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Preparation method, related intermediate, and application of anti-epidermal growth factor receptor drug-resistance mutation inhibitor

A technology for epidermal growth factor and drug resistance, which is applied in the preparation of novel ectopic inhibitors and the preparation of novel inhibitors against epidermal growth factor receptor drug resistance mutations, and can solve the problem of preparing compounds of formula I that have not been reported in published literature. methods, etc., to achieve the effect of good repeatability, easy purification, and process safety

Active Publication Date: 2018-06-22
SHANGHAI SUNTECH PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Nature 534,129–132 (02 June 2016) publicly reported the compound of formula I and its application in the treatment of lung cancer for the first time, but there is still no published literature reporting the preparation method of the compound of formula I

Method used

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  • Preparation method, related intermediate, and application of anti-epidermal growth factor receptor drug-resistance mutation inhibitor
  • Preparation method, related intermediate, and application of anti-epidermal growth factor receptor drug-resistance mutation inhibitor
  • Preparation method, related intermediate, and application of anti-epidermal growth factor receptor drug-resistance mutation inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Preparation of 2-(5-fluoro-2-hydroxyphenyl)-2-(1-oxa-2,3-dihydro-1H-2-indenyl)acetic acid II

[0026] Add isoindolin-1-one (13g, 1.0eq (equivalent)) into a 250ml three-necked flask, add trifluoroacetic acid (65g) and concentrated sulfuric acid (26g) under stirring, adjust and control the temperature to maintain at 30°C, Glyoxylic acid monohydrate (9 g, 1.0 eq) was added into the reaction system, and the reaction was stirred at 30° C. for 20 hours. After the reaction was detected by TLC, p-fluorophenol (13.1 g, 1.2 eq) was added to the reaction system, and stirred at 30° C. for 50 hours. After the completion of the reaction detected by TLC, the reaction solution was diluted with water (200 g) and added to 20% sodium hydroxide solution (58.5 g), and the temperature of the mixture was controlled at 20° C. The mixture was stirred for 0.5 hours. After the aqueous phase was extracted twice with isopropyl acetate (500 g each), the organic phases were combined. The organic p...

Embodiment 2

[0029] Example 2 Preparation of 2-(carbonylmethylene)-1-oxa-2-isoindolinium (intermediate III)

[0030] Add isoindolin-1-one (6.5g, 1.0eq) into a 250ml three-necked flask, add acetic acid (123g) and concentrated sulfuric acid (13g) while stirring, adjust and control the temperature to keep at 30°C, add Glyoxylic acid monohydrate (9g, 1.0eq), stirred and reacted at 20-30°C for 20 hours. TLC detected that the reaction was completed to obtain 2-(carbonylmethylene)-1-oxa-2-isoindolinium (intermediate III).

Embodiment 3

[0031] Example 3 Preparation of 2-(5-fluoro-2-hydroxyphenyl)-2-(1-oxa-2,3-dihydro-1H-2-indenyl)acetic acid II

[0032] Add isoindolin-1-one (13g, 1.0eq) into a 50ml three-necked flask, add acetic acid (123g) and concentrated sulfuric acid (26g) under stirring, adjust and control the temperature to keep at 20°C, add ethyl alcohol to the reaction system Aldehydic acid monohydrate (9g, 1.0eq), stirred and reacted at 20°C for 16 hours. After the reaction was detected by TLC, p-fluorophenol (13.1 g, 1.2 eq) was added to the reaction system and stirred at 20-30° C. for 45 hours. After the reaction was detected by TLC, the reaction solution was diluted with water (200 g) and added to 20% sodium hydroxide solution (58.5 g), and the temperature of the mixture was controlled at 10°C. The mixture was stirred for 0.5 hours. After the aqueous phase was extracted twice with isopropyl acetate (500 g each), the organic phases were combined. The organic phase was dried over anhydrous sodium...

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Abstract

The invention provides a preparation method of an anti-epidermal growth factor receptor drug-resistance mutation inhibitor, 2-(5-fluoro-2-hydroxyphenyl)-2-(isoindoline-1-one)-N-(2-thiazolyl)acetamide(I). The method includes steps of: performing an acid catalytic reaction to isoindoline-1-one, a glyoxylic acid hydrate, and p-fluorophenol in an acidic solvent to obtain a novel intermediate compound(II): 2-(5-fluoro-2-hydroxyphenyl)-2-(1-oxo-2,3-dihydro-1H-2-indenyl)acetic acid; and then performing a condensation reaction with 2-aminothiazole to obtain the compound (I). The method has short reaction route, simple operation, safe processes, high yield, gentle conditions, good repeatability and low cost, is suitable for industrial production and has great application value.

Description

technical field [0001] The present invention relates to the field of drug synthesis, in particular to a preparation method of a novel anti-epidermal growth factor receptor mutation inhibitor (EAI045), in particular to a novel ectopic anti-epidermal growth factor receptor mutation-resistant lung cancer Preparation methods of inhibitors, preparation of related intermediates and applications thereof. Background technique [0002] A novel ectopic inhibitor (EAI045) of anti-epidermal growth factor receptor (EGFR) drug-resistant mutant lung cancer, the molecular formula of which is C 19 h 14 FN 3 o 3 S, CAS number: 1942114-09-1, Chinese name is 2-(5-fluoro-2-hydroxyphenyl)-2-(isoindoline-1-one)-N-(-2-thiazole Base) acetamide; English name: [0003] 2-(5-fluoro-2-hydroxyphenyl)-2-(1-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide; its structural formula is shown in formula I: [0004] [0005] The compound represented by formula I is currently the first inhibitor in the worl...

Claims

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Application Information

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IPC IPC(8): C07D417/12C07D209/46A61P35/00
CPCC07D209/46C07D417/12
Inventor 刘学军郭利军郝璐刘辉陈晓冬
Owner SHANGHAI SUNTECH PHARMA
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