Synthesis Of The Anti-Cancer Agent Gefitinib

Gefitinib, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3- ?(4- ?morpholinyl)?propoxy] quinazolin-4-amine, is developed as tyrosine kinase inhibitor of epidermal growth factor receptor in treatment of non-small-cell lung cancer by AstraZeneca.The aim of this thesis is to develope the preparation of Gefitinib, which is suitable for industrialization.Objective: To establish and optimize the preparation of Gefitinib.Methods: According to the literatures, a new synthetic route of Gefitinib was designed. 3,4-Dimethoxybenzoic acid(â…¡) was used as the starting material to react with nitric acid to give 4,5-dimethoxy-2-nitrobenzoic acid(â…¢), which was demethylated and esterified to synthesize methyl5-hydroxy-4-methoxy-2-nitrobenzoate(â…¤). Methyl 2-amino-4-methoxy-5-(3-morpholinopropoxy)benzoate(â…¦) was obtained by reduction of4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzoate(â…¥), which was synthesized from the compound(â…¤) and 4-(3-chloropropyl)morpholine.Transformation of the compound(â…¦) and formamidine acetate to7-methoxy-6-(3-morpholinopropoxy)quinazolin-4(3H)-one( â…§), followed by reaction with phosphorus oxychloride, afforded 4-(3-((4-chloro-7-methoxyquinazolin-6-yl)oxy)propyl)morpholine(â…¨). Finally, Gefitinib was prepared from the compound(â…¨) and 3-chloro-4-fluoroaniline by nucleophilic substitution.Results: Gefitinib was successfully synthesized and the structure was confirmed by MS and 1H-NMR.Conclusions: Gefitinib was prepared from 3,4-dimethoxybenzoic acid followed by the eight reaction. The overall yield was 20.7%. And the synthetic process was optimized to suit for industrialized production.