Multigram-scale Synthesis of Volasertib, an Inhibitor of Polo-like Kinases in Clinical Evaluation

Abstract

This paper described the development of a practical, improved and efficient method for the multigram-scale synthesis of Volasertib, an injectable bioavailable potent and selective inhibitor of PLK1. The key to this optimization was the design and development of a novel synthetic strategy, which involved the preparation of key intermediate 4-amino-N-{4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexyl}-3-methoxybenzamide (W-5) through nitro reduction sequence and (7R)-2-Chloro-7-ethyl-7,8-dihydro-8-(1-methylethyl)-6(5H)-pteridinone (W-11) through reductive cyclization and N-methylation reaction. The developed process provided 46.1% overall yield, which enabled us to rapidly synthesize multi-gram quantities of Volasertib in 99.42% purity.