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Method for preparing Afatinib

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

Active Publication Date: 2013-08-21
铜陵尚东高新科创有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This method has many steps, the total yield is also 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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  • Method for preparing Afatinib
  • Method for preparing Afatinib
  • Method for preparing Afatinib

Examples

Experimental program
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Effect test

Embodiment 1

[0025] Add 2-cyano-4-[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino-5-[(S)- into a 500mL three-necked flask (tetrahydrofuran-3-yl)oxy]aniline (II) (12.0 g, 0.036 mol), N,N-dimethylformamide dimethyl acetal (DMF-DMA) (6.5 g, 0.054 mol) and toluene 150mL. Add catalyst anhydrous acetic acid 3.5mL under stirring. The temperature was raised to 105-110° C., and the temperature was maintained for 3 hours to react (methanol was collected with an oil-water separator), and the reaction was monitored by TLC to complete. Toluene was recovered by distillation under reduced pressure at 50° C. to obtain 12.8 g of a light brown oil with a yield of 92.4%, which can be directly used in the following reaction without separation.

[0026] The above oil was dissolved in 150 mL of anhydrous acetic acid, and transferred to a 500 mL three-necked flask. 3-Chloro-4-fluoroaniline (7.13 g, 0.049 mol) was added. After stirring, the temperature was raised to 115-125° C. and kept under reflux for 6 hou...

Embodiment 2

[0028] Add 2-cyano-4-[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino-5-[(S)- into a 500mL three-necked flask (tetrahydrofuran-3-yl)oxy]aniline (II) (12.0 g, 0.036 mol), N,N-dimethylformamide dimethyl acetal (DMF-DMA) (6.5 g, 0.054 mol) and toluene 150mL. Add catalyst anhydrous formic acid 3.4mL under stirring. The temperature was raised to 105-110° C., and the temperature was maintained for 3 hours to react (methanol was collected with an oil-water separator), and the reaction was monitored by TLC to complete. After cooling, the toluene was recovered by distillation under reduced pressure at 50° C. to obtain 12.1 g of a brown oil with a yield of 87.3%, which can be directly used in the following reaction without separation.

[0029] The above oil was dissolved with 25mL of anhydrous acetic acid and 125mL of toluene, and transferred to a 500mL three-necked flask. 3-Chloro-4-fluoroaniline (7.0 g, 0.048 mol) was added. After stirring, the temperature was raised to 120-130° C....

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Abstract

The invention discloses a method for preparing Afatinib (I). The method comprises the following steps: 2-cyano-4-[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino-5-[(S)-(tetrahydrofuran-3-yl)oxy]aniline (II) and N,N-dimethylformamide dimethylacetal (DMF-DMA) are subjected to condensation reaction so as to produce an intermediate (III), and the intermediate (III), without to the need of separation, is directly subjected to cyclization reaction with 4-fluoro-3-chloroaniline so as to prepare Afatinib (I). According to the method, the steps for preparing Afatinib are reduced obviously, and the cost is reduced greatly.

Description

[0001] For the patent application of the present invention, reference may be made to two other patent applications for invention submitted by the applicant on the same day, which are respectively titled "Method for preparing an intermediate of afatinib" and "A method for preparing afatinib". 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 of Germany, which belongs to the irreversible inhibitor of epidermal growth factor receptor (EGFR) and human epidermal receptor (HER2) tyrosine kinase , is also the first lung cancer treatment drug for the failure of epidermal growth factor receptor inhibitor therapy. Clinically, it can be used for the treatment of advanced non-small cell lung cancer, advanced bre...

Claims

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Application Information

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Patent Type & Authority Applications(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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