Preparation method of lenvatinib

A technology of lenvatinib and compounds, applied in the field of preparation of lenvatinib, can solve the problems of impurities, amino protection, toxic large phenol, etc., and achieve the effects of good quality, low energy consumption, and simple and easy-to-obtain raw materials

Active Publication Date: 2018-10-09
YANCHENG TEACHERS UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Investigating the above two synthetic routes A and B, although lenvatinib can be prepared, the raw materials d and e in routes A and B do not protect the amino group, which will produce impurities; route B uses chlorine with certain toxicity Phenyl formate is used as a raw material to produce toxic phenol in the subsequent reaction

Method used

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  • Preparation method of lenvatinib
  • Preparation method of lenvatinib
  • Preparation method of lenvatinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Example 1: Preparation of 4-(3-chloro-4-nitrophenoxy)-7-methoxyquinoline-6-carboxamide compound C

[0056]

[0057] A (23.6 g, 0.1 mol), B (19.4 g, 0.11 mol) and cesium carbonate (91.2 g, 0.28 mol) were added to 250 ml of dimethyl sulfoxide, and heated and stirred at 90° C. for 10 hours. The reaction solution was lowered to room temperature, poured into 750ml of water, stirred for 30 minutes, filtered and dried to obtain 35.36g of compound (C). (yield is 94.6%)

Embodiment 2

[0058] Example 2: Preparation of 4-(3-chloro-4-nitrophenoxy)-7-methoxyquinoline-6-carboxamide compound C

[0059] Add A (23.6 g, 0.1 mol), B (20.83 g, 0.12 mol) and cesium carbonate (97.75 g, 0.3 mol) to 250 ml of dimethyl sulfoxide, and heat and stir at 95° C. for 8 hours. The reaction solution was cooled to room temperature, poured into 750 ml of water, stirred for 30 minutes, filtered and dried to obtain 34.57 g of the title compound (C). (yield is 92.5%)

Embodiment 3

[0060] Example 3: Preparation of 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide compound D

[0061]

[0062] Compound C (10g, 26.7mmol) was dissolved in methanol (50ml), added 10% Pd / C (1.0g), and washed with H 2 Replacement reaction system four times, in H 2 Stir overnight at room temperature under ambient (0.5MPa), TLC analysis, the reaction is complete, the reaction solution is filtered with diatomaceous earth, and the filtrate is concentrated under reduced pressure to obtain 9.114g of compound D, with a yield of 99.3%.

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PUM

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Abstract

The invention relates to a preparation method of lenvatinib, and belongs to the field of medicine chemistry. The preparation method of lenvatinib uses a brand-new preparation scheme; a target compoundmeeting the requirement can be obtained no matter from which intermediates. The method provided by the invention has the advantages that the steps are short; the reaction operation is simple; the safety and the reliability are realized; the yield is high; the cost is low; the purity is high; the pollution is low; the operation is simple, and the like. The total yield of lenvatinib can reach about84 percent; the purity can reach 99.7 percent.

Description

technical field [0001] The invention relates to a preparation method of lenvatinib, which belongs to the field of medicine and chemical industry. Background technique [0002] Lenvatinib is an orally effective multi-kinase inhibitor developed by Japan Eisai Company, which mainly acts on multiple targets such as c-Kit, Ret and VEGFR-2, and is used for the treatment of glioma , thyroid tumors, kidney cancer, liver cancer and ovarian cancer and other solid tumors. In February 2013, it was approved as an orphan drug by the US FDA, and it is clinically used for the treatment of follicular, medullary, undifferentiated metastatic or locally advanced papillary thyroid carcinoma. [0003] The chemical name of lenvatinib is: 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide, and its structure is as follows: [0004] [0005] The preparation of lenvatinib has been disclosed in the prior art, such as CN1478078 and CN1878751, EP1683785A1, EP16986...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/48
CPCC07D215/48
Inventor 孙雅泉张立洁顾慧雯陈志远杨康纵朝阳
Owner YANCHENG TEACHERS UNIV
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