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Method for synthesizing lenvatinib

A synthesis method and technology of lenvatinib are applied in the field of medicinal chemical synthesis to achieve the effects of reducing the use of chlorinating agents and mild reaction conditions

Inactive Publication Date: 2018-02-27
NANJING CHICO PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, the chlorination of the 4-position of 4-chloro-7-methoxyquinoline-6-carboxamide requires the use of highly dangerous and environmentally polluting chemicals such as thionyl chloride or phosphorus oxychloride

Method used

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  • Method for synthesizing lenvatinib
  • Method for synthesizing lenvatinib
  • Method for synthesizing lenvatinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] (1) Synthesis of 4-(4-amino-3-chloro-phenoxy)-7-methoxy-6-formamide (compound III):

[0031] 7-Methoxy-4-oxo-1,4-dihydroquinoline-6-carboxamide (10.9g, 0.05mol) and bis(3-chloro-4-amino)phenyltrifluoromethanesulfonic acid Iodine (31.7g, 0.06mol) was dissolved in dimethyl sulfoxide (80mL, 0.9mol), and cesium carbonate (48.8g, 0.15mol) was added, that is, compound I, compound II, base (cesium carbonate), organic solvent (di The molar ratio between methyl sulfoxide) is (1.0:1.2:3.0:18). The reaction mixture was heated by microwave at 80°C for 60 minutes in a CEM microwave synthesizer (100W), and the reaction was confirmed by TLC spotting. After adding water (200mL) and ethyl acetate (200mL x 3) for separation and extraction, the organic layer was separated and collected. The organic layer was washed with saturated aqueous sodium chloride solution (100 mL), and the organic phase was collected and dried over sodium sulfate. The solvent was distilled off under reduced press...

Embodiment 2

[0040] The preparation method is the same as in Example 1, but the mol ratio between compound I, compound II, alkali (cesium carbonate), organic solvent (dimethyl sulfoxide) in step (1) is (1.0:1.0:2.5:10) , microwave heating temperature was 90°C, 1.0 reaction for 40min gave 12.8g light yellow solid 4-(4-amino-3-chloro-phenoxy)-7-methoxy-6-carboxamide (compound III). rate 74.5%;

[0041] In step (2), the molar ratio between compound III, compound IV, base (pyridine), and organic solvent (N,N-dimethylformamide) is (1.0:1.2:3.0:10.0), and the reaction temperature is 60°C , reacted for 4h to obtain 15.2g yellow solid 4-[3-chloro-4-(benzyloxycarbonyl)aminophenoxy]-7-methoxyquinoline-6-carboxamide (compound V), yield 88.2% ;

[0042] In step (3), the molar ratio between compound V, cyclopropylamine, condensing agent (N,N'-carbonyldiimidazole), base (N,N-diisopropylethylamine), and organic solvent (tetrahydrofuran) is ( 1.0:1.0:1.5:4.0:10), the reaction temperature was 80°C, and ...

Embodiment 3

[0044] The preparation method is the same as in Example 1, but the mol ratio between compound I, compound II, alkali (cesium carbonate), organic solvent (dimethyl sulfoxide) in step (1) is (1.0:1.6:4.0:20) , the temperature of microwave heating was 70°C, and 13.08g of light yellow solid 4-(4-amino-3-chloro-phenoxy)-7-methoxy-6-carboxamide (compound III) was obtained after 80 minutes of reaction. The yield 76.1%;

[0045] In step (2), the molar ratio between compound III, compound IV, base (pyridine), and organic solvent (N,N-dimethylformamide) is (1.0:1.7:6.0:20), and the reaction temperature is 30°C , reacted for 12h to obtain 16.2g of yellow solid 4-[3-chloro-4-(benzyloxycarbonyl)aminophenoxy]-7-methoxyquinoline-6-carboxamide (compound V), yield 91.6% ;

[0046] In step (3), the molar ratio between compound V, cyclopropylamine, condensing agent (N,N'-carbonyldiimidazole), base (N,N-diisopropylethylamine), and organic solvent (tetrahydrofuran) is ( 1.0:1.6:1.9:5.5:20), the...

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Abstract

The invention discloses a method for synthesizing lenvatinib. The method comprises the following steps: with 7-methoxy-4-oxo-1,4-dihydro-quinoline-6-formamide as an initial raw material, carrying outan oxo-arylation reaction on the initial raw material and bis(3-chloro-4-amino)phenyl iodine trifluoro-methanesulfonate, carrying out an amidation reaction between 4-(4-amino-3-chloro-phenoxy)-7-methoxy-6-formamide, a product of oxo-arylation reaction, and phenyl chloroformate, and carrying out a urea reaction on a product of amidation reaction and cyromazine, thereby obtaining lenvatinib. The synthetic method has few process route steps and is simple in operation, 7-methoxy-4-oxo-1,4-dihydro-quinoline-6-formamide innovatively replaces 4-chloro-7-methoxyquinoline-6-formamide to serve as the initial raw material, and the method is environmental-friendly and is applicable to industrialized production.

Description

technical field [0001] The invention relates to a synthesis method of lenvatinib, which belongs to the field of pharmaceutical chemical synthesis. Background technique [0002] Lenvatinib (Lenvatinib, 1, alias E7080), the chemical name is 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide , the molecular formula is C 21 h 19 ClN 4 o 4 , the molecular weight is 522.96, and its chemical structural formula is: [0003] [0004] The drug is an oral multi-target receptor tyrosine kinase inhibitor developed by Japan's Eisai company. Studies have shown that in addition to inhibiting RTKs related to pro-angiogenic and carcinogenic signaling pathways, it can also selectively inhibit vascular Kinase activity of the endothelial growth factor (VEGF) receptor. The drug was approved by the U.S. FDA on February 13, 2015. Its trade name is Lenvima, and it is used for the treatment of locally recurrent or metastatic, radioiodine-refractory, progre...

Claims

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Application Information

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IPC IPC(8): C07D215/48
CPCC07D215/48
Inventor 吴学平邢继刚严东洋陈耀
Owner NANJING CHICO PHARMA CO LTD
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