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Preparation method of Afatinib intermediate

A technology of compound and zinc powder, which is applied in the field of preparation of afatinib intermediates, can solve the problems of high production cost, low yield, and easy-to-corrosion reaction kettle, and achieve low production cost, low pollution, and high product yield Effect

Active Publication Date: 2015-12-23
SHINEWAY PHARMA GRP LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The above method uses the Fe-HAc system to complete the reduction reaction. Although it has the advantage of low cost, the reaction kettle is easily corroded during the reaction, a large amount of iron sludge is produced, the target product and other organic substances are seriously adsorbed, and a large amount of methanol and methylene chloride are used for post-treatment. processing, its yield is low, industrial pollution is serious, and production cost is high

Method used

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  • Preparation method of Afatinib intermediate
  • Preparation method of Afatinib intermediate
  • Preparation method of Afatinib intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Take 1.0g (2.47mmol) 4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline, 20mL Add ethanol, 1.5mL glacial acetic acid, and 10mL water into the reaction flask, heat to reflux, add 0.50g (7.69mmol) of zinc powder in batches, keep stirring at reflux for 1h, filter while hot, rinse the filter cake with a small amount of ethanol, and wash the filtrate Distill under reduced pressure until the volume is reduced by about half, then cool naturally to room temperature, add ammonia water dropwise to neutral, filter with suction, rinse the filter cake with 20mL water to obtain off-white solid N 4 -(3-Chloro-4-fluorophenyl)-7-[[(3S)-tetrahydro-3-furyl]oxy]-4,6-quinazolinediamine. After drying and testing, mass: 0.79g, yield: 85.36%, purity 96.09%.

Embodiment 2

[0023] Take 1.0g (2.47mmol) 4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline into 20mL Methanol, take a catalytic amount of calcium chloride dissolved in 10ml of water and add to the reaction flask, stir evenly, add 0.50g (7.69mmol) of zinc powder, keep stirring at reflux for 2h, filter while hot, rinse the filter cake with a small amount of methanol, and combine After the filtrate was poured into 50ml of water, a small amount of 10% NaOH was added dropwise until the solution was weakly alkaline, and solids were precipitated, filtered with suction, and the filter cake was rinsed with 10mL of water to obtain off-white solid N 4 -(3-Chloro-4-fluorophenyl)-7-[[(3S)-tetrahydro-3-furyl]oxy]-4,6-quinazolinediamine. After drying and testing, mass: 0.69g, yield: 74.53%, purity 97.32%.

Embodiment 3

[0025] Take 2.0g (4.94mmol) 4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline, 35mL Add ethanol, 6.5mL of concentrated hydrochloric acid, and 35mL of water into the reaction flask, heat to reflux, and slowly add 1.60g (24.7mmol) of zinc powder in batches. Keep stirring under reflux for 1 hour, filter while it is hot, rinse the filter cake with a small amount of ethanol, distill the filtrate under reduced pressure until the volume is reduced by half, cool naturally to room temperature, add ammonia water dropwise until neutral, filter with suction, and rinse the filter cake with 50mL water washed to give an off-white solid N 4 -(3-Chloro-4-fluorophenyl)-7-[[(3S)-tetrahydro-3-furyl]oxy]-4,6-quinazolinediamine. After drying and testing, mass: 1.55g, yield: 83.72%, purity 97.59%.

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Abstract

The invention provides a preparation method of an Afatinib intermediate and particularly provides a preparation method of N<4>-(3-chloro-4- fluorophenyl)-7-[[(3S)-tetrahydro-3-furyl]oxy]-4,6-quinazoline diamine. According to the method, 4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline, zinc powder and an acidic material are mixed in a mixed solvent of a polar solvent and water for a reduction reaction, a product is filtered and alkalified, and the Afatinib intermediate is obtained. The preparation method has the advantages of high product yield, low pollution degree, low production cost and the like.

Description

technical field [0001] The invention relates to the fields of organic chemistry and medicinal chemistry, in particular to a preparation method of an afatinib intermediate. Background technique [0002] Afatinib is an irreversible inhibitor of epidermal growth factor receptor (EGFR) and human epidermal receptor tyrosine kinase (HER2). It is the first drug for the treatment of lung cancer after failure of EGFR inhibitor therapy. Treatment of advanced non-small cell lung cancer, advanced breast cancer, and bowel cancer. [0003] Patent Document No. WO200250043A1 and WO03094921A2 disclose a preparation method of afatinib: the mother nucleus 4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-fluoroquinazoline ( Compound VII) is used as a raw material, and afatinib dimaleate is obtained through substitution of fluorine atom, reduction of nitro group, amidation reaction of amino group and salt formation. [0004] [0005] Among them, N 4 -(3-Chloro-4-fluorophenyl)-7-[[(3S)-tetrahyd...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/12
CPCC07D405/12
Inventor 康旺余大海
Owner SHINEWAY PHARMA GRP LTD
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