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Preparation method of afatinib intermediate

A technology for afatinib and intermediates, applied in the field of organic synthesis route design and the preparation of raw materials and intermediates, can solve the problems of undisclosed preparation methods of intermediates, achieve stable process, easy access to raw materials, and low cost Effect

Active Publication Date: 2013-08-21
鄄城县人民医院
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the preparation method of the intermediate (I) is not disclosed in the prior art, so it is necessary to provide a new preparation method for the intermediate (I)

Method used

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  • Preparation method of afatinib intermediate
  • Preparation method of afatinib intermediate
  • Preparation method of afatinib intermediate

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Experimental program
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Effect test

Embodiment 1

[0026] 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, 3-nitro-4-hydroxybenzonitrile was added (II) (0.5g, 3.0mmol), 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 was...

Embodiment 2

[0028] Add 3-amino-4-[(S)-(tetrahydrofuran-3-yl)oxy]benzonitrile (IV) (0.51g, 2.5mmol) and triethylamine (0.25g, 2.5mmol) into a 100mL three-necked flask and dichloromethane 20mL, warm up to 40-45°C, and stir until the system is uniformly dissolved. 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 3-[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino-4 -[(S)-(tetrahydrofuran-3-yl)oxy]benzonitrile (V) 0.72 g, yield 91.4%.

Embodiment 3

[0030] Add 2-nitro-5-[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino-4-[(S)- (tetrahydrofuran-3-yl)oxy]benzonitrile (VI) (3.6 g, 10 mmol), 5% palladium on carbon (0.36 g, 10% w / w) and ethanol 50 mL. Keep a pressure of 3-4 kg at room temperature and react for about 12 hours. Suction filtration, recovery palladium carbon catalyst. Ethanol was recovered under reduced pressure, and the residue was recrystallized from ethyl acetate to obtain a white solid 2-cyano-4-[4-(N,N-dimethylamino)-1-oxo-2-butene-1- 3.1 g of amino]amino-5-[(S)-(tetrahydrofuran-3-yl)oxy]aniline (I), the yield was 94.0%.

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Abstract

The invention discloses a preparation method of an afatinib intermediate. The preparation method comprises the following steps of: sequentially carrying out nitrification, etherification, reduction, amidation, nitrification and reduction on 4-cyanol phenol serving as the starting raw material to prepare 2-cyano-4-[4-(N,N-dimethylamino)-1-oxo-2-butene-1-yl]amino-5-[(S)-tetrahydrofuran-3-yl]oxy]phenylamine (I). The preparation method has the advantages that the process is stable, raw materials are easily available, cost is low and all reactions are classic reactions; therefore, the preparation method meets the requirement of industrial amplification.

Description

[0001] The patent of this invention can refer to the other two invention patent applications submitted by the applicant on the same day, the titles of which are respectively "a preparation method of afatinib" 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 an afatinib intermediate. Background technique [0003] Afatinib (Afatinib, chemical name 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2 -buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline) was developed by Boehringer Ingelheim in Germany for the first time for epidermal growth factor Drugs for the treatment of lung cancer after failure of receptor inhibitor therapy. Clinically, it can be used for the treatment of advanced lung cancer, breast cancer and colon cancer. The drug passed the US Food ...

Claims

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Application Information

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IPC IPC(8): C07D307/20
Inventor 许学农
Owner 鄄城县人民医院
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