Synthesis method of cabozantinib dimer

A technology of cabozantinib dimer and synthesis method, which is applied in the field of cabozantinib dimer synthesis, and can solve the problems of complex structure of cabozantinib, many potential impurities, long synthetic route steps, etc.

Pending Publication Date: 2020-07-17
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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  • Synthesis method of cabozantinib dimer
  • Synthesis method of cabozantinib dimer
  • Synthesis method of cabozantinib dimer

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Embodiment Construction

[0018] The technical solutions of the present invention will be further described below through the drawings and embodiments.

[0019] The invention provides a method for synthesizing cabozantinib dimer, which includes the following steps:

[0020] Preparation of S1, 4-chloro-6, 7-dimethoxyquinoline: add 4-hydroxy-6, 7-dimethoxyquinoline, acetonitrile and phosphorus oxychloride to the reactor in turn, and heat to React at 75°C for 24h. After the reaction is complete, it is evaporated to dryness and poured into ice water. Adjust PH=7 with alkali and ammonia as alkali. Extract and evaporate to dryness with DCM. Beat and filter with 1.5L PE / 1.5L TBME to obtain 4-chloro-6. 7-Dimethoxyquinoline, the specific reaction formula is:

[0021]

[0022] S2. Preparation of Intermediate 1: Add organic solvent and base to the reactor and stir for 10 min. Organic solvent is DMSO and base is potassium tert-butoxide. After adding p-hydroxyaniline and stirring for 20 min, add 4-chloro-6, 7- Dimethoxy...

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Abstract

The invention discloses a synthesis method of a cabozantinib dimer. The method comprises the following steps: preparation of 4-chloro-6,7-dimethoxyquinoline, preparation of an intermediate 1, and preparation of a cabozantinib dimer impurity; and preparation of cabozantinib dimer impurities: adding an organic solvent into a reactor at room temperature, stirring for 10 min, adding cyclopropanedicarboxylic acid, stirring for 20 min, then adding an intermediate 1 with the mass ratio of the intermediate 1 to the cyclopropanedicarboxylic acid being 400:115, carrying out a reaction for 3 h, enablingthe raw material to remain 4%, heating to 45 DEG C until the reaction is complete, adding water, separating out the product, and carrying out suction filtration to obtain the cabozantinib dimer impurities. By adopting the synthesis method of the cabozantinib dimer, no high-temperature and high-pressure reaction exists in the synthesis process, the synthesis method is mild and easy to operate, allthe steps are mild and controllable, the operation is simple, and the controllability is high.

Description

technical field [0001] The invention relates to the technical field of medicine preparation, in particular to a synthesis method of cabozantinib dimer. 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, and the steps of the synthetic...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/22C07D215/18
CPCC07D215/22C07D215/18
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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