Preparation method of lenvatinib

A technology of lenvatinib and compounds, applied in the field of drug synthesis, can solve the problems of many reaction steps, long reaction time, and difficult post-processing, and achieve the effects of less difficult-to-remove impurities, convenient research, and convenient quality control

Active Publication Date: 2016-10-05
CHIA TAI TIANQING PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] Considering the above two synthetic routes of A and B, although lenvatinib can be prepared, t

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

[0032] Embodiment 1: the preparation of compound m

[0033]

[0034] At 25°C, N,N'-carbonyldiimidazole (1g, 6.1mmol) was stirred and dissolved in dichloromethane (10ml), and cyclopropylamine (0.35g, 6.1mmol) was slowly added dropwise, and the reaction was monitored by TLC. The reaction solution was washed with water (5ml×2), the organic phase was dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain compound m (0.77g) with a yield of 82.5%.

[0035] ESI-MS[M+H] + :152.0821.

[0036] 1 H NMR (300MHz, DMSO-d6): δ8.5139(s,1H),8.1999(s,1H),7.6316(s,1H),7.0034(s,1H),2.7471(m,1H),0.7363(m ,2H),0.6111(m,2H).

[0037] 13 C NMR (75 MHz, DMSO-d6): δ 149.60, 135.81, 129.38, 116.52, 23.12, 5.67.

Embodiment 2

[0038] Embodiment 2: the preparation of lenvatinib

[0039]

[0040] Add 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (compound g) (1 g, 2.9 mmol) and compound m (0.44 g, 2.9 mmol) into the reaction vessel mmol), then add DMF (10ml), stir and dissolve at 25°C, add N,N'-diisopropylethylamine (0.75g, 5.8mmol) after complete dissolution, the reaction solution is slowly heated to 85°C, monitored by TLC The reaction is over. Add water (50ml) and stir, filter, wash the filter cake with water, and dry to obtain Delvatinib (1.1g), the yield is 88.6%. Purity: 98.7%.

[0041] ESI-MS[M+H] + :427.1144.

[0042] 1 H NMR (300MHz, DMSO-d6): δ8.6755(s, 2H), 8.2794(d, J=9.1Hz, 1H), 7.9722(s, 1H), 7.8388(s, 1H), 7.7132(s, 1H ), 7.5209(m, 1H), 7.4876(d, J=2.6Hz, 1H), 7.2442(dd, J=2.6, 9.1Hz, 1H), 7.1869(d, J=2.6Hz, 1H), 6.5360(d , J=5.2Hz, 1H), 4.0376(s, 3H), 2.5736(m, 1H), 0.6723(m, 2H), 0.4370(m, 2H).

[0043] 13 C NMR(75MHz,DMSO-d6):δ165.71,161.49,158.00,155.41,153...

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Abstract

The invention relates to a preparation method of lenvatinib, in particular to the preparation of lenvatinib through a one-step urea forming reaction. The preparation method of lenvatinib according to the present invention produces less difficult-to-remove impurities, facilitates post-processing, facilitates the quality control of raw material drug production, and also provides convenience for subsequent research on preparations.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and relates to a preparation method of lenvatinib, in particular to the preparation of lenvatinib through a one-step urea forming reaction. Background technique [0002] Lenvatinib is an oral polytyrosine kinase inhibitor developed by Japan's Eisai Company, which targets vascular endothelial growth factor receptor (VEGFR) 1-3, fibroblast growth factor receptor (FGFR) 1-3, stem cell growth factor receptor and beta-type platelet-derived growth factor receptor (PDGFR). Lenvatinib has antitumor activity and is the first choice for differentiated thyroid cancer that cannot be treated with radioactive iodine. It is currently in phase III clinical trials. In August 2012, it was awarded Orphan Drug (ODD) for the treatment of thyroid cancer in Japan; in February 2013, it was granted Orphan Drug Designation by the US FDA for the treatment of follicular, medullary, undifferentiated metastatic or locally advan...

Claims

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Application Information

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IPC IPC(8): C07D215/48C07D233/56
Inventor 朱益忠张喜全刘飞顾红梅汤剑秋朱波汤松王路路
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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