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

2000; American Chemical Society; Volume: 65; Issue: 23 Linguagem: Inglês

10.1021/jo001080s

1520-6904

Andrew J. Walz, Richard J. Sundberg,

Synthesis and pharmacology of benzodiazepine derivatives

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 degrees 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.