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

Multigram‑scale synthesis of BTK inhibitor BIIB068

Donghao Jia, Mingfang Gu, Xinyue Yu, Kunyang Yuan, Sixuan Wang, Mingzhang Guo, and Ping Gong

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

E-mail: gongpinggp@126.com

Received: 1 December 2022  Accepted: 20 June 2023

Abstract:

This paper describes the development of a relatively feasible, economic, and safe method for the multigram-scale synthesis of BIIB068, an efficient reversible BTK inhibitor. The new process is highlighted by an economical construction of a 2-amino-4 substituted pyrimidine employing a simple nucleophilic substitution reaction and a green reduction of the cyano group. The developed process provided an overall yield of 32%, with an HPLC purity of 99%. The structure of BIIB068 was confirmed by MS, IR, ¹H-NMR, and ¹³C-NMR, and the structures of some intermediates were confirmed by MS and ¹H-NMR.

Graphical abstract

Keywords: BTK inhibitor; BIIB068; Synthesis; Process optimization

Full paper is available at www.springerlink.com.

DOI: 10.1007/s11696-023-02951-9

Chemical Papers 77 (11) 6471–6481 (2023)