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Preparation method of afatinib (I)

A technology of afatinib and amino, which is applied in the field of preparation of afatinib, can solve the problems of difficult acquisition of raw materials, difficult process control, and many steps, etc., and achieve the effect of easy availability of raw materials, promotion of development, and simple process

Inactive Publication Date: 2013-09-11
鄄城县人民医院
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The above-mentioned methods all still have the defects that the raw materials are not easy to obtain, the steps are many and the process is difficult to control.

Method used

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  • Preparation method of afatinib (I)
  • Preparation method of afatinib (I)
  • Preparation method of afatinib (I)

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] At room temperature, add diisopropyl azodicarboxylate (3mL, 15mmol) and 5mL of tetrahydrofuran into a three-neck flask, add triphenylphosphine (4.0g, 15mmol) in 25mL of tetrahydrofuran solution dropwise at room temperature, and keep the reaction at room temperature for 2 hours . 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, 6-amino-7-hydroxy-3, 4-Dihydroquinazolin-4-one (II) (0.53 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 ...

Embodiment 2

[0027] Add 6-amino-7-[(S)-(tetrahydrofuran-3-yl)oxy]-3,4-dihydroquinazolin-4-one (III) (0.62g, 2.5mmol) into the three-necked flask , triethylamine (0.25g, 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 the reaction at room temperature after the drop is complete 6 After 1 hour, TLC detected that the reaction was over. 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 6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino} -7-[(S)-(tetrahydrofuran-3-yl)oxy]-3,4-dihydroquinazolin-4-one (IV) 0.80 g, yield 89.4%.

Embodiment 3

[0029] Under nitrogen protection, add 6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(S)- (Tetrahydrofuran-3-yl)oxy]-3,4-quinazolin-4-one (IV) (3.58g, 10mmol), benzotriazol-1-yloxytris(dimethylamino) Phosphonium hexafluorophosphate (BOP) (6.63 g, 15 mmol) and acetonitrile 50 mL. Under stirring, 1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU) (2.28 g, 15 mmol) was added dropwise, and the reaction was carried out at room temperature for 12 hours. Be warming up to 60 DEG C, continue reaction 12 hours. The solvent was distilled off under reduced pressure, dissolved in 100 mL of ethyl acetate, and washed with 20 mL of 2M sodium hydroxide. The organic phase was separated, dried and concentrated under reduced pressure. The residue was dissolved in 100 mL of tetrahydrofuran, 4-chloro-3-fluoroaniline (1.89 g, 13 mmol) and sodium hydride (0.32 g, 13 mmol) were added, the temperature was raised to 50 ° C, and the reaction was stirred for 5 hours, and the reaction was monitored by TL...

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Abstract

The invention discloses a preparation method of afatinib (I). The preparation method comprises the following steps that 6-amino-7-hydroxy-3,4-dihydroquinazoline-4-ketone (II) and (S)-3-hydroxytetrahydrofuran carry out etherification reaction to generate 6-amino-7-[(S)-(tetrahydrofuran-3-yl)oxy]-3,4-dihydroquinazoline-4-ketone (III), the compound (III) and 4-(N,N-dimethylamino)-2-ene-butyryl chloride carry out acylation reaction to generate 6-{[4-(N,N-dimethylamino)-1-oxo-2-butene-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-3,4-dihydroquinazoline-4-ketone (IV), and the compound (IV) and 4-fluoro-3-chloroaniline carry out condensation reaction to prepare the afatinib (I). The preparation method is concise, economical and environment-friendly in process and is suitable for the requirement of industrial amplification.

Description

[0001] For the patent application of the present invention, reference may be made to another patent application for invention named "6-amino-7-hydroxyl-3,4-dihydroquinazolin-4-one" submitted by the applicant on the same day. 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. It is an irreversible inhibitor of epidermal growth factor receptor (EGFR) and human epidermal receptor (HER2) tyrosine kinase, and it is also the first drug for lung cancer treatment after 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 passed the US Food and Drug ...

Claims

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Application Information

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IPC IPC(8): C07D405/12
Inventor 许学农
Owner 鄄城县人民医院
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