Preparation method for erlotinib hydrochloride impurity

A technology for erlotinib hydrochloride and impurities, applied in the field of medicinal chemistry, can solve problems such as no public reports, and achieve the effects of improving quality standards, short synthesis routes, and simple operations

Active Publication Date: 2014-08-27
NINGBO MENOVO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The present invention provides a kind of preparation method of erlotinib hydrochloride impurity N-(3-vinylphenyl)-[6,7-bis-(2-methoxyethoxy)]-quinolineamine

Method used

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  • Preparation method for erlotinib hydrochloride impurity
  • Preparation method for erlotinib hydrochloride impurity
  • Preparation method for erlotinib hydrochloride impurity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Step (1): In a 5ml reaction flask, add 100mg of 6,7-bis-(2-methoxyethoxy)-4(3H)-quinazolinone, 240mg of thionyl chloride and 2ml of toluene in sequence, Slowly heat up to 50°C under stirring, the reaction lasts for 3h under stirring, then turn off the heating, and cool to room temperature under stirring, then add 1ml of water to the reactor to quench the reaction, separate the organic layer and use saturated chlorinated Wash it with sodium aqueous solution, dry it with anhydrous sodium sulfate, and finally concentrate to obtain 102 mg of a light yellow solid. After identification, the main component of the light yellow solid is 4-chloro-6,7-bis-(2-methoxy Ethoxy)-quinazoline, the yield is 96%;

[0026] Step (2): In a 5ml reaction bottle, add 100mg of 4-chloro-6,7-bis-(2-methoxyethoxy)-quinazoline and 76mg of m-amino Styrene and 3ml of ethyl acetate were slowly heated to 70°C under stirring, the reaction was continued for 3 hours under stirring, then the heating was tur...

Embodiment 2

[0029] Step (1): In a 25ml reaction flask, add 1.00g of 6,7-bis-(2-methoxyethoxy)-4(3H)-quinazolinone, 2.59g of oxalyl chloride and 15ml of tetrahydrofuran in sequence, Slowly heat up to 65°C under stirring, the reaction is continued for 3h under stirring, then turn off the heating, and cool to room temperature under stirring, then add 1ml of water to the reactor to quench the reaction, separate the organic layer and use saturated chlorinated Wash it with an aqueous sodium solution, dry it with anhydrous sodium sulfate, and finally concentrate to obtain 1.34 g of a light yellow solid. After identification, the main component of the light yellow solid is 4-chloro-6,7-bis-(2-methyl Oxyethoxy)-quinazoline, the yield is 97%;

[0030] Step (2): In a 25ml reaction bottle, add 1.00g of 4-chloro-6,7-bis-(2-methoxyethoxy)-quinazoline and 1.12g obtained in step (1) successively m-aminostyrene and 20ml of toluene, slowly heated up to 120°C under stirring, the reaction was continued for ...

Embodiment 3

[0036] Step (1): In a 250ml reaction flask, add 10g of 6,7-bis-(2-methoxyethoxy)-4(3H)-quinazolinone, 20.8g of phosphorus oxychloride and 200ml of toluene in sequence , slowly heated up to 80°C under stirring, the reaction was continued for 3h under stirring, then the heating was turned off, and cooled to room temperature under stirring, then 50ml of water was added to the reactor to quench the reaction, the organic layer was separated and washed with saturated chlorine Wash it with sodium chloride aqueous solution, dry it with anhydrous sodium sulfate, and finally concentrate to obtain 10.2 g of a light yellow solid. After identification, the main component of the light yellow solid is 4-chloro-6,7-bis-(2- Methoxyethoxy)-quinazoline, the yield is 96%;

[0037] Step (2): In a 250ml reaction bottle, add 10g of 4-chloro-6,7-bis-(2-methoxyethoxy)-quinazoline obtained in step (1) and 7.49g of Aminostyrene and 200ml of ethanol are slowly heated to 60°C under stirring, the reaction...

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Abstract

The present invention relates to a preparation method for an erlotinib hydrochloride impurity N-(3-vinyl-phenyl)--quinolineamine hydrochloride. Firstly, 6,7-bis-(2-methoxyethoxy)-4(3H)-quinazolinone reacts with an acylating reagent to obtain 4-chloro-6,7-bis-(2-methoxyethoxy)-quinazoline, then the 4-chloro-6,7-bis-(2-methoxyethoxy)-quinazoline reacts with m-aminostyrene to generate the target product N-(3-vinyl-phenyl)--quinolineamine hydrochloride. The present method has characteristics of a short synthetic route, simple operation and high product purity up to 99.77%, and provides conditions for the qualitative and quantitative analysis of impurity in the production of erlotinib hydrochloride, thereby further improving the quality standards of erlotinib hydrochloride and providing guidance for safe medication of people.

Description

technical field [0001] The present invention relates to the technical field of medicinal chemistry, especially the field of preparation method of erlotinib hydrochloride impurity, specifically refers to a kind of N-(3-vinylphenyl)-[6,7-bis-(2-methoxyethoxy) )]-the preparation method of quinoline amine hydrochloride. Background technique [0002] Erlotinib hydrochloride is the 4-aminophenylquinazoline oral antineoplastic drug developed by U.S. SOI Pharmaceuticals company. Its English name is Erlotinib Hydrochloride, and its chemical name is N-(3-ethynylphenyl)-[6,7 -two-(2-methoxyethoxy)]-quinolinamine hydrochloride, the structural formula is as follows: [0003] [0004] Erlotinib hydrochloride was first launched in the United States in 2004 for the treatment of pancreatic cancer and metastatic non-small cell lung cancer. It is currently the only targeted anticancer drug in the world that has been proven to significantly prolong the life of patients and improve their qua...

Claims

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Application Information

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IPC IPC(8): C07D239/94
CPCC07D239/94
Inventor 居鸿江吴禹伟张萍陈海荣姚成志
Owner NINGBO MENOVO PHARMA
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