Synthesis method of lenvatinib and new intermediate

Abstract

The invention discloses a synthesis method of lenvatinib and a new intermediate. The method comprises the following steps: step 1, taking 4-amino-3-chlorophenol hydrochloride and 4-chloro-7-methoxy-6-amido quinoline as initial raw materials, and carrying out a condensation reaction, so as to obtain a target product 4-(4-amino-3-chloro-phenoxy)-7-methoxy-6-carboxamide quinoline; carrying out amidation reaction on the obtained product and phenyl chloroformate to obtain 4-(4-(phenoxycarbonyl) amino-3-chloro-phenoxy)-7-methoxy-6-formamide quinoline, carrying out amidation reaction on the 4-(4-(phenoxycarbonyl) amino-3-chloro-phenoxy)-7-methoxy-6-formamide quinoline and cyclopropylamine to form urea to obtain lenvatinib, and carrying out salifying reaction with methanesulfonic acid to obtain lenvatinib mesylate. The synthesis method has few steps, is simple and convenient to operate, and omits Boc protection and deprotection steps by selecting a solvent. In the research process, it is foundthat for the reaction in the first step, a new compound 4-(4-hydroxy-2-chloro-anilino)-7-methoxy-6-carboxamide quinoline is obtained in a high-yield mode by replacing a solvent.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a synthesis method, a process route, and a new intermediate found in the synthesis process of lenvatinib. Background technique [0002] Lenvatinib is a variety of tyrosine kinase RTKs inhibitors developed by Japan's Eisai Company. It has inhibitory effect on VEGFR1, VEGFR2, VEGFR3, FGFR, PDGFRKIT, RET, and can inhibit tumor progression. For thyroid cancer and unresectable hepatocellular carcinoma. [0003] The chemical name of lenvatinib is 4-(4-(cyclopropylaminocarbonyl)amino-3-chloro-phenoxy)-7-methoxy-6-carboxamidoquinoline, molecular formula: C 21 h 19 ClN 4 o 4 , CAS number: 417716-92-8, the structural formula is as follows: [0004] [0005] The synthesis route and preparation method of lenvatinib have been reported: the route mentioned in the patent CN 104876864 A has the disadvantage of long synthesis process route and involves Boc protection and dep...

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Problems solved by technology

[0011] The synthesis route of lenvatinib is also reported in the patent: CN 106660964 A, but this route does not separate and purify the intermediate, but directly carries out the next step reaction with a one-pot method, thus removing the salt-forming step, The route has only two steps

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