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Preparation method of cabozantinib defluorination impurity

A technology for cabozantinib and impurities, which is applied in the field of drug preparation and can solve the problems of complex structural formula of cabozantinib, long synthetic route steps, and many potential impurities.

Inactive Publication Date: 2020-08-14
廊坊市泽康医药科技有限公司
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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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  • Preparation method of cabozantinib defluorination impurity
  • Preparation method of cabozantinib defluorination impurity
  • Preparation method of cabozantinib defluorination impurity

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Embodiment Construction

[0020] The technical solutions of the present invention will be further described below through the accompanying drawings and embodiments.

[0021] The invention provides a method for preparing cabozantinib defluorinated impurities, comprising the following steps:

[0022] S1. Preparation of Intermediate 1: First, add cyclomalonic acid and ethyl acetate to the reactor, add triethylamine when the temperature is lower than 5°C, control the temperature to less than 10°C, react for 1 hour, and then control the temperature to less than 10°C Add thionyl chloride dropwise, react for 1 hour, add aniline when the temperature is less than 10°C, and react for 16 hours. PE / 1L TBME is beaten, filtered and dried to obtain intermediate 1, and the specific reaction formula is:

[0023]

[0024] Preparation of S2, 4-chloro-6,7-dimethoxyquinoline: 4-hydroxyl-6,7-dimethoxyquinoline, acetonitrile, phosphorus oxychloride are added to the reactor successively, and the temperature is raised to ...

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Abstract

The invention discloses a preparation method of a cabozantinib defluorination impurity. The method comprises the following steps: preparing an intermediate 1, preparing 4-chloro-6, 7-dimethoxyquinoline, preparing an intermediate 2, and removing fluorine impurities from cabozantinib; and adding an organic solvent into a reactor at room temperature, stirring for 10 minutes, adding the intermediate 1, stirring for 20 minutes, adding the intermediate 2, reacting for 3 hours to left 14% of the raw materials, heating to 35 DEG C until the 14% of the raw materials are completely reacted, adding water, separating out the product, and carrying out suction filtering to obtain the cabozantinib defluorination impurity. By adopting the preparation method of the cabozantinib defluorination impurity, nohigh-temperature and high-pressure reaction exists in the synthesis process, the synthesis method is mild and easy to operate, all the steps are mild and controllable, the operation is simple, and thecontrollability is high.

Description

technical field [0001] The invention relates to the technical field of medicine preparation, in particular to a method for preparing cabozantinib to remove fluorinated impurities. 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 complex, an...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/22
CPCC07D215/22
Inventor 杨卫民孙玉琴
Owner 廊坊市泽康医药科技有限公司
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