Method for preparing known impurities of gefitinib

A gefitinib, impurity technology, applied in the field of medicinal chemistry, can solve the problems of no impurities, no CAS registration number, etc., and achieve the effects of high product purity, short reaction time and high reaction efficiency

Active Publication Date: 2014-04-23
NANJING YOUKE BIOLOGICAL MEDICAL RES +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since this compound is rarely reported in the open literature, and there is no CAS registration number so far, there is no relevant report on the preparation of this impurity (Formula I) in the prior art

Method used

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  • Method for preparing known impurities of gefitinib
  • Method for preparing known impurities of gefitinib
  • Method for preparing known impurities of gefitinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] 2-amino-4-methoxy-5-(3-morpholine propoxy)benzonitrile (30g, 0.103mol), 3-fluoro-4-chloroaniline (15g, 0.103mol), triethyl orthoformate Ester (23g, 0.155mol), and 135mL of acetic acid solvent, mix well, heat up to 80°C, stir for 1.5h, TLC monitors the reaction progress; after the reaction is completed, slowly lower the internal temperature to 50°C, add 140mL of saturated saline , stir evenly, continue to cool down to an internal temperature of 5°C, stir and crystallize for 2 hours, and obtain an off-white precipitated solid by suction filtration, suspend the above solid in aqueous sodium bicarbonate solution (pH 8-9) and stir for 1 hour, and suction filter to dryness, that is 28g of impurity crude product must be changed. The crude impurity was heated and dissolved in 180 mL of ethanol / ethyl acetate (2:1, v / v) mixed solvent; under the condition of heat preservation, 0.9 g of activated carbon was added, and stirred for 1 h to decolorize; ℃ stirring and crystallizing, su...

Embodiment 2

[0040]2-Amino-4-methoxy-5-(3-morpholinepropoxy)benzonitrile (27g, 0.093mol), 3-fluoro-4-chloroaniline (14.9g, 0.101mol), orthoformic acid tris Methyl ester (16g, 0.148mol), and 148mL of acetic acid solvent, mix well, raise the temperature to 105°C, stir the reaction for 2h, monitor the reaction progress by TLC; after the reaction is completed, slowly lower the internal temperature to 60°C, add 152mL of saturated saline , stir evenly, continue to cool down to an internal temperature of 10°C, stir and crystallize for 3 hours, and obtain an off-white precipitated solid by suction filtration, suspend the above solid in aqueous sodium bicarbonate solution (pH 8-9) and stir for 1 hour, and suction filter until dry, that is 25g of impurity crude product must be changed. The crude impurity was dissolved by heating with 150mL of methanol / acetone (1:1, v / v) mixed solvent; under the condition of heat preservation, 0.9g of activated carbon was added, and stirred for 1h to decolorize; suct...

Embodiment 3

[0043] 2-Amino-4-methoxy-5-(3-morpholinepropoxy)benzonitrile (14g, 0.048mol), 3-fluoro-4-chloroaniline (7.7g, 0.0528mol), orthoformic acid tris Ethyl ester (12g, 0.0816mol), and 70mL of acetic acid solvent, mix well, raise the temperature to 90°C, stir for 2h, monitor the reaction progress by TLC; after the reaction is completed, slowly lower the internal temperature to 52°C, add 80mL of saturated saline , stir evenly, continue to cool down to an internal temperature of 7°C, stir and crystallize for 2 hours, and obtain an off-white precipitated solid by suction filtration, suspend the above solid in aqueous sodium bicarbonate solution (pH 8-9) and stir for 1 hour, and suction filter until dry, that is 14g of impurity crude product must be changed. The crude impurity was heated and dissolved with 70 mL of ethanol / ethyl acetate (4:1, v / v) mixed solvent; under the condition of heat preservation, 0.5 g of activated carbon was added, and stirred for 1 h to decolorize; ℃, stirring ...

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Abstract

The invention discloses a method for preparing known impurities of gefitinib, comprising: mixing initial raw materials: 2-amino-4-methoxy-5-(3-morpholine propanolato) cyanophenyl, 3-fluorine-4-chloroaniline and acetate solvent with trimethyl orthoformate or triethyl orthoformate, simply preparing a crude product of the impurities of gefitinib, and recrystallizing to obtain the high purity known impurities of gefitinib, that is N-(4-chloro-3-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine. The method has advantages of short synthesis route, simple operation, and high purity of obtained product, and can be used for reference substance research.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of known impurities of gefitinib. Background technique [0002] Gefitinib is a small molecule inhibitor of EGFR tyrosine kinase developed by AstraZeneca. It was first launched in Japan in 2002 for the treatment of locally advanced or recurrent non-small cell lung cancer that was ineffective or unsuitable for chemotherapy. In May 2003, it was approved as a third-line monotherapy for advanced non-small cell lung cancer in the United States and Australia. It is The first targeted small molecule tyrosine kinase inhibitor for the treatment of solid tumors. [0003] Gefitinib was approved by the State Food and Drug Administration (SFDA) in February 2005 and officially launched in China (trade name: Gefitinib) for the treatment of locally advanced or metastatic non-small cell lung cancer who have received chemotherapy . Gefitinib is 4-(3-chloro-4-fl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/94
CPCC07D239/94
Inventor 刘永东闵涛车晓明张峰薛峪泉
Owner NANJING YOUKE BIOLOGICAL MEDICAL RES
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