Multigram‑scale synthesis of BTK inhibitor BIIB068

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, 1 H-NMR, and 13 C-NMR, and the structures of some intermediates were confirmed by MS and 1 H-NMR. Graphical abstract