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The preparation method of afatinib dimaleate

A technology of afatinib and acetic acid, applied in the preparation of carboxylate, organic chemistry and other directions, can solve the problems of many steps and difficult process control, and achieve the effects of convenient preparation, short route and lower production cost.

Active Publication Date: 2019-05-03
JIANGSU HANSOH PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] It can be seen from this that the preparation technology of afatinib has the defects of many steps and difficult process control. Finding a new preparation method suitable for industrialization is very important for the economic and technological development of this drug.

Method used

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  • The preparation method of afatinib dimaleate
  • The preparation method of afatinib dimaleate
  • The preparation method of afatinib dimaleate

Examples

Experimental program
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Effect test

Embodiment 1

[0028] At low temperature, add 27.0 g of potassium tert-butoxide into a 500 ml single-necked bottle, stir 100 ml of DMF until dissolved, add 5.5 g of (S)-3-hydroxy-tetrahydrofuran, and keep stirring for one hour. 10 g of compound (II) was added. Keep warm and stir for 2 hours. Add 300ml of water, adjust pH=6-7 with 1.3M hydrochloric acid, stir overnight, filter with suction, and dry to obtain 13g.

Embodiment 2

[0030] Add 4.1g of compound (III) to 66ml of ethanol, 33ml of water and 10ml of acetic acid, heat the oil bath to reflux, add 3.9g of iron powder, and the reaction solution releases gas. It was detected by TLC that the starting material disappeared. Diatomaceous earth filter aid. Prepare a mixed solvent of dichloromethane:methanol=9:1, stir and wash the reaction solution 3 times with 300ml. The combined organic phases were separated, dried, filtered, and concentrated to obtain 3.3 g.

Embodiment 3

[0032] Add 4.135g of CDI and 30ml of THF to a 500ml single-necked bottle in sequence, and stir at 40°C until it dissolves. Add 5 g of diethylphosphonoacetic acid and wash with 7.5 ml of THF. The reaction solution was exothermic, and after stirring for 30 minutes, 5 g of compound (IV) was added. The reaction solution was refluxed, and the TLC reaction was completed. Cool to room temperature, add 300ml of MTBE, stir, filter with suction, and dry under vacuum at room temperature to obtain 9g.

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Abstract

The invention relates to a preparation method of afatinib dimaleate, and concretely relates to a preparation method of an antitumor medicine afatinib dimaleate. The method comprises the following steps: carrying out a substitution reaction on 6-amino-7-fluoro-3,4-dihydroquinazolin-4-one and (S)-3-hydroxytetrahydrofuran, reducing, amidating, condensing, and carrying out salt formation to prepare afatinib dimaleate with the structure represented by formula (I). The preparation method has the advantages of concise technology, economy, environmental protection, and suitableness for industrial production.

Description

technical field [0001] The present invention relates to the fields of organic chemistry and medicinal chemistry, in particular to 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo The preparation method of -2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline dimaleate. Background technique [0002] Afatinib is a multi-targeted oral small-molecule drug developed by Boehringer Ingelheim in Germany, which is an irreversible inhibitor of epidermal growth factor receptor (EGFR) and human epidermal receptor 2 (HER2) tyrosine kinases. Inhibitors. It is a second-generation highly potent dual irreversible tyrosine kinase inhibitor. The drug was approved by the US FDA on July 12, 2013. The trade name is Tovok. [0003] Afatinib dimaleate (I), the chemical name is 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino) )-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline dimaleate. [0004] [0005] There are currently two m...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D405/12C07C57/145C07C51/41
CPCC07D405/12
Inventor 陈安丰杨勇张亮
Owner JIANGSU HANSOH PHARMA CO LTD
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