Preparation method for cabozantinib degradation impurity without p-fluoroaniline

Abstract

The invention discloses a preparation method for a cabozantinib degradation impurity without p-fluoroaniline. The method comprises the following steps: preparation of 4-chloro-6,7-dimethoxyquinoline;preparation of an intermediate 1; and preparation of p-fluoroaniline impurities by degrading cabozantinib: adding an organic solvent into a reactor at room temperature, carrying out stirring for 10 min, adding cyclopropanedicarboxylic acid, conducting stirring for 20 minutes, then adding an intermediate 1, wherein a mass ratio of the intermediate 1 to the cyclopropanedicarboxylic acid of 400: 334.5, performing reacting for 3 hours, carrying out heating to 35 DEG C until a reaction is complete, adding water, separating out a product, and carrying out suction filtration to obtain the cabozantinib degradation impurity without p-fluoroaniline. According to the preparation method for the cabozantinib degradation impurity without p-fluoroaniline, no high-temperature and high-pressure reaction exists in the synthesis process, the method is mild and easy to operate, all the steps are mild and controllable, operation is simple, and controllability is high.

Description

technical field [0001] The invention relates to the technical field of medicine preparation, in particular to a preparation method for degrading de-p-fluoroaniline impurities by cabozantinib. Background technique [0002] Cabozantinib was developed by Exelixis Biopharmaceutical Company of the United States. It is a multi-target broad-spectrum anticancer drug. The targets that can be inhibited include: MET, VEGFR1 / 2 / 3, ROS1, RET, AXL, NTRK, KIT, etc. At least 9. At present, cabozantinib has demonstrated good therapeutic effects in various solid tumors such as renal cancer, thyroid cancer, liver cancer, soft tissue sarcoma, non-small cell lung cancer, prostate cancer, breast cancer, ovarian cancer, and bowel cancer. The effect on the control of bone metastases is particularly prominent. Because of its broad effectiveness against a variety of cancers, cabozantinib is known as the "magic balm" among targeted drugs. [0003] The structural formula of cabozantinib is relatively...

AI Technical Summary

Problems solved by technology

[0003] The structural formula of cabozantinib is relatively complex, and the steps of the synthetic route are long. This situation leads to many potential impurities in the API of cabozantinib. The synthesis of this series of impurity reference substances is of great significance to the quality research of cabozantinib

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