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Anti-tumor drug cabozantinib impurity, preparation method thereof and application thereof

An anti-tumor drug, the technology of cabozantinib, which is applied in the field of biomedicine to achieve the effect of accurate measurement

Inactive Publication Date: 2020-04-10
LEPU PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There is no relevant report about this compound at present, it is a new compound molecule, and it has similar functional groups with the finished product, which has a great influence on the quality research of cabozantinib malate

Method used

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  • Anti-tumor drug cabozantinib impurity, preparation method thereof and application thereof
  • Anti-tumor drug cabozantinib impurity, preparation method thereof and application thereof
  • Anti-tumor drug cabozantinib impurity, preparation method thereof and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Add 1.0g of 1,1-cyclopropyldicarboxylic acid (7.68mmol) into the reaction flask, 20g of tetrahydrofuran, 3.1g of DIPEA, stir to dissolve, add 6.0g of HCTU and heat to 40°C, stir to activate 1,1-cyclopropane Add 2.4g (22mmol) of p-aminophenol after 1.5 hours of base dicarboxylic acid, and react at 20~40°C for 10~20 hours. After the reaction is completed, add 5wt% sodium carbonate solution to adjust the pH to 7~8, and then add 20g of purified water to crystallize , filtered and dried to obtain intermediate compound c 1.6g, yield 73%.

Embodiment 2

[0039]Add 20g of 1,1-cyclopropyldicarboxylic acid (153.7mmol) into the reaction flask, 140g of tetrahydrofuran, 60g of DIPEA, stir to dissolve, add 101.8g of HCTU and heat to 40°C, stir to activate 1,1-cyclopropyldicarboxylic acid After 1.5 hours of carboxylic acid, add 40g of p-aminophenol (366.5mmol), react at 20~40°C for 10~20 hours, after the reaction is completed, add 5wt% sodium carbonate solution to adjust the pH to 7~8, then add 80g of purified water to crystallize, filter After drying, 40.1 g of intermediate compound c was obtained, with a yield of 83%.

[0040] Take 30g of compound c, add it to 200g DMAC, add 32.3g of potassium tert-butoxide under stirring, stir until the temperature is stable, add 64.4g of 4-chloro-6,7-dimethoxyquinoline (compound d), and heat to React at 90-100°C for 8-10 hours, stop heating, add 300 g of purified water dropwise, let it cool down to room temperature for crystallization overnight, filter and wash to obtain the crude compound II. Th...

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Abstract

The invention discloses an antitumor drug cabozantinib impurity, a preparation method and application thereof and belongs to the technical field of biological medicine. The structural formula of the anti-tumor drug cabozantinib impurity is shown in the specification. Meanwhile, the invention also provides a synthesis method of a compound. The method comprises the following synthesis steps: (1) dissolving cyclopropane-carboxylic acid and an acid-binding agent in a solvent, activating by a condensing agent, adding p-aminophenol, and carrying out a condensation reaction to obtain a compound c; and (2) dissolving the compound c in the solvent, adding alkali to form a salt with the compound c, adding a compound d, and carrying out a substitution reaction to obtain a target compound II.

Description

technical field [0001] The invention belongs to the field of biomedicine, and the specific technology relates to an antitumor drug cabozantinib impurity, its preparation method and application. Background technique [0002] Cabozantinib malate is a multi-target tyrosine kinase inhibitor, which can effectively inhibit hepatocyte growth factor receptor, vascular endothelial growth factor receptor, stem cell growth factor receptor, tyrosine kinase receptor, FMS-like tyrosine Tyrosine kinase activity of AXL, EGF-like domain tyrosine kinase 2. The above kinase receptors play an important role in the growth of normal cells and tumor cells. Abnormal expression of the above receptors plays an important role in the occurrence and development of various tumors, including inhibiting tumor cell apoptosis and participating in pathological processes such as tumor angiogenesis and invasion. Cabozantinib exerts an anti-tumor effect by inhibiting the above-mentioned kinase activity, can ki...

Claims

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Application Information

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IPC IPC(8): C07D215/22
CPCC07D215/22
Inventor 席元骆献丽刘帅刘洋王振卫付晓宁
Owner LEPU PHARMACEUTICAL CO LTD
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