阅读说明：本技术 卡博替尼脱氟杂质的制备方法 (Preparation method of cabozantinib defluorinated impurity ) 是由 杨卫民 孙玉琴 于 2020-05-27 设计创作，主要内容包括：本发明公开了一种卡博替尼脱氟杂质的制备方法,包括以下步骤：中间体1的制备、4-氯-6、7-二甲氧基喹啉的制备、中间体2的制备、卡博替尼脱氟杂质：室温下,将有机溶剂加入到反应器中,搅拌10min,加入中间体1后再搅拌20min,之后再加入中间体2,反应3h后原料剩余14％,升温至35℃至反应完全,加入水,产品析出抽滤得到卡博替尼脱氟杂质。本发明采用上述卡博替尼脱氟杂质的制备方法,此合成过程中无高温高压反应,合成方法温和易操作,所有步骤都温和可控,操作简单,可控性强。(The invention discloses a preparation method of a cabozantinib defluorinated impurity, which comprises the following steps: preparation of intermediate 1, preparation of 4-chloro-6, 7-dimethoxyquinoline, preparation of intermediate 2, defluorination of cabozantinib impurities: adding an organic solvent into a reactor at room temperature, stirring for 10min, adding the intermediate 1, stirring for 20min, adding the intermediate 2, reacting for 3h, heating to 35 ℃ until the reaction is complete, adding water, separating out a product, and performing suction filtration to obtain the cabozantinib defluorinated impurity. According to the preparation method of the cabozantinib defluorinated impurity, the synthesis process is free of high-temperature and high-pressure reaction, the synthesis method is mild and easy to operate, all steps are mild and controllable, and the operation is simple and strong in controllability.)

1. A preparation method of a cabozantinib defluorinated impurity is characterized by comprising the following steps:

s1, preparation of intermediate 1: firstly, adding cyclopropane diacid and ethyl acetate into a reactor, cooling to less than 5 ℃, adding triethylamine, controlling the temperature to be less than 10 ℃, reacting for 1h, then controlling the temperature to be less than 10 ℃, dropwise adding thionyl chloride, reacting for 1h, then controlling the temperature to be less than 10 ℃, adding aniline, reacting for 16h, adding an alkali aqueous solution to adjust the pH value to be 3-4, extracting with ethyl acetate, spin-drying, pulping with 1L of PE/1L of TBME, and performing suction filtration and drying to obtain an intermediate 1;

preparation of S2, 4-chloro-6, 7-dimethoxyquinoline: sequentially adding 4-hydroxy-6, 7-dimethoxyquinoline, acetonitrile and phosphorus oxychloride into a reactor, heating to 75 ℃ for reaction for 24 hours, evaporating to dryness, pouring into ice water, adjusting pH to 7 with alkali, extracting with DCM to dryness, pulping with PE/1.5L TBME, and filtering to obtain 4-chloro-6 and 7-dimethoxyquinoline;

s3, preparation of intermediate 2: adding alkali and an organic solvent into a reactor, stirring for 10min, adding p-hydroxyaniline, stirring for 20min, adding 4-chloro-6, 7-dimethoxyquinoline, heating to 100 ℃ for reaction for 5h, stopping the reaction when the content of the raw material is less than 1%, cooling to room temperature, adding a saturated solution of potassium carbonate, stirring for 5h, carrying out suction filtration, carrying out reflux dissolution on a filter cake by using methanol, decolorizing by using activated carbon for 5h, carrying out suction filtration, carrying out cold precipitation, carrying out suction filtration and drying to obtain an intermediate 2;

s4, defluorination of cabozantinib: adding an organic solvent into a reactor at room temperature, stirring for 10min, adding the intermediate 1, stirring for 20min, adding the intermediate 2, reacting for 3h, heating to 35 ℃ until the reaction is complete, adding water, separating out a product, and performing suction filtration to obtain the cabozantinib defluorinated impurity.

2. The method of claim 1, wherein the preparation of the cabozantinib defluorinated impurity comprises: when the cyclopropane diacid and the ethyl acetate in the step S1 are mixed, the temperature is reduced to 0 ℃, and the alkali is potassium carbonate.

3. The method of claim 1, wherein the preparation of the cabozantinib defluorinated impurity comprises: the alkali in the step S2 is ammonia water.

4. The method of claim 1, wherein the preparation of the cabozantinib defluorinated impurity comprises: the organic solvent in the S3 is DMSO, namely dimethyl sulfoxide, and the base is potassium tert-butoxide.

5. The method of claim 1, wherein the preparation of the cabozantinib defluorinated impurity comprises: the organic solvent in step S4 is a mixture of DMF, HCTU, DIEA.

Technical Field

The invention relates to the technical field of medicine preparation, in particular to a preparation method of a cabozantinib defluorinated impurity.

Background

Cabozantinib, developed by Exelixis biopharmaceutical corporation of usa, is a multi-target broad-spectrum anticancer drug, and targets capable of inhibiting include: at least 9 of MET, VEGFR1/2/3, ROS1, RET, AXL, NTRK, KIT, etc. At present, cabozantinib has proved a better treatment effect 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, intestinal cancer and the like, and the control effect on bone metastasis is particularly prominent. Cabozantinib is known as "taggant oil" in targeted drugs because of its broad effectiveness against a variety of cancers.

The cabozantinib structural formula is complex, the synthesis route is long, potential impurities in the cabozantinib API are more due to the condition, the series of impurity reference substances are synthesized, and the method has important significance for the quality research of cabozantinib.

Disclosure of Invention

The invention aims to provide a preparation method of a cabozantinib defluorinated impurity, wherein the synthesis process has no high-temperature high-pressure reaction, the synthesis method is mild and easy to operate, all steps are mild and controllable, and the operation is simple and strong in controllability.

In order to achieve the above object, the present invention provides a method for preparing a cabozantinib defluorinated impurity, comprising the steps of:

s1, preparation of intermediate 1: firstly, adding cyclopropane diacid and ethyl acetate into a reactor, adding triethylamine when the temperature is reduced to be less than 5 ℃, controlling the temperature to be less than 10 ℃, reacting for 1h, then dropwise adding thionyl chloride when the temperature is controlled to be less than 10 ℃, reacting for 1h, then adding aniline when the temperature is controlled to be less than 10 ℃, reacting for 16h, adding an alkali aqueous solution to adjust the pH value to be 3-4, extracting with ethyl acetate, spin-drying, pulping with 1L of PE/1L of TBME, performing suction filtration and drying to obtain an intermediate 1, wherein the specific reaction formula is as follows:

preparation of S2, 4-chloro-6, 7-dimethoxyquinoline: sequentially adding 4-hydroxy-6, 7-dimethoxyquinoline, acetonitrile and phosphorus oxychloride into a reactor, heating to 75 ℃ for reaction for 24 hours, evaporating to dryness, pouring into ice water, adjusting pH to 7 with alkali, extracting with DCM to dryness, pulping with PE/1.5L TBME, and performing suction filtration to obtain 4-chloro-6 and 7-dimethoxyquinoline, wherein the specific reaction formula is as follows:

s3, preparation of intermediate 2: adding alkali and an organic solvent into a reactor, stirring for 10min, adding p-hydroxyaniline, stirring for 20min, adding 4-chloro-6, 7-dimethoxyquinoline, heating to 100 ℃ for reaction for 5h, stopping the reaction when the content of the raw material is less than 1%, cooling to room temperature, adding a saturated solution of potassium carbonate, stirring for 5h, carrying out suction filtration, carrying out reflux dissolution on a filter cake by using methanol, decolorizing the filter cake by using activated carbon for 5h, carrying out suction filtration, carrying out cold precipitation, suction filtration and drying to obtain an intermediate 2, wherein the specific reaction formula is as follows:

s4, defluorination of cabozantinib: at room temperature, adding an organic solvent into a reactor, stirring for 10min, adding the intermediate 1, then stirring for 20min, then adding the intermediate 2, reacting for 3h, heating the raw material to 35 ℃ until the reaction is complete, adding water, precipitating a product, and performing suction filtration to obtain the cabozantinib defluorinated impurities, wherein the specific reaction formula is as follows:

preferably, the temperature of the mixture of the cyclopropane diacid and the ethyl acetate in the step S1 is reduced to 0 ℃, and the base is potassium carbonate.

Preferably, the base in step S2 is ammonia water.

Preferably, the organic solvent in S3 is DMSO, i.e., dimethyl sulfoxide, and the base is potassium tert-butoxide. Preferably, the organic solvent in step S4 is a mixture of DMF, HCTU, DIEA.

Therefore, the preparation method of the cabozantinib defluorinated impurity is adopted, high-temperature and high-pressure reaction does not exist in the synthesis process, the synthesis method is mild and easy to operate, all steps are mild and controllable, and the operation is simple and strong in controllability.

The technical solution of the present invention is further described in detail by the accompanying drawings and embodiments.

Drawings

FIG. 1 is a schematic diagram of the synthetic route of an embodiment of a process for the preparation of a defluorinated impurity of cabozantinib of the present invention;

Detailed Description

The technical solution of the present invention is further illustrated by the accompanying drawings and examples.

The invention provides a preparation method of a cabozantinib defluorinated impurity, which comprises the following steps:

s1, preparation of intermediate 1: firstly, adding cyclopropane diacid and ethyl acetate into a reactor, cooling to less than 5 ℃, adding triethylamine, controlling the temperature to be less than 10 ℃, reacting for 1h, controlling the temperature to be less than 10 ℃, dropwise adding thionyl chloride, reacting for 1h, controlling the temperature to be less than 10 ℃, adding aniline, reacting for 16h, adding an aqueous solution of alkali to adjust the pH to be 3-4, extracting with ethyl acetate, spin-drying, pulping with 1L of PE/1L of TBME, performing suction filtration and drying to obtain an intermediate 1, wherein the specific reaction formula is as follows:

preparation of S2, 4-chloro-6, 7-dimethoxyquinoline: sequentially adding 4-hydroxy-6, 7-dimethoxyquinoline, acetonitrile and phosphorus oxychloride into a reactor, heating to 75 ℃ for reaction for 24 hours, evaporating to dryness, pouring into ice water, adjusting pH to 7 with alkali, extracting with DCM to dryness, pulping with PE/1.5L TBME, and performing suction filtration to obtain 4-chloro-6 and 7-dimethoxyquinoline, wherein the specific reaction formula is as follows:

s3, preparation of intermediate 2: adding alkali and an organic solvent into a reactor, stirring for 10min, wherein the organic solvent is DMSO, namely dimethyl sulfoxide, the alkali is potassium tert-butoxide, adding p-hydroxyaniline, stirring for 20min, adding 4-chloro-6, 7-dimethoxyquinoline, heating to 100 ℃, reacting for 5h, stopping the reaction when the raw material is less than 1%, cooling to room temperature, adding a saturated solution of potassium carbonate, stirring for 5h, carrying out suction filtration, dissolving a filter cake by methanol in a refluxing manner, decolorizing the filter cake by activated carbon for 5h, carrying out suction filtration, carrying out cold precipitation, suction filtration and drying to obtain an intermediate 2, and the specific reaction formula is as follows:

s4, defluorination of cabozantinib: at room temperature, adding an organic solvent into a reactor, wherein the organic solvent is a mixture of DMF, HCTU and DIEA, stirring for 10min, adding the intermediate 1, stirring for 20min, then adding the intermediate 2, reacting for 3h, keeping the raw materials at the residual content of 14%, heating to 35 ℃ until the reaction is complete, adding water, precipitating a product, and performing suction filtration to obtain the cabozantinib defluorinated impurities, wherein the specific reaction formula is as follows: