Synthesis method of lenvatinib

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...

Examples

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]...

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...

Examples

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]...

Images