Synthesis method of lenvatinib

A synthesis method and technology of lenvatinib, which are applied in the field of medicinal chemical synthesis, can solve the problems of low intermediate purity, low yield, danger and the like, and achieve the effects of simple reaction steps, simple and easy-to-obtain raw materials, and low production cost.

Inactive Publication Date: 2021-08-27
SHANDONG HUIHAI PHARMA & CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The reaction in the first step of the process route is not complete, the yield is low, the purity of the obtained intermediate (3) is low, and the production is not easy to operate
The use of phenyl chloroformate in the second step of the reaction will generate a large amount of gas, and the production scale-up has certain risks, and the safety is low. At the same time, the reaction temperature needs to be controlled at -15 degrees, and the production scale-up is not easy to control.
[0032] In summary, the current synthetic route of lenvatinib has problems in production operation, reagent toxicity, production cost and yield, so it is important to develop a low-cost, low-pollution and easy-to-operate process route suitable for industrial production. significance

Method used

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  • Synthesis method of lenvatinib
  • Synthesis method of lenvatinib
  • Synthesis method of lenvatinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Dissolve methyl 2-chloro-4-hydroxybenzoate in dimethyl sulfoxide, add potassium carbonate and 4-chloro-7-methoxyquinoline-6-amide at room temperature, stir and heat to reflux for 10 hours . The molar ratio of methyl 2-chloro-4-hydroxybenzoate, 4-chloro-7-methoxyquinoline-6-amide and base is 1:0.5:1.1. After the reaction was completed, naturally cool to room temperature, concentrate under reduced pressure, pour the residue into ice water, filter, wash the filter cake with water, and recrystallize with isopropanol to obtain 4-(3-chloro-4-methoxycarbonylphenoxy) -7-methoxy-6-quinolinecarboxamide, yield 83.3%.

[0052] Dissolve 4-(3-chloro-4-methoxycarbonylphenoxy)-7-methoxy-6-quinolinecarboxamide in methanol, add 1 mol / L sodium hydroxide aqueous solution, and stir at room temperature for 18 hours. The molar ratio of 4-[3-chloro-4-methoxycarbonylphenoxy]-7-methoxy-6-quinolinecarboxamide to base is 1:2.0; 4-[3-chloro-4-methoxy The weight ratio of carbonylphenoxy]-7-methox...

Embodiment 2

[0055] Dissolve methyl 2-chloro-4-hydroxybenzoate in N,N-dimethylformamide, add sodium carbonate and 4-chloro-7-methoxyquinoline-6-amide at room temperature, stir and heat to Reflux for 10 hours. The molar ratio of methyl 2-chloro-4-hydroxybenzoate, 4-chloro-7-methoxyquinoline-6-amide and base is 1:0.9:1.5. After the reaction was completed, naturally cool to room temperature, concentrate under reduced pressure, pour the residue into ice water, filter, wash the filter cake with water, and recrystallize with isopropanol to obtain 4-(3-chloro-4-methoxycarbonylphenoxy) -7-methoxy-6-quinoline carboxamide, yield 83.9%.

[0056] Dissolve 4-(3-chloro-4-methoxycarbonylphenoxy)-7-methoxy-6-quinolinecarboxamide in ethanol, add 1 mol / L potassium hydroxide aqueous solution, and stir at room temperature for 18 hours. The molar ratio of 4-[3-chloro-4-methoxycarbonylphenoxy]-7-methoxy-6-quinolinecarboxamide to base is 1:3.0; 4-[3-chloro-4-methoxy The weight ratio of carbonylphenoxy]-7-meth...

Embodiment 3

[0059] Dissolve methyl 2-chloro-4-hydroxybenzoate in acetonitrile, add potassium hydroxide and 4-chloro-7-methoxyquinoline-6-amide at room temperature, stir and heat to reflux for 10 hours. The molar ratio of 2-chloro-4-hydroxybenzoic acid methyl ester, 4-chloro-7-methoxyquinoline-6-amide and base is 1:1.5:0.9. After the reaction was completed, naturally cool to room temperature, concentrate under reduced pressure, pour the residue into ice water, filter, wash the filter cake with water, and recrystallize with isopropanol to obtain 4-(3-chloro-4-methoxycarbonylphenoxy) -7-methoxy-6-quinoline carboxamide, yield 81.5%.

[0060] Dissolve 4-(3-chloro-4-methoxycarbonylphenoxy)-7-methoxy-6-quinolinecarboxamide in tetrahydrofuran, add 1mol / L sodium hydroxide aqueous solution, and stir at room temperature for 18 hours. The molar ratio of 4-[3-chloro-4-methoxycarbonylphenoxy]-7-methoxy-6-quinolinecarboxamide to base is 1:2.5; 4-[3-chloro-4-methoxy The weight ratio of carbonylphenoxy]...

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Abstract

The invention relates to a systhesis method of lenvatinib. The method comprises the following steps: by taking 2-chloro-4-methyl hydroxybenzoate and 4-chloro-7-methoxyquinoline-6-amide as starting raw materials, carrying out substitution reaction to obtain 4-[3-chloro-4-methoxycarbonyl phenoxy]-7-methoxy-6-quinolinecarboxamide, carrying out an alkaline hydrolysis reaction to obtain 4-(3-chloro-4-carboxyphenoxy)-7-methoxy-6-quinolinecarboxamide, carrying out a Curtius rearrangement reaction on the 4-(3-chloro-4-carboxyphenoxy)-7-methoxy-6-quinolinecarboxamide and diphenyl azide phosphate (DPPA), and carrying out a reaction on the obtained product and cyclopropylamine to obtain lenvatinib through a one-pot method. The invention provides a novel method for synthesizing lenvatinib. The method has the advantages of simple reaction steps, simple and easily available raw materials, simple operation and low production cost.

Description

technical field [0001] The invention belongs to the field of pharmaceutical chemical synthesis, and in particular relates to a synthesis method of lenvatinib. Background technique [0002] Lenvatinib (Lenvatinib, Lenvatinib) is an oral multi-target lysine kinase inhibitor developed by Japan's Eisai (Eisai), the main targets are epidermal growth factor receptor, vascular endothelial growth factor Receptors and other receptor tyrosine kinases, etc., control tumor growth and inhibit tumor angiogenesis by acting on multiple signaling pathways, so as to prevent tumor progression and promote tumor death. It was first approved by the FDA in 2015 for the treatment of thyroid cancer, renal cell carcinoma and hepatocellular carcinoma. Lenvatinib has the characteristics of high efficiency, rapid onset of action and low side effects. On September 4, 2018, lenvatinib was approved for import in China (trade name: Lenvima), which is the second first-line targeted therapy drug for liver ca...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/48
CPCC07D215/48
Inventor 赵攀峰姜福元付德修王亮亮王明飞梅泉
Owner SHANDONG HUIHAI PHARMA & CHEM
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