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Potential impurity compound of Nintedanib, as well as preparation method, application and detection method of potential impurity compound

A technology of nintedanib and compounds, which is applied in the field of potential impurity compounds of nintedanib, can solve the problems of public reporting of no impurities, and achieve the effect of improving quality standards

Inactive Publication Date: 2017-05-31
REYOUNG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] At present, there is no public report of this impurity in domestic and foreign literature

Method used

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  • Potential impurity compound of Nintedanib, as well as preparation method, application and detection method of potential impurity compound
  • Potential impurity compound of Nintedanib, as well as preparation method, application and detection method of potential impurity compound
  • Potential impurity compound of Nintedanib, as well as preparation method, application and detection method of potential impurity compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] 3-[methoxy(phenyl)methylene]-2-oxoindoline-6-carboxylic acid methyl ester (8.8g, 28mol) and N-methylpiperazine (5.6g, 57mmol) Add 80mL of methanol, stir and react at 60°C, the reaction is completed in 2-5 hours, the reaction solution is cooled, and a solid precipitates, the solid is filtered, rinsed with methanol, and 8.9g of impurity compound is obtained as a light red solid.

[0057] HPLC detection, product purity 96.2%.

[0058] The HPLC method is: take 5 mg of the impurity compound, add it to a 25 mL volumetric flask, and use an appropriate amount of mobile phase A-mobile phase B (45:55) to dissolve and dilute to the mark with an appropriate amount of ultrasound, as the test solution.

[0059] The chromatographic conditions are:

[0060] (1) Chromatographic column: octadecylsilane bonded silica gel.

[0061](2) Mobile phase: mobile phase A is 20mmol / L potassium dihydrogen phosphate solution (adjust pH value to 3.0 with phosphoric acid), mobile phase B is acetonitr...

Embodiment 2

[0066] Methyl N-acetyl-3-[methoxy(phenyl)methylene]-2-oxoindoline-6-carboxylate (10 g, 28 mmol) and N-methylpiperazine (5.6 g, 57mmol) was added into 50mL of methanol and 5mL of N,N-dimethylformamide, reflux reaction at 68°C, after 2-4 hours of reaction, piperidine (4.8g, 57mmol) was added, and the reaction was continued for 2 hours. The reaction solution was cooled, and the temperature was lowered to precipitate a solid, which was filtered, and the residue was slurried with 30 mL of methanol, and filtered to obtain 5.7 g of impurity compound as a light red solid. As detected by HPLC, the purity of the impurity compound was 97.4%.

Embodiment 3

[0068] Methyl N-chloroacetyl-3-[methoxy(phenyl)methylene]-2-oxoindoline-6-carboxylate (10 g, 28 mmol) and N-methylpiperazine ( 5.6 g, 57 mmol) was added into 30 mL of N,N-dimethylformamide, and reacted at 80° C. After 2 hours of reaction, piperidine (4.8 g, 57 mmol) was added, and the reaction was continued for 2 hours. The reaction solution was cooled, added with 100 mL of water, extracted with 100 mL of dichloromethane, and washed with 50 mL of saturated sodium chloride solution x 3. The organic phase was dried over anhydrous sodium sulfate, filtered, and dichloromethane was distilled off from the filtrate under reduced pressure. The residue was crystallized by adding 50 mL of isopropanol, and filtered to obtain 7.4 g of impurity compound as a light red solid. HPLC detection showed that the purity of the impurity compound was 98.5%.

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Abstract

The invention relates to a potential impurity compound of Nintedanib, and a preparation method, application and detection method of the potential impurity compound. The structure of the potential impurity compound is shown in the formula (as shown in the specification). The invention aims to improve the quality standard of Nintedanib through study on impurities to guarantee the safe medication of Nintedanib. According to the preparation method disclosed by the invention, the pure potential impurity compound of Nintedanib is obtained, so that a reference substance for qualitative and quantitative analysis is provided for the detection of a finished Nintedanib product.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a potential impurity compound of nintedanib, a preparation method, an application and a detection method thereof. [0002] technical background [0003] Nintedanib Esylate was developed by Boehringer Ingelheim and was approved by the US Food and Drug Administration (FDA) on October 15, 2014, and then approved in Europe on November 21, 2014. The Drug Administration (EMA) approved the marketing, and then was approved by the Japanese Medicines and Medical Devices Administration (PMDA) on July 3, 2015, and was marketed by Boehringer Ingelheim. [0004] NintedanibEsylate is a multiple tyrosine kinase inhibitor that works by inhibiting growth factor receptors associated with the pathogenesis of idiopathic pulmonary fibrosis (IPF). It has been approved for the treatment of idiopathic pulmonary fibrosis (IPF) and non-small cell lung cancer (NSCLC). [0005] It has not yet been markete...

Claims

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Application Information

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IPC IPC(8): C07D209/34G01N30/02
CPCC07D209/34G01N30/02G01N2030/027
Inventor 苗得足胡清文丛超王宏光于志波
Owner REYOUNG PHARMA
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