Kilogram Synthesis of Crebinostat

Abstract

A kilogram-scale synthetic route to crebinostat, a small molecule inhibitor of histone deacetylases (HDACs), is developed successfully. Starting from pimelic acid, dimethyl pimelate is obtained in high yield via methyl esterification. The latter is ammoniated by hydrazine and hydroxylamine successively to give the key intermediate 7-hydrazinyl-N-hydroxy-7-oxoheptanamide, which is coupled with 4-biphenylcarboxaldehyde in ethanol to give crebinostat in 37% yield over four steps. The final product with 99.5% total purity (HPLC) contains E/Z-isomers in a ratio of around 1.3:1, which is confirmed by ¹H NMR spectroscopy. Purification methods of the intermediates and the final product involved in the route are given, which make this process environmentally friendly, cost-effective, and feasible for scale-up operation.

Key words

crebinostat - synthetic process - kilogram-scale - HDACs inhibitor - green chemistry

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