A Next Generation Synthesis of BACE1 Inhibitor Verubecestat (MK-8931)
David A. Thaisrivongs, William J. Morris, Lushi Tan, Zhiguo J. Song, Thomas W. Lyons, Jacob H. Waldman, John R. Naber, Wenyong Chen, Lu Chen, Baoyun Zhang, Jun Hyeok Yang · Organic Letters · 2018
The development of a commercial manufacturing route to verubecestat (MK-8931) is described, highlights of which include the application of a continuous processing step to outcompete fast proton transfer in a Mannich-type ketimine addition, a copper-catalyzed amidation reaction, and an optimized guanidinylation procedure to form the key iminothiadiazine dioxide core.