Synthesis of 3-(5-isopropyl-2,4-dimethoxyphenyl)-4-methoxybenzo[d]isoxazole-5-amine and its application for the preparation of new Hsp90 inhibitors

An efficient synthetic scheme for 5-amino-4-methoxybenzo[ d ]isoxazoles has been developed starting from 3-(5-isopropyl-2,4-dimethoxyphenyl)-6,7-dihydrobenzo[ d ]isoxazole-4(5 H )-one – a scaffold for the preparation of new Hsp90 inhibitors. The key stages in the synthesis included dibromination at position 5, aromatization, and subsequent copper-catalyzed cross-coupling of 5-bromo-4-methoxybenzo[ d ]isoxazole with sodium azide, with simultaneous reduction to 5-amino-4-methoxybenzo[ d ]isoxazole. Using the developed scheme, a potential Hsp90 inhibitor was obtained, which showed high antiproliferative activity against breast cancer cells of BT-474 line (IC 50 = 5 µM) and moderate activity against MCF-7 cells.