Synthesis of 8-Methoxy-1-methyl-1H-benzo[d e][1,6]naphthyridin-9-ol (Isoaaptamine) and Analogues

• Published in: Journal of organic chemistry Vol. 65; no. 23; pp. 8001 - 8010
• Main Authors: Walz, Andrew J, Sundberg, Richard J
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 17-11-2000
• Subjects: Enzyme Inhibitors - chemical synthesis; Naphthyridines - chemical synthesis; Protein Kinase C - antagonists & inhibitors
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo001080s

8-Methoxy-1-methyl-1H-benzo[de][1,6]naphthyridin-9-ol, isoaaptamine, a PKC inhibitor isolated from sponge was synthesized. The synthesis parallels a synthesis of 8,9-dimethoxybenzo[de][1,6]naphthyridine, aaptamine, but uses a nitromethyl substituent as a precursor of the key 5-(2-aminoethyl)-1H-quinolin-4-one intermediate. The quinolone intermediates were prepared by thermolysis (220−240 °C) of anilinomethylene derivatives of Meldrum's acid. The quinolone intermediates were N-methylated prior to cyclization to the benzo[de][1,6]naphthyridine derivatives. Aaptamine and several analogues of aaptamine and isoaaptamine were prepared including 9-demethylaaptamine, 1-methyl-8-demethylaaptamine, 1-methylaaptamine, and the 8,9-methylenedioxy analogues of aaptamine and 1-methylaaptamine.