ISSN print edition: 0366-6352 ISSN electronic edition: 1336-9075 Registr. No.: MK SR 9/7 Published monthly

Multigram-scale synthesis of volasertib, an inhibitor of polo-like kinases in clinical evaluation

Kang Wang, Dong Zhao, Mingli Jin, Yuan Li, Lei Sun, Yanli Zhu, Chen Wang, Shuang Li, Yu Wang, Qianying Miao, Xiao Chen, Yanfang Zhao, and Yunlei Hou

School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, People’s Republic of China

E-mail: yanfangzhao@126.com

Received: 20 April 2024  Accepted: 20 September 2024

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% overall yield, which enabled us to rapidly synthesize multi-gram quantities of volasertib in 99.42% purity.

Graphical abstract

Keywords: Multigram-scale synthesis; Volasertib; PLK1 inhibitor; SNAr reaction

Full paper is available at www.springerlink.com.

DOI: 10.1007/s11696-024-03708-8

Chemical Papers 78 (17) 8965–8977 (2024)