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Lenvatinib synthesizing method

A lenvatinib and synthetic method technology, applied in the field of synthesis of new anti-tumor drug lenvatinib, can solve the problems of increasing reaction steps and purification operations, reducing yield, etc., to simplify operations, reduce side reactions, and technical Reasonable effect of the plan

Inactive Publication Date: 2016-07-27
湖南欧亚药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] This route involves Boc protection and deprotection of the amino group, because there are -NH and -OH groups on the substrate structure, which can reduce the competitive side reactions of different positions in the substitution reaction, thereby avoiding the generation of impurities, but thus increasing The reaction steps and purification operations are shortened, reducing the overall yield

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0032] A) Preparation of 4-(benzyloxycarbonyl)amino-3-chlorophenol:

[0033] 4-Amino-3-chlorophenol (10.0g, 0.07mol) was dissolved in tetrahydrofuran (75mL), stirred, benzyl chloroformate (14.3g, 0.08mol) was added, and N,N-diisopropylethylamine ( 36.0g, 0.28mol), the reaction mixture was stirred and reacted at 50°C for 8 hours, and the reaction was confirmed by TLC spotting. Evaporate and concentrate to dryness, and recrystallize from a methanol-isopropanol mixed solvent to obtain 4-(benzyloxycarbonyl)amino-3-chlorophenol as an off-white solid (17.0 g), with a yield of 88.0%. The reaction formula of this step is as follows:

[0034]

[0035] B) Preparation of 4-[3-chloro-4-(benzyloxycarbonyl)aminophenoxy]-7-methoxyquinoline-6-carboxamide:

[0036] 4-(Benzyloxycarbonyl)amino-3-chlorophenol (17.0g, 0.06mol) and 4-chloro-7-methoxyquinoline-6-carboxamide (18.1g, 0.08mol) were dissolved in dichloromethane ( 75 mL), sodium hydride (6.0 g, content 60%, 0.15 mol) was added, the ...

Embodiment 2

[0042] A) Preparation of 4-(benzyloxycarbonyl)amino-3-chlorophenol:

[0043] 4-Amino-3-chlorophenol (12.5g, 0.09mol) was dissolved in chloroform (90mL), stirred, benzyl chloroformate (18.6g, 0.11mol) was added, triethylamine (39.6g, 0.39mol) was added dropwise, The reaction mixture was stirred and reacted at 55°C for 7 hours, TLC was spotted to confirm the completion of the reaction, the reaction solution was concentrated to dryness by rotary evaporation, adjusted to neutrality by adding dilute hydrochloric acid, extracted by adding ethyl acetate, dried by magnesium sulfate, concentrated to dryness by rotary evaporation, methanol- Recrystallized from a mixed solvent of isopropanol to obtain 4-(benzyloxycarbonyl)amino-3-chlorophenol as an off-white solid (21.1 g), with a yield of 87.2%. The reaction formula of this step is the same as in Example 1;

[0044] B) Preparation of 4-[3-chloro-4-(benzyloxycarbonyl)aminophenoxy]-7-methoxyquinoline-6-carboxamide:

[0045] 4-(Benzyloxyc...

Embodiment 3

[0049] A) Preparation of 4-(benzyloxycarbonyl)amino-3-chlorophenol:

[0050] 4-Amino-3-chlorophenol (8.5g, 0.06mol) was dissolved in acetonitrile (60mL), stirred, added benzyl chloroformate (14.1g, 0.08mol), added 4-dimethylaminopyridine (36.2g, 0.30mol ), the reaction mixture was stirred and reacted at 60° C. for 6 hours, and TLC was spotted to confirm that the reaction was complete. The reaction solution was concentrated to dryness by rotary evaporation, adjusted to neutrality by adding dilute hydrochloric acid, extracted by adding ethyl acetate, dried over magnesium sulfate, and concentrated to dryness by rotary evaporation. Recrystallization from a mixed solvent of methanol-isopropanol gave 4-(benzyloxycarbonyl)amino-3-chlorophenol as an off-white solid (14.7 g), with a yield of 89.5%. The reaction formula of this step is the same as in Example 1;

[0051] B) Preparation of 4-[3-chloro-4-(benzyloxycarbonyl)aminophenoxy]-7-methoxyquinoline-6-carboxamide:

[0052] 4-(Benzyl...

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Abstract

The invention discloses a lenvatinib synthesizing method.The method includes the steps that 4-amino-3-chlorophenol and benzyl chloroformate are subjected to amidation reaction, the obtained 4-(carbobenzoxy)amino-3-chlorophenol and 4-chlorine-7-methoxyquinoline-6-formamide are subjected to condensation reaction, the obtained 4-[3-chlorine-4-(carbobenzoxy)aminophenoxy]-7-methoxyquinoline-6-formamide and cyclopropylamine are subjected to amidation reaction, and the finished product lenvatinib is obtained.The method is short in process route step, operation is simplified, cost is low, and the method is environmentally friendly and suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and in particular relates to a synthesis method of lenvatinib, a new antitumor drug used for treating thyroid cancer. Background technique [0002] The chemical name of Lenvatinib, an oral multireceptor tyrosine kinase (RTK) inhibitor, is 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7- Methoxyquinoline-6-carboxamide, its chemical structural formula is: [0003] [0004] Lenvatinib is a new anti-tumor drug developed by Japan's Eisai (Eisai) for the treatment of thyroid cancer. It is a new type of multi-receptor tyrosine kinase inhibitor with a novel binding mode. In addition to other pro-angiogenic and oncogenic signaling pathway-related RTKs, it can also selectively inhibit the kinase activity of vascular endothelial growth factor (VEGF) receptors. The FDA has approved lenvatinib for the treatment of locally recurrent or metastatic, advanced, radioiodine-re...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/48
CPCC07D215/48
Inventor 李兴民
Owner 湖南欧亚药业有限公司
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