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Synthesis method of cabozantinib and intermediate thereof

A technology of cabozantinib and its synthetic method, which is applied in the field of synthesis of cabozantinib and its intermediates, and can solve the problems of low production cost and the like

Pending Publication Date: 2021-02-23
LUNAN PHARMA GROUP CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] In a word, there are still many problems in the method for the synthesis of cabozantinib in the prior art, and the research is to find a synthesis of cabozantinib that is suitable for industrialized production with mild reaction conditions, simple and convenient operation process, high product yield, high purity and low production cost. The route is still a problem to be solved for now

Method used

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  • Synthesis method of cabozantinib and intermediate thereof
  • Synthesis method of cabozantinib and intermediate thereof
  • Synthesis method of cabozantinib and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0081] 1,1-Dicyanocyclopropane (9.2g, 0.1mol) was dissolved in 156ml of dichloromethane, tetrabutylammonium bisulfate (6.8g, 0.02mol) and potassium hydroxide aqueous solution (which contained potassium hydroxide 14.0g, 0.25mol), the temperature was controlled at 55°C to 60°C, and the reaction was carried out for 12h. After the reaction, the organic layer was washed with water, and the organic layer was taken, dried over sodium sulfate (5.0g) and spin-dried to obtain a white solid, which was washed with ethyl acetate ( 40ml) to obtain 1,1-dicarboxamidocyclopropane with a yield of 96.9% and a purity of 99.65%.

Embodiment 2

[0083] Dissolve 1,1-dicyanocyclopropane (9.2g, 0.1mol) in 184ml of dichloromethane, add 18 crown 6 (7.9g, 0.03mol) and potassium carbonate aqueous solution (which contains potassium carbonate 41.4g, 0.30mol ), the temperature was controlled at 60°C to 70°C, and the reaction was carried out for 10h. After the reaction, the organic layer was washed with water, the organic layer was taken, dried with sodium sulfate (5.0g) and spin-dried to obtain a white solid, which was beaten with ethyl acetate (40ml) to obtain 1 , 1-Diformamidocyclopropane, yield 95.3%, purity 99.54%.

Embodiment 3

[0085] Dissolve 1,1-dicyanocyclopropane (9.2g, 0.1mol) in 92ml of dichloromethane, add α-cyclodextrin (9.7g, 0.01mol) and lithium hydroxide aqueous solution (which contains lithium hydroxide 4.8 g, 0.20mol), the temperature is controlled at 15°C to 20°C, react for 20h, wash the organic layer with water after the reaction, take the organic layer, dry it with sodium sulfate (5.0g) and spin dry to obtain a white solid, wash with ethyl acetate (40ml ) beating to obtain 1,1-dicarboxamidocyclopropane with a yield of 94.6% and a purity of 99.12%.

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Abstract

The invention provides a synthesis method of cabozantinib and an intermediate thereof, and belongs to the field of medicinal chemistry. According to the invention, cyclopropane-1,1-dicarboxylic acid amine is used as a key intermediate, and reacts with substituted fluorobenzene and 4-((6,7-dimethyl-quinoline-4-yl)oxy) substituted benzene respectively to obtain the product cabozantinib; and by-products are effectively prevented from being generated, the yield of the prepared cabozantinib and the utilization rate of raw materials are increased, the production cost is saved, and the method is moresuitable for industrial production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a synthetic method of cabozantinib and an intermediate thereof. Background technique [0002] The chemical name of Cabozantinib is cyclopropane-1,1-dicarboxylic acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-phenyl]amide (4- Fluoro-phenyl) amides, the molecular formula is C 28 h 24 FN 3 o 5 , the relative molecular weight is 502, and the density is 1.396g / cm 3 . It is a quinolinyloxydiphenylcyclopropane dicarboxamide derivative developed by Exelixis in the United States. It is a multi-target (MET, VEGFR1, VEGFR2, VEGFR3, RET, ROS1, KITAXL, NTRK) anticancer drug , effectively inhibit the growth and metastasis of cancer cells. Approved by the US FDA in 2012, the indications for marketing are relapsed and refractory advanced medullary thyroid cancer and advanced kidney cancer that failed Sutent treatment. The indications in the clinical trial stage include liver cance...

Claims

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Application Information

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IPC IPC(8): C07D215/22C07C231/12C07C233/59C07C231/06C07C233/58
CPCC07C231/06C07C231/12C07D215/22C07C2601/02C07C233/59C07C233/58
Inventor 张贵民宋长江虞海天
Owner LUNAN PHARMA GROUP CORPORATION
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