Preparation method of quinazoline derivate

A technology for quinazoline and derivatives, applied in the field of preparation of quinazoline derivatives, can solve the problems of large environmental pollution, low yield, harsh reaction conditions and the like

Inactive Publication Date: 2012-01-18
SHANGHAI CHANGLIN CHEM TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] The technical problem to be solved by the present invention is to overcome the defects of harsh reaction conditions, low yield and relatively large environmental pollution in the synthetic method of erlotinib in the prior art, and provide a preparation of a class of quinazoline derivatives The method has cheap and easy-to-obtain raw materials, mild reaction conditions, few side reactions, high yield, little environmental pollution, and is suitable for industrial production

Method used

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  • Preparation method of quinazoline derivate
  • Preparation method of quinazoline derivate
  • Preparation method of quinazoline derivate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] The preparation of embodiment 1 compound I (compound I is R in the general formula compound I f 1 for H compounds)

[0049]

[0050] Under nitrogen protection, compound II (186mg, 0.63mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (361mg, 0.83mmol) were dissolved in 6.3ml of acetonitrile, added 3-ethynylaniline (223mg, 1.9mmol) and 1,8-diazabicyclo-bicyclo(5,4,0)-7-undecene (0.15ml), stirring at room temperature for 12 hours, warming up to 60 °C, stirring was continued for 12 hours. The solvent was evaporated, and the residue was dissolved in 50ml of ethyl acetate, washed with aqueous sodium hydroxide solution (10ml, 1mol / l), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and recrystallized from ethanol to obtain 125mg of compound I with a yield of 50 %.

[0051] Its structural identification data are as follows:

[0052] ESI-MS[M+H] + :295.1;

[0053] 1 H NMR (d 6 -DMSO): 11.44(s, 1H), 8.84(s, 1H),...

Embodiment 2

[0054] The preparation of embodiment 2 compound I

[0055]

[0056]Under nitrogen protection, compound II (186mg, 0.63mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.63mmol) were dissolved 3-Ethynylaniline (0.63 mmol) and triethylamine (0.63 mmol) were added to 6.3 ml of dimethyl sulfoxide, and the reaction was stirred at -20°C. After the reaction was complete, the solvent was evaporated, and the residue was dissolved in 50 ml of ethyl acetate, washed with aqueous sodium hydroxide solution (10 ml, 1 mol / l), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and recrystallized from ethanol to obtain 190 mg of compound I. The yield is 75%, and its structural identification data are the same as those in Example 1.

Embodiment 3

[0057] The preparation of embodiment 3 compound I

[0058]

[0059] Under nitrogen protection, compound II (186mg, 0.63mmol) and dicyclohexylcarbodiimide (3.2mmol) were dissolved in 6.3ml N,N-dimethylformamide, and 3-ethynylaniline (3.2mmol) and n-butyl Lithium (32mmol), stirred at 20°C. After the reaction was completed, the solvent was evaporated, and the residue was dissolved in 50 ml of ethyl acetate, washed with aqueous sodium hydroxide solution (10 ml, 1 mol / l), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and recrystallized from ethanol to obtain 120 mg of compound I. The yield is 48%, and its structural identification data are the same as in Example 1.

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Abstract

The invention discloses a preparation method of a quinazoline derivate. Compared with the prior art, the method disclosed by the invention has the advantages that raw materials are cheap and easy to obtain, the reaction condition is mild, side effects are fewer, the yield is high, the pollution to the environment is small, and the method is suitable for industrial production and provides a new way for preparing erlotinib.

Description

technical field [0001] The invention relates to a preparation method of a class of quinazoline derivatives. Background technique [0002] Erlotinib, the hydrochloride salt of compound I, is a selective inhibitor of the tyrosine kinase domain of the epidermal growth factor receptor (EGFR). Overexpression of EGFR is present in some types of cancer cells in humans, such as lung and breast cancers. This leads to inappropriate activation of the anti-apoptotic signaling cascade Ras, ultimately leading to uncontrolled cell proliferation. Studies of erlotinib-sensitive non-small cell lung cancer have shown that mutations in the epidermal growth factor receptor tyrosine kinase domain are the main cause of activation of anti-apoptotic pathways. [0003] [0004] Erlotinib inhibits EGFR tyrosine kinase by binding to adenosine triphosphate (ATP) at its binding site. Thus, the Ras signaling cascade activated by epidermal growth factor receptor tyrosine kinase is inhibited, and the ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/94
Inventor 应律徐志刚丁悦沙雪辉王喆
Owner SHANGHAI CHANGLIN CHEM TECH
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