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DOI: 10.1039/A905611D (Paper) Reference Section for: J. Chem. Soc., Perkin Trans. 1, 1999, 2755-2758

A large-scale synthesis of the bioreductive drug 1,4-bis{[2-(dimethylamino)ethyl]amino}-5,8-dihydroxyanthracene-9,10-dione bis-N-oxide (AQ4N)

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Ho H. Lee and William A. Denny

Abstract

A large-scale synthesis of the bis-bioreductive drug 1,4-bis{[2-(dimethylamino)ethyl]amino}-5,8-dihydroxyanthracene-9,10-dione bis-N-oxide (AQ4N) has been developed. This six-step synthesis provides AQ4N in 20% overall yield from readily available tetrachlorophthalic anhydride. The key step was a KF–NaF-mediated conversion of 3,6-dichlorophthalic anhydride to 3,6-difluorophthalic anhydride, which could be achieved in 77% yield on a 100 g scale. A trace impurity in AQ4N was determined (by LC-MS and independent synthesis) to be the mono-N-oxide 1-amino-4-[2-(dimethylamino)ethyl]amino-5,8-dihydroxyanthracene-9,10-dione N-oxide. This is formed spontaneously from AQ4N under a number of conditions, including during HPLC on reversed-phase columns.

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