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Preparation method of Cabozantinib

A technology of cabozantinib and compounds, which is applied in the field of synthesis of cabozantinib and its intermediates, and can solve the problems of cumbersome operation, high cost, and low industrial production efficiency

Active Publication Date: 2019-07-09
JIANGSU HANSOH PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method is costly, complicated to operate, and industrial production efficiency is low

Method used

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  • Preparation method of Cabozantinib
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  • Preparation method of Cabozantinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Example 1 Preparation of 4-((6,7-dimethoxy-4-yl)oxy)aniline

[0028]

[0029] Add 4-chloro-6,7-dimethoxyquinoline (10g, 0.045mol, 1.0eq.), 4-aminophenol (6.9g, 0.063mol, 1.4eq.) to 50mL N,N-dimethyl In dimethylacetamide, cool down to 0°C, slowly add a suspension of sodium tert-butoxide (6.1g, 0.063mol, 1.4eq.) and 50mL N,N-dimethylacetamide, after the addition is complete, heat up to 100°C , reacted for 5 hours, cooled the reaction liquid to 0°C, added 400 mL of purified water, stirred and crystallized for 15-16 hours. Stop stirring, filter, and wash the filter cake with 20 mL of purified water to obtain 11.2 g of 4-((6,7-dimethoxy-4-yl)oxy)aniline with a yield of 84.5% and a purity of 99.1%.

[0030] MS(ESI): m / z 297.20[M+H] + .

[0031] 1 H NMR (DMSO-d 6 ,400MHz): δ3.94(s,6H),5.19(s,2H),6.38(d,J=2.8Hz,1H),6.68(d,J=8.4Hz,2H),6.93(d,J= 8.8Hz, 2H), 7.37(s, 1H), 7.51(s, 1H), 8.43(d, J=5.2Hz, 1H).

Embodiment 2

[0032] Example 2 Preparation of 4-((6,7-dimethoxy-4-yl)oxy)aniline

[0033]

[0034] Add 4-chloro-6,7-dimethoxyquinoline (10g, 0.045mol, 1.0eq.), 4-aminophenol (6.9g, 0.063mol, 1.4eq.) to 50mL N,N-dimethyl In dimethylacetamide, cool down to 0°C, slowly add a suspension of sodium tert-butoxide (6.1g, 0.063mol, 1.4eq.) and 50mL N,N-dimethylacetamide, after the addition is complete, heat up to 110°C , reacted for 4 hours, cooled the reaction solution to 0°C, added 400 mL of purified water, stirred and crystallized for 15-16 hours. Stop stirring, filter, and wash the filter cake with 20 mL of purified water to obtain 11.5 g of 4-((6,7-dimethoxy-4-yl)oxy)aniline with a yield of 86.8% and a purity of 99.2%.

[0035] The mass spectrum and hydrogen spectrum data are basically consistent with Example 1.

Embodiment 3

[0036] Example 3 Preparation of 4-((6,7-dimethoxy-4-yl)oxy)aniline

[0037]

[0038] Add 4-chloro-6,7-dimethoxyquinoline (10g, 0.045mol, 1.0eq.), 4-aminophenol (6.9g, 0.063mol, 1.4eq.) to 50mL N,N-dimethyl In acetamide, cool down to 0°C, slowly add a suspension of potassium tert-butoxide (7.1g, 0.063mol, 1.4eq.) and 50mL N,N-dimethylacetamide, after the addition is complete, heat up to 100°C , reacted for 5 hours, cooled the reaction liquid to 0°C, added 400 mL of purified water, stirred and crystallized for 15-16 hours. Stop stirring, filter, and wash the filter cake with 20 mL of purified water to obtain 10.9 g of 4-((6,7-dimethoxy-4-yl)oxy)aniline, with a yield of 82.3% and a purity of 99.1%.

[0039] The mass spectrum and hydrogen spectrum data are basically consistent with Example 1.

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PUM

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Abstract

The invention relates to a preparation method of Cabozantinib, and belongs to the field of pharmaceutical chemistry. The Cabozantinib compound is prepared through two steps. The preparation method comprises following steps: 1, a compound III and a compound VI are subjected to condensation reaction to prepare a compound V; and 2, the compound V and p-fluoroaniline are subjected to condensation reaction to prepare Cabozantinib. The preparation method possesses following characteristics: operation is simple and convenient; reaction conditions are mild; yield is high; and industrial applications are convenient.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and organic chemistry, and specifically relates to the synthesis of cabozantinib and its intermediates. Background technique [0002] Cabozantinib, the chemical name is cyclopropane-1,1-dicarboxylic acid [4-(6,7-dimethoxyquinolin-4-yloxy)-phenyl]-amide (4-fluorophenyl )-amide, the structure is as shown in formula I. [0003] [0004] Cabozantinib is a multi-target tyrosine kinase inhibitor targeting MET, VEGFR2, AXL, Tie2, KIT, FLT3 and RET developed by Exelixis. In January 2013, it was first launched in the United States with the indication of progressive and metastatic medullary thyroid carcinoma, and it was approved in Europe in March 2014; on April 2, 2016, the new indication of renal cell carcinoma was approved in the United States. According to IMS statistics, cabozantinib sold US$2.206 million in Europe in 2015, an increase of 426% over 2014. Thomson forecasts U.S. sales of $400 mil...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/22
CPCC07D215/22
Inventor 张丰盈葛广存刘普根张长华袁恒立
Owner JIANGSU HANSOH PHARMA CO LTD
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