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Preparation method of lenvatinib

A technology for lenvatinib and synthetic products, which is applied in the field of new preparation of oral tyrosine kinase inhibitor lenvatinib, can solve problems such as harsh reaction conditions, achieve low reaction temperature, novel synthetic route, and no dangerous steps Effect

Pending Publication Date: 2020-04-10
安徽省诚联医药科技有限公司
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Problems solved by technology

[0009] The technical problem to be solved in the present invention is to overcome the relatively harsh defect of the reaction conditions of the preparation method of lenvatinib in the prior art, and provide a new method for the preparation of lenvatinib with low cost and easy operation

Method used

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Experimental program
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Effect test

Embodiment

[0049] Synthesis of S1, 4-nitro-2-methoxybenzonitrile (a)

[0050] Take 181g of 4-nitro-2-chlorobenzonitrile, dissolve it in 300g of methanol, heat and reflux to dissolve, add 300g of 30% sodium methoxide solution dropwise to the system, and drop it for 1 hour. After the drop, keep the reaction system for 12 hours. After the reaction, most of the methanol was recovered under reduced pressure, the residue was poured into ice water, a large amount of yellow solid was precipitated, filtered, the filter cake was washed with water until neutral, and the filter cake was recrystallized with isopropanol to obtain 147 g of yellow solid with a yield of 83%.

[0051] Synthesis of S2, 4-cyano-2-methoxyaniline (b)

[0052]Take 17.8 g of 4-nitro-2-methoxybenzonitrile, dissolve it in 50 ml of ethanol, first replace the air in the system with nitrogen for three times, then pass through the reaction system for hydrogen replacement three times, add 1.5 g of Pd / C, and the system Raise the tempe...

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Abstract

The invention discloses a preparation method of lenvatinib, which comprises the following steps: by using 4-nitro-2-chlorobenzonitrile as an initial raw material, introducing nitro into molecules forelectron withdrawing, thereby greatly lowering the electron cloud density of benzene rings, wherein it is beneficial to nucleophilic substitution reaction and can greatly lower the reaction temperature; carrying out amino protection: taking ZnO as Lewis acid, so that the reaction is green; carrying out Friedel-Crafts acylation, deprotection and intramolecular alkylation cyclization. Compared witha traditional high-temperature reaction, the method is novel in synthetic route, low in reaction temperature, mild in condition, green, free of dangerous steps and suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of lenvatinib, in particular to a new preparation method of oral tyrosine kinase inhibitor lenvatinib. Background technique [0002] Lenvatinib (E7080), the chemical name is 4-(3-chloro-4-(cyclopropylaminocarbonyl) aminophenoxy)-7-methoxy-6-quinoline carboxamide, which is produced by Japan Eisai Co., Ltd. (Eisai), an oral multi-receptor tyrosine kinase inhibitor, is a potential therapeutic drug for thyroid cancer, liver cancer, non-small cell lung cancer and other solid tumors. In February 2013, lenvatinib was granted orphan drug designation by the FDA for the treatment of follicular, myeloid, undifferentiated and metastatic or locally advanced papillary thyroid carcinoma. On February 13, 2015, lenvatinib was approved by the FDA for the treatment of Treatment of radioactive iodine-refractory differentiated thyroid cancer. [0003] The synthesis of lenvatinib is mainly prepared by reacting the intermediate...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/48
CPCC07D215/48Y02P20/55
Inventor 刘辉龚博文冯成亮
Owner 安徽省诚联医药科技有限公司
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