Preparation method of Cabozantinib

A technology of cabozantinib and compounds, which is applied in the fields of medicinal chemistry and organic chemistry, can solve the problems of cumbersome operation and low industrial production efficiency, and achieve the effects of low reaction cost, convenient operation and simple preparation method

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

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Problems solved by technology

The method uses thionyl chloride post-treatment operation is loaded d

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

[0034] Example 1 Preparation of 4-((6,7-dimethoxy-4-yl)oxy)aniline

[0035]

[0036] 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%.

[0037] MS(ESI): m / z 297.20[M+H] + .

[0038] 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

[0039] Example 2 Preparation of 4-((6,7-dimethoxy-4-yl)oxy)aniline

[0040]

[0041] 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 11.8 g of 4-((6,7-dimethoxy-4-yl)oxy)aniline, with a yield of 89.1% and a purity of 99.1%.

[0042] The mass spectrum and hydrogen spectrum data are basically consistent with Example 1.

Embodiment 3

[0043] Example 3 Preparation of 4-((6,7-dimethoxy-4-yl)oxy)aniline

[0044]

[0045] 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 11.1 g of 4-((6,7-dimethoxy-4-yl)oxy)aniline with a yield of 83.8% and a purity of 99.2%.

[0046] The mass spectrum and hydrogen spectrum data are basically consistent with Example 1.

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Abstract

The invention belongs to the field of pharmaceutical chemistry, and relates to a preparation method of Cabozantinib. The preparation method comprises following steps: 4-halogenated-6, 7-dimethoxyquinoline is reacted with 4-aminophenol to prepare a compound represented by formula III; cyclopropane-1, 1-dicarboxylic acid/ester and p-fluoroaniline are reacted to prepare a compound represented by formula V; and then condensation reaction is carried out to obtain the Cabozantinib compound. The preparation method is simple and convenient in operation, high in yield, low in cost, and promising in industrialization prospect.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and organic chemistry, in particular to cyclopropane-1,1-dicarboxylic acid [4-(6,7-dimethoxyquinolin-4-yloxy)-phenyl]-amide (4 Synthesis of -fluorophenyl)-amide (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-receptor tyrosine kinase inhibitor (tyrosinekinases inhibitor) developed by Exelixis, targeting RET, MET, VEGFR-1, -2, -3, KIT, TRKB, FLT-3, AXL, TIE-2, etc. Tyrosine kinases play a very important role in the occurrence and development of tumors. The research and development of drugs targeting tyrosine kinases has become a hot spot in the research of anti-tumor drugs in the world. Tyrosinase inhibitors achieve anti-tumor effects by inhibiting...

Claims

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Application Information

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IPC IPC(8): C07D215/22
CPCC07D215/22
Inventor 葛广存张长华张景乐刘普根袁恒立
Owner JIANGSU HANSOH PHARMA CO LTD
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