Gefitinib synthesis

Protein-Tyrosine Kinase Inhibitors Imatinib (Gleevec) and Gefitinib (Iressa), In Contemporary Drug Synthesis, Li, J. J. Johnson, D. S. Sliskovic, D. R. Roth, B. D., John Wiley Sons Hoboken, 2004, pp 29-38. 

The Niementowski synthesis is still used today to prepare a host of quinazolines and quinazolinones of biological significance. For example, the original Niementowski synthesis was used as a key step in the synthesis of gefitinib (Iressa) by Richards and co-workers. ° Fusion of 4,5-dimethyoxyanthranilic acid and formamide fiimished the desired quinazolinone in 20% yield. This yield was significantly improved in later work by Orfi and co-workers using formadine acetate and formamide under microwave conditions to provide the product in quantitative yield. 

Slight modifications to the conventional reaction conditions have resulted in improved yields for this transformation. For example, 19, a key intermediate in the synthesis of gefitinib (Iressa) was synthesized in only 20% yield by the conventional fusion of formamide with 4,5-dimethoxyanthranilic acid (18). Orfi et al. reported that heating a variety of anthranilic acids in the presence of formamidine acetate and formamide, either imder thermal conditions or microwave conditions, produced excellent yields of 4-... 

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