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Afatinib preparation method

A technology of afatinib and amino, which is applied in the field of preparation of afatinib, can solve the problems of unsuitable industrialization requirements, many steps, low total yield, etc., and achieve the promotion of development, simple process, and easy availability of raw materials Effect

Active Publication Date: 2015-03-25
铜陵尚东高新科创有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method has many steps, the raw materials are not easy to obtain, the total yield is low, and most of the steps need to be separated and purified by column chromatography, so it is not suitable for the requirements of industrialization

Method used

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Experimental program
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Embodiment 1

[0027] At room temperature, add diisopropyl azodicarboxylate (3mL, 15mmol) and 5mL of tetrahydrofuran into a 100mL three-necked flask, add dropwise a solution of triphenylphosphine (4.0g, 15mmol) in 25mL of tetrahydrofuran at room temperature, and keep at room temperature for reaction 2 Hour. Under nitrogen protection, (S)-3-hydroxytetrahydrofuran (0.3g, 3.4mmol) in tetrahydrofuran 5mL solution was added dropwise to the above reaction system, after the addition was complete, 4-chloro-6-amino-7- Hydroxyquinazoline (II) (0.59 g, 3.0 mmol), stirred at room temperature for 4 hours. A 5 mL solution of (S)-3-hydroxytetrahydrofuran (0.23 g, 2.6 mmol) in tetrahydrofuran was added dropwise, and the reaction was continued at room temperature for 2 hours, and the reaction was completed by TLC monitoring. The solvent was recovered by distillation under reduced pressure, the residue was adjusted to pH=5-6 with dilute hydrochloric acid, extracted with ethyl acetate, and the organic phase w...

Embodiment 2

[0029] Add 4-chloro-6-amino-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline (III) (0.66g, 2.5mmol), triethylamine (0.25 g, 2.5mmol) and 20mL of dichloromethane, the temperature was raised to 40-45°C, and stirred until the system was dissolved uniformly. Drop below 10°C, slowly add 4-(N,N-dimethylamino)-2-ene-butyryl chloride (0.42g, 2.8mmol) in dichloromethane 10mL solution dropwise, continue to react at room temperature for 6 hours , TLC detects that the reaction is complete. The reaction solution was washed with 10% sodium bicarbonate solution and water, and dried over anhydrous sodium sulfate. The solvent was recovered under reduced pressure, and the residue was recrystallized from ethyl acetate to obtain a white solid 4-chloro-6-{[4-(N,N-dimethylamino)-1-oxo-2-butene-1- Base]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline (IV) 0.84g, yield 89.4%.

Embodiment 3

[0031] Add 4-chloro-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(S) into a 100mL three-necked flask -(Tetrahydrofuran-3-yl)oxy]quinazoline (IV) (1.13g, 3.0mmol), triethylamine (0.45g, 4.5mmol) and 30mL of isopropanol were stirred until the system was uniformly dissolved. A solution of 4-fluoro-3-chloroaniline (0.48 g, 3.3 mmol) in 20 mL of isopropanol was slowly added dropwise. After the drop was completed, the reaction was continued at room temperature for 12 hours, and the reaction was detected by TLC. The reaction solution was poured into 100 mL of ice water and filtered. After the filter cake was dried, it was recrystallized with absolute ethanol to obtain 1.15 g of afatinib (I) as a white solid with a yield of 79.0%.

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Abstract

The invention discloses an Afatinib (I) preparation method which comprises the following steps: performing etherification reaction on 4-chloro-6-amino-7-hydroxyquinazoline (II) and (S)-3-hydroxytetrahydrofuran to generate 4-chloro-6-amino-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline (III); performing acylation reaction on the compound (III) and 4-(N,N-dimethylamino)-2-ene-butyryl chloride to generate 4-chloro-6-{[4-(N,N-dimethylamino)-1-oxo-2-butene-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline (IV); and performing condensation reaction on the compound (IV) and 4-fluoro-3-chloroaniline to obtain Afatinib (I). The preparation method is simple, economic and environment-friendly in process, and meets the requirements for large-scale industrialization.

Description

[0001] The patent of the present invention can refer to the other two invention patent applications submitted by the applicant on the same day, the names of which are respectively "Preparation method of 4-chloro-6-amino-7-hydroxyquinazoline" and "A kind of 4-chloro-6 - Preparation method of amino-7-hydroxyquinazoline". technical field [0002] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, and in particular relates to a preparation method of afatinib. Background technique [0003] Afatinib is a multi-target small molecule drug developed by Boehringer Ingelheim in Germany, which belongs to the irreversible inhibitor of epidermal growth factor receptor (EGFR) and human epidermal receptor (HER2) tyrosine kinase, It is also the first drug for the treatment of lung cancer after failure of epidermal growth factor receptor inhibitor therapy. Clinically, it can be used for the treatment of advanced ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D405/12
Inventor 许学农
Owner 铜陵尚东高新科创有限公司
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