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

Multigram-scale synthesis of GS-4997, an inhibitor of apoptosis signal-regulating kinase 1

Hao Yue, Yating Zhang, Jing Feng, Jun Zhang, Yaning Yao, Yunlei Hou, Yanfang Zhao, and Ping Gong

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

E-mail: houyunlei901202@163.com

Received: 8 November 2022  Accepted: 13 April 2023

Abstract:

This paper describes the development of a practical, efficient and reproducible preparation of ASK1 inhibitor GS-4997 (Selonsertib). Our efforts were committed to designing and developing a novel synthetic strategy. The novel route involved high-yielding preparation of 5-(4-cyclopropyl-1H-imidazole-1-yl)-2-fluoro-4-methylbenzoic acid (5) through adjusting reaction sequence, and the one-pot procedure for the synthesis of 6-(4-isopropyl-4H-1,2,4-triazol-3-yl) pyridin-2-amine (7). The developed process provided an overall yield of 45.8%, which enabled us to rapidly synthesize multi-gram quantities of GS-4997 in 99.3% purity.

Graphical Abstract

Keywords: Multigram-scale synthesis; GS-4997; ASK1 inhibitor; Formylation; ‘One-pot’ procedure

Full paper is available at www.springerlink.com.

DOI: 10.1007/s11696-023-02835-y

Chemical Papers 77 (9) 4797–4806 (2023)