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Method for preparing antitumor drug cabozantinib

A technology of cabozantinib and reaction, which is applied in the field of preparation of anti-tumor drug cabozantinib, can solve the problems of difficult monoamide product separation, increased material consumption, difficult control, etc., to simplify the operation process, simplify material consumption, Obvious effect

Pending Publication Date: 2017-11-17
仁合熙德隆药业有限公司 +2
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AI Technical Summary

Problems solved by technology

The main disadvantages of these methods are as follows: first, 1,1-cyclopropyldicarboxylic acid is a dibasic acid with a special structure. When preparing monoacyl chlorides by chlorination, it is difficult to control them in the monoacyl chloride stage, and there must be a considerable proportion The diacyl chlorides are generated, and these generated diacyl chlorides will inevitably generate symmetrical diamide by-products when preparing 1,1-cyclopropyl dicarboxylic acid monoamide in the next step, and it is difficult to separate them from the monoamide products
Second, when diamide is prepared from 1,1-cyclopropyl dicarboxylic acid monoamide, no matter what method is used, the reaction steps and reaction difficulty are increased on the one hand, and the material consumption is increased on the other hand.

Method used

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  • Method for preparing antitumor drug cabozantinib
  • Method for preparing antitumor drug cabozantinib

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Embodiment

[0017] Add 200g of 1,1-cyclopropyldicarboxylic acid into the reaction flask, add 560g of thionyl chloride, slowly heat to 20±2°C under stirring and react for 2 hours, stop the reaction and evaporate excess chloride under reduced pressure below 30°C Sulfoxide (about 200g), stop the distillation, add 1000g of tetrahydrofuran, 360g of triethylamine, stir and cool down to below 5°C. While stirring at this temperature, slowly add 440g of 4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (dissolved in 600g of tetrahydrofuran) below 5°C into the above reaction system dropwise, Add about 1 hour. Continue to stir the reaction for more than 5h. It was detected by TLC that the reaction of 4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline was complete, and the temperature was raised to about 40°C, and 180g of p-fluoroaniline (diluted with 100g of tetrahydrofuran) was slowly added dropwise, about 1 hour added. Then raise the temperature to 50±5°C, continue to stir and react for more than 6 hours, change ...

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Abstract

The invention discloses a method for preparing an antitumor drug cabozantinib and belongs to the field of biological pharmacy. The method disclosed by the invention is realized through the following steps: taking 1,1-cyclopropanedicarboxylic acid and a chlorinating agent to react to generate 1,1-cyclopropyl diacyl chloride (an intermediate 1); and taking the 1,1-cyclopropyl diacyl chloride to react with 4-[(6,7-dimethoxy-4-quinolyl)oxyl]aniline and para-fluoroaniline in sequence to prepare the cabozantinib. Three-step reactions are carried out in the same reactor and an intermediate product does not need to be separated. Compared with the prior art, the method has the characteristics of few reaction steps, few byproducts, simplicity and convenience for operation, high yield and the like.

Description

technical field [0001] The invention relates to a new method for preparing antitumor drug cabozantinib, which belongs to the field of biomedicine. technical background [0002] Cabozantinib as an antineoplastic drug has been clinically used. There are many domestic and foreign reports on the preparation method of cabozantinib malate. Reference WO 2013 / 166296 A1. The common point of the above synthetic routes is that 1,1-cyclopropyl dicarboxylic acid is chlorinated first to obtain monoacyl chloride, and then reacted with aromatic amine to obtain monoamide. Then, the other carboxyl group in 1,1-cyclopropyl dicarboxylic acid monoamide is chlorinated into acid chloride by secondary chlorination, and then reacted with another molecule of aromatic amine to make the target molecule; or in the presence of a special condensing agent, The target product is obtained by reacting 1,1-cyclopropyl dicarboxylic acid monoamide with another aromatic amine. The main disadvantages of these me...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/22
CPCC07D215/22
Inventor 罗峥席元张方杰陈军邱祯孟庆乐罗琦崔浩
Owner 仁合熙德隆药业有限公司
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