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 unsuitability for industrialization, low total yield, and many steps, and achieve the effect of promoting the development of economy and technology, and the preparation process is simple

Inactive Publication Date: 2013-08-21
SUZHOU MIRACPHARMA TECH +1
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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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Embodiment 1

[0025] Add 3-chloro-4-fluoroaniline (14.5g, 0.10mol), N,N-dimethylformamide dimethyl acetal (DMF-DMA) (17.8mL, 0.14mol) and toluene into a 500mL three-necked flask 150mL, add 2.8mL of catalyst anhydrous acetic acid 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 19.5 g of a colorless oil with a yield of 97.4%. The colorless oil 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. Add 2-cyano-4-[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino-5-[(S)-(tetrahydrofuran-3- yl)oxy]aniline (II) (23.8 g, 0.072 mol). After stirring, the temperature was raised to 115-120° C. and kept under reflux for 4 h...

Embodiment 2

[0028] Add 3-chloro-4-fluoroaniline (14.5g, 0.10mol), N,N-dimethylformamide dimethyl acetal (DMF-DMA) (17.8mL, 0.14mol) and toluene into a 500mL three-necked flask 150mL, add catalyst anhydrous formic acid 2.5mL under stirring. The temperature was raised to 105-110° C., and the temperature was maintained for 4 hours (methanol was collected with an oil-water separator), and the reaction was monitored by TLC. Toluene was recovered by distillation under reduced pressure at 50° C. to obtain 19.2 g of a colorless oil with a yield of 96.2%. The colorless oil 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. Add 2-cyano-4-[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino-5-[(S)-(tetrahydrofuran-3- yl)oxy]aniline (II) (22.5 g, 0.068 mol). Stir, raise the temperature to 120-130° C., and maintain reflux for 4 hours, and monitor th...

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Abstract

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

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 titles of which are "Preparation Method of Afatinib Intermediate" and "Afatinib Preparation Method". 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 breast cancer and intestinal cancer. The drug ...

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 SUZHOU MIRACPHARMA TECH
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