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Preparation method of 6, 7-dimethoxy quinazoline-4-ketone

A technology of dimethoxyquinazoline and dimethoxyindoline, which is applied in the field of preparation of 6,7-dimethoxyquinazolin-4-one, can solve problems such as high risk, and achieve Improve safety, yield and quality, and reduce costs

Active Publication Date: 2010-06-30
安徽尖峰北卡药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The above-mentioned nitration and hydrogenation reduction process of nitro all have higher risk

Method used

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  • Preparation method of 6, 7-dimethoxy quinazoline-4-ketone

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Experimental program
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Effect test

Embodiment 1

[0042] Preparation of Intermediate I:

[0043] Add 10.0L of water, 0.64kg of chloral hydrate, and 9.1kg of anhydrous sodium sulfate into the reaction kettle, and raise the temperature to 30°C for use.

[0044] Dissolve 0.53kg of 3,4-dimethoxyaniline and 0.78kg of hydroxylamine hydrochloride in 6L of 6.23% dilute hydrochloric acid (v / v), and stir to clarify. Control the temperature below 30°C, add the solution dropwise into the reaction kettle, raise the temperature to 70°C after dropping, and react for 4 hours. TLC monitoring (developer: petroleum ether / ethyl acetate = 2 / 1), filtered after the reaction was complete, washed the filter cake three times with water (0.5L×3), recrystallized with 2.0L ethanol, and filtered. The obtained solid was air-dried at 70° C. for 6 hours to obtain 0.43 kg of an off-white solid, which was the product, and the yield was 55.0%. The H-NMR spectrum identified the product as 2-oximino-N-(3,4-dimethoxyphenyl)acetamide.

[0045] Preparation of Int...

Embodiment 2

[0052] Preparation of Intermediate I:

[0053] Add 5.0L of water, 0.86kg of chloral hydrate, and 5.0kg of anhydrous sodium sulfate into the reaction kettle, and raise the temperature to 40°C for use. Dissolve 0.53 kg of 3,4-dimethoxyaniline and 0.96 kg of hydroxylamine hydrochloride in 6 L of 10% dilute hydrochloric acid (v / v), and stir to clarify. Control the temperature below 40°C, add the solution dropwise into the reaction kettle, raise the temperature to reflux at 100°C after dropping, and react for 3 hours. TLC monitoring (developer: petroleum ether / ethyl acetate = 2 / 1), filtered after the reaction was complete, washed the filter cake three times with water (0.5L×3), recrystallized with 2.5L ethanol, and filtered. The obtained solid was air-dried at 70° C. for 6 hours to obtain 0.40 kg of an off-white solid, which was the product, and the yield was 51.6%. The H-NMR spectrum identified the product as 2-oximino-N-(3,4-dimethoxyphenyl)acetamide.

[0054] Preparation of I...

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Abstract

The invention provides a preparation method of 6, 7-dimethoxy quinazoline-4-ketone, comprising the following steps of: acylating the amino of 3, 4-dimethoxyaniline as the raw material to generate 2-oximido-N-(3, 4-dimethoxy phenyl) acetamide; (b) cyclizing the 2-oximido-N-(3, 4-dimethoxy phenyl) acetamide to form 5, 6-dimethoxy indoline-2, 3-diketone; (c) decyclizing the 5, 6-dimethoxy indoline-2, 3-diketone to form carboxylic acid and generate 2-amino-4, 5 dimethoxy benzoic acid; and (d) enabling the 2-amino-4, 5 dimethoxy benzoic acid to form a molecule lactam ring and generate 6, 7-dimethoxy quinazoline-4-ketone. The preparation method prevents N from being introduced through nitration and hydrogenation reduction, greatly enhances the reaction safety, has most aqueous-phase reaction and mild condition in the reaction process, very easy and convenient post-processing and easy industrialized production.

Description

technical field [0001] The invention relates to a preparation method of 6,7-dimethoxyquinazolin-4-one, an important synthetic intermediate of erlotinib hydrochloride and gefitinib. Background technique [0002] Erlotinib Hydrochloride (Erlotinib Hydrochloride), jointly developed by Genetech, OSI, and Roche, and produced by Roche (Roche), is used to treat locally advanced or metastatic non-small cell lung cancer that has failed at least one chemotherapy regimen (NSCLC) innovative medicine. It was approved by the US FDA in November 2004, approved by the European Union in September 2005, and launched in China in April 2006. FDA also approved the combination of erlotinib and gemcitabine for the treatment of advanced pancreatic cancer in 2005, becoming the first approved drug for the treatment of advanced pancreatic cancer in the past 10 years. [0003] Gefitinib (Gefitinib) is a new type of antineoplastic drug developed by AstraZeneca. It is an orally available small molecule ...

Claims

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Application Information

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IPC IPC(8): C07D239/88
Inventor 孙婧吕伟张五军张平李倩康立涛
Owner 安徽尖峰北卡药业有限公司
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