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Method for preparing antitumor drug cabozantinib intermediate by solid base catalysis

A solid base and oxide technology, applied in chemical instruments and methods, chemical/physical processes, physical/chemical process catalysts, etc., can solve problems such as containing, and achieve the effects of reducing production costs and high yields

Inactive Publication Date: 2018-10-16
张淑华
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0013] The method has achieved a yield of 83%, which is greatly improved compared with the yield of p-nitrophenol; but in this process, 3 times the molar amount of sodium hydroxide is used to directly add water in the later stage to crystallize as an anti-solvent, resulting in a large amount of alkaline waste water. And the wastewater contains a large amount of unreacted p-aminophenol

Method used

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  • Method for preparing antitumor drug cabozantinib intermediate by solid base catalysis
  • Method for preparing antitumor drug cabozantinib intermediate by solid base catalysis
  • Method for preparing antitumor drug cabozantinib intermediate by solid base catalysis

Examples

Experimental program
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Effect test

Embodiment 1

[0050] Prepare the Mg / Al composite metal oxide solid base of Zr doping as follows:

[0051] 1) dissolving zirconium nitrate pentahydrate (20mmol), magnesium nitrate hexahydrate (60mmol) and aluminum nitrate hexahydrate (20mmol) in water to form a nitrate mixture;

[0052] 2) Prepare 2mol / L sodium hydroxide dissolved in water to obtain an alkaline solution;

[0053] 3) Raise the temperature of the nitrate mixture to 60-70°C, keep the speed at 800rpm, and then use the DMD15-13 peristaltic pump (Langer Constant Flow Pump Co., Ltd.) to drop the alkaline mixture to keep the pH of the nitrate system at 8.5 Between -9.5, heat preservation and stirring for 16-18h, then centrifuge, wash the filter cake with deionized water until the filtrate becomes neutral, and then dry at 75-80°C to constant weight to obtain a Zr-doped Mg / Al composite metal hydroxide solid base precursor;

[0054] 4) The Mg / Al composite metal hydroxide solid alkali precursor of Zr doping is placed in saturated pota...

Embodiment 1-A

[0064] Adopt single factor variable method to study the influence of Zr doping on solid base catalytic performance: compare with the preparation method of sequence 5 in the table 1 of embodiment 1, do not add zirconium nitrate pentahydrate in step 1), all the other are LDO in the embodiment 1 The preparation method of -300 is exactly the same; the prepared solid base is named LDO-300-A.

Embodiment 1-B

[0066] Adopt single factor variable method to study the impact of potassium carbonate replacement on solid base catalytic performance: compare with the preparation method of sequence 5 in the table 1 of embodiment 1, do not carry out the processing of step 4), all the other are the same as that of LDO-300 in the embodiment 1 The preparation method is exactly the same; the prepared solid base is named LDO-300-B.

[0067] Replace LDO-300 in Example 1 with LDO-300-A and LDO-300-B respectively, and catalyze 4-chloro-6,7-dimethoxyquinoline and 4-aminophenol according to the preparation method in Example 1 reaction, wherein the conversion rate of the LDO-300-A catalytic system is 67.2%, and the conversion rate of the LDO-300-B catalytic system is 72.3%.

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Abstract

The invention belongs to the technical field of catalytic materials, and in particular relates to a method for preparing an antitumor drug cabozantinib intermediate by solid base catalysis. Accordingto the method provided by the invention, Zr is used as a third metal element to modify Mg / Al bimetal, a Zr-doped Mg / Al composite metal hydroxide is prepared by a co-precipitation method, then ion exchange is carried out through potassium carbonate, high-temperature calcination is carried out, and finally reforming is carried out in water to finally prepare a Zr-doped Mg / Al composite metal oxide solid base with a three-dimensional structure. The solid base prepared by the method provided by the invention can replace sodium hydroxide to catalyze the preparation of 4-chloro-6,7-dimethoxyquinolinewhich is condensed with 4-aminophenol to prepare 4-(4-aminophenoxy)-6,7-dimethoxyquinoline, an antitumor drug cabozantinib intermediate. The catalytic system provided by the invention is green and pollution-free, avoids the generation of alkaline waste water and has a high yield and meets the requirements of green chemical industry.

Description

technical field [0001] The invention belongs to the technical field of catalytic materials, and in particular relates to a method for preparing an intermediate of an antitumor drug cabozantinib catalyzed by a solid base. Background technique [0002] The chemical name of cabozantinib is N'-[4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl]-N-(4-fluorophenyl)- 1,1-Cyclopropanedicarboxamide is a targeted small molecule multi-receptor tyrosine kinase inhibitor developed by Exelixis Biotechnology Company of the United States. It can target and inhibit MET, VEGFR2 and RET signaling pathways, kill tumor cells, reduce tumor metastasis and inhibit angiogenesis, and it also has inhibitory effect on gefitinib-resistant non-small cell lung cancer. Its (S)- Malate (trade name Cometriq) was approved by the US FDA in November 2012 for clinical use in the treatment of metastatic medullary thyroid cancer; it was launched in Europe in March 2014. In April 2016, the US FDA approved it for advanced...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/22B01J21/10
CPCB01J21/10C07D215/22
Inventor 张淑华陈向向孟震康健韩斌
Owner 张淑华
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