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A kind of preparation method of tyrosine kinase inhibitor and its intermediate

An aminophenol and compound technology, which is applied in the preparation of carboxylic acid amides, the preparation of organic compounds, chemical instruments and methods, etc., can solve the problems of high price and cumbersomeness, and achieve the effects of simple operation, high yield and mild reaction conditions.

Active Publication Date: 2016-05-04
正大天晴(广州)医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This route also needs to use expensive cyclopropane-1,1-dicarboxylic acid, and the first route also increases the step of nitro reduction, which is relatively cumbersome

Method used

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  • A kind of preparation method of tyrosine kinase inhibitor and its intermediate
  • A kind of preparation method of tyrosine kinase inhibitor and its intermediate
  • A kind of preparation method of tyrosine kinase inhibitor and its intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 11

[0066] The preparation of embodiment 11-(ethoxycarbonyl) cyclopropane formic acid

[0067]

[0068] Add 200ml of ethanol and 30g (161mmol) of diethyl 1,1-cyclopropanedicarboxylate into a 500ml three-necked flask, cool to 10°C, add dropwise sodium hydroxide solution (NaOH6.4g, 161mmol; water 32ml) while stirring . After dropping, the mixture was reacted at room temperature for 3 hours. After the reaction was completed, the solvent was evaporated under reduced pressure to obtain a white solid. Add 200ml of water and 100ml of ethyl acetate to the solid, stir and separate the layers, and discard the organic phase. The aqueous layer was adjusted to pH 3-4 with 2mol / L hydrochloric acid, extracted with ethyl acetate (100ml×2), and the ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a colorless translucent oily substance 20.0 g (78.5%).

Embodiment 21

[0069] The preparation of embodiment 21-(methoxycarbonyl) cyclopropanecarboxylic acid

[0070]

[0071] Using the method of Example 1, 1-(methoxycarbonyl)cyclopropanecarboxylic acid was prepared from 1,1-cyclopropanedicarboxylic acid dimethyl ester as a raw material.

Embodiment 31

[0072] Preparation of Example 31-(isopropoxycarbonyl)cyclopropanecarboxylic acid

[0073]

[0074] Using the method of Example 1, 1-(isopropoxycarbonyl)cyclopropanecarboxylic acid was prepared from 1,1-cyclopropanedicarboxylate diisopropyl ester as raw material.

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Abstract

The invention relates to a preparation method for a tyrosine kinase inhibitor and a midbody thereof. According to the method, a compound 1,1-cyclopropane dicarboxylic acid diester is taken as a raw material, and 1-((4-((6,7-dimethoxy quinoline-4-yl) oxy) phenyl) carbamoyl) cyclopropane formic ether is prepared by two ways and reacts with p-fluoro aniline after being hydrolyzed so as to prepare Cabozantinib. The reaction conditions of the preparation method are mild, the synthesis cost is lowered, and the preparation method is simple and convenient to operate and is applicable to industrial production.

Description

technical field [0001] The present invention relates to the fields of organic chemistry and medicinal chemistry, specifically, the present invention relates to N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-N'-( A preparation method of 4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Cabozantinib) and its intermediates. Background technique [0002] Hepatocyte growth factor (HGF) is a cytokine secreted by mesenchymal cells with various biological activities, which can promote the growth, division and morphogenesis of various cells, and participate in angiogenesis and embryonic development. The specific membrane receptor of HGF is a tyrosine kinase receptor encoded by the proto-oncogene c-Met. Abnormal activation of the HGF / c-Met signaling pathway has been found in various tumor tissues. This abnormal activation is involved in and regulates the occurrence, development or metastasis of these tumors. Blocking the HGF / c-Met signaling pathway can effectively inhibit the growth and ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D215/233C07C233/60C07C231/02
CPCA61K31/47
Inventor 史祥飞赵锐孟庆义张喜全
Owner 正大天晴(广州)医药有限公司
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