Preparation method of lenvatinib or lenvatinib mesylate impurity

A technology of lenvatinib and mesylate, applied in the field of preparation of process impurities in the production process of lenvatinib or mesylate

Inactive Publication Date: 2019-06-07
YANGTZE RIVER PHARM GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

After searching, no reports on the preparation of impurities A and B were found

Method used

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  • Preparation method of lenvatinib or lenvatinib mesylate impurity
  • Preparation method of lenvatinib or lenvatinib mesylate impurity
  • Preparation method of lenvatinib or lenvatinib mesylate impurity

Examples

Experimental program
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Effect test

Embodiment 1

[0050] Lenvatinib mesylate impurity—preparation of 4-((2-chloro-4-hydroxyphenyl)amino)-7-methoxyquinoline-6-carboxamide

[0051] Add 4-chloro-7-methoxyquinoline-6-amide (10g) and 4-amino-3-chlorophenol hydrochloride (11.5g), potassium iodide (25g) into the reaction flask, add ethanol (150ml) Under stirring, heated to reflux, stirred and reacted for 20 hours, and TLC monitored that the reaction was complete (the developing solvent was dichloromethane:methanol=10:1, 4-((2-chloro-4-hydroxyphenyl)amino)-7-methanol The Rf value of oxyquinoline-6-carboxamide is 0.3), the reaction solution is cooled to room temperature, and water (450ml) is added to stir and crystallize for 2 hours, and 13.5g of the target product is obtained by filtration (mass yield 135%), HPLC purity 98.7 %. MS (ESI): 342.3 [M-H] - .

Embodiment 2

[0053] Lenvatinib mesylate impurity-4-(4-((6-carbamoyl-7-methoxyquinolin-4-yl)amino)-3-chlorophenoxy)-7-methoxy Preparation of quinoline-6-carboxamide

[0054] Weigh 1ml of purified water and add it to the reaction flask, and at the same time weigh potassium hydroxide (0.71g) and add it to the reaction flask, stir until it dissolves, add 9ml of DMSO, and stir to dissolve 4-((2-chloro-4-hydroxybenzene Base) amino)-7-methoxyquinoline-6-formamide (2.18g) and 4-chloro-7-methoxyquinoline-6-amide (1.0g) were added to the reaction flask successively, and the temperature was raised to Stir the reaction at 110°C for 2 hours, and TLC monitors that the reaction is complete (the developing solvent is dichloromethane:isopropanol=20:1,4-(4-((6-carbamoyl-7-methoxyquinoline-4- Base) amino)-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide Rf value 0.2), add 3ml acetone and 27ml purified water in reaction solution, cool to room temperature, stir and crystallize 2 hour, filtered, the filter c...

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Abstract

The invention discloses a preparation method of lenvatinib or a lenvatinib mesylate impurity. The preparation method comprises the following steps: taking 4-chloro-7-methoxyquinoline-6-amide as a rawmaterial to carry out a substitution reaction with 4-amino-3-chlorophenol hydrochloride under the action of a catalyst to obtain 4-((2-chloro-4-hydroxyphenyl)amino)-7-methoxyquinoline-6-formamide. Thelenvatinib or the lenvatinib mesylate impurity is as shown in a formula (I), wherein the definition of R is as shown in the specification. Through the preparation method, the lenvatinib or the lenvatinib mesylate impurity is obtained through chemical synthesis for the first time. In addition, a target compound can be obtained by efficient and quick separation.

Description

technical field [0001] The invention belongs to but not limited to the field of pharmacy, and specifically relates to a method for preparing process impurities in the production process of lenvatinib or its mesylate. Background technique [0002] Lenvatinib mesylate is a multi-targeted tyrosine kinase inhibitor that targets the vascular endothelial growth factor (VEFG) receptors VEGFR1, VEGFR2 and VEGFR3. Lenvatinib also inhibits other tyrosine kinase inhibitors involved in pathological angiogenesis, tumor growth, and cancer progression, including fibroblast growth factor receptors (FGFR) 1-4, platelet-derived growth factor receptor alpha (PDGFRα ), KIT and RET. In vitro tests, it acts most effectively on VEGFR2 and VEGFR3, and has a slightly weaker effect on VEGFR1. The selectivity of VEGFR2.VEGFR3 is about 10 times higher than that of FGFR1 and PDGFRα / β. Lenvatinib mesylate is an orally administered molecularly targeted drug. [0003] The chemical name of lenvatinib mes...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/48
Inventor 范兴宝袁鑫祥徐浩宇刘海峰周崴海郝秀斌黄淑萍李浩冬王竞
Owner YANGTZE RIVER PHARM GRP CO LTD
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