light. The main peak and the separation of known impurities are compared to the amount of impurities generated and the reduction of main components to evaluate the effectiveness and applicability of the analytical method. At the same time, the DAD detector is used to check the peak purity: in the spectrum obtained from the degradation test, when the purity factor of the main component is greater than the threshold, it meets the requirements, that is, the main peak does not contain other unknown impurities.

[0108] According to the chromatographic conditions of Example 1, the samples processed under different strong degradation conditions were detected by high performance liquid chromatography, and the specific detection res...

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Abstract

The invention relates to the field of chemical analysis, in particular to a detection method for a quinazoline-7-ether compound and related substances thereof. The detection method comprises the following step: detecting the content of a to-be-tested sample with the synthetic quinazoline-7-ether compound by using high performance liquid chromatography to respectively obtain the contents of the quinazoline-7-ether compound and the related substances thereof in the to-be-tested sample, wherein the quinazoline-7-ether compound has a structure shown in the formula I; the related substances of thequinazoline-7-ether compound comprise one or more of structural compounds shown in the formulas (II) to (IV); and a mobile phase used in the high performance liquid chromatography detection process isan ammonium acetate-phosphate buffer solution, methanol and acetonitrile. According to the detection method of the quinazoline-7-ether compound, disclosed by the invention, an ammonium acetate-phosphate buffer solution-methanol-acetonitrile elution system is adopted, so that the detection of the quinazoline-7-ether compound and other related substances is benefited. (The formula is shown in the description).

Description

technical field [0001] The invention belongs to the field of chemical analysis, in particular to a method for detecting quinazoline-7-ether compounds and related substances. Background technique [0002] Quinazoline-7-ether compound, the chemical name is (E)-4-(3-chloro-4-fluorophenyl)amino)-6-{[4-(N,N-dimethylamino)-1 -Oxo-2-buten-1-yl]amino}-7-((S)(3-oxabicyclo[3.1.0]hexane-6-methoxy)-quinazoline, the structure As shown in the following formula: [0003] [0004] The quinazoline-7-ether compound is a structurally modified new compound of afatinib, and its preclinical pharmacodynamics shows strong activity. In July 2013, the US FDA approved quinazoline-7-ether compound pharmaceutical products for the treatment of patients with advanced (metastatic) non-small cell lung cancer (NSCL) with epidermal growth factor receptor (EGFR) gene mutations. [0005] Quinazoline-7-ether compounds will inevitably produce intermediates and side reaction products during the synthesis pro...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G01N30/02
CPCG01N30/02
Inventor 萧伟陈保来仲艳刘永友李家春郭庆明王振中
Owner JIANGSU KANION PHARMA CO LTD
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