Alternate Synthesis of HSP90 Inhibitor AT13387

Abstract

AT13387 is a novel HSP90 inhibitor, and it is currently used in clinical trials for the treatment of refractory gastrointestinal stromal tumors (GIST). In this article, two synthetic routes are described for synthesizing the title compound via [2 + 2 + 2] cycloaddition of dipropargylamine derivatives and propargyl alcohol as a key step. The alternate synthetic methods are economical and suitable for multigram-scale preparation of AT13387 and the related isoindoline derivatives.

GRAPHICAL ABSTRACT

Keywords:

• AT13387
• cycloaddition
• HSP90
• inhibitors
• synthesis

Notes

^a Catalyst: Cp*RuCl(PPh₃)₂ = pentamethylcyclopenta-dienylbis-(triphenylphosphine)ruthenium(II) chloride; CpRuCl(PPh₃)₂ = cyclopentadienylbis-(triphenylphosphine)ruthenium(II) chloride; (PPh₃)₃RhCl = tris(triphenylphosphine)rhodium(I) chloride.

^b NR, no reaction.