Tandem Michael-addition/cyclization synthesis and EGFR kinase inhibition activity of pyrido[2,3-d]pyrimidin-7(8H)-ones

✍ Scribed by Eric E. Boros; James B. Thompson; Edgar R. Wood; O. Bradley McDonald; Timothy D. Spitzer; Andrea M. Sefler; Bryan R. Reep

• Publisher: Journal of Heterocyclic Chemistry
• Year: 2004
• Tongue: English
• Weight: 136 KB
• Volume: 41
• Category: Article
• ISSN: 0022-152X
• DOI: 10.1002/jhet.5570410308

✦ Synopsis

Abstract

5‐Methoxy and 5‐anilinopyrido[2,3‐d]pyrimidin‐7(8__H__)‐ones 2a‐2f were obtained by a tandem Michael addition‐cyclization reaction of methanol and anilines with pyrimidinylpropynoate 5. Methoxy derivative 2a was obtained in 62% yield by treatment of 5 with methanol and potassium carbonate. Anilino derivatives 2b‐2f were prepared in 31–71% yields by reacting 5 with the corresponding anilines in refluxing methanol. This methodology accomplishes Michael‐addition and pyridopyrimidinone ring formation in one‐pot and affords the desired products in reasonable yield without chromatography. Propynoate 5 did not react with 4‐cyanoaniline under these conditions. Reaction of 5 with 2‐aminopyridine gave the unexpected arylpyrido[2,3‐d]pyrimidinone 8 in 58% yield and reaction of 5 with imidazole afforded Michael‐adduct 9 in 69% yield. Compounds 2a and 5 were submicromolar inhibitors of epidermal growth factor receptor (EGFR) tyrosine kinase.