Synthesis of beta-site amyloid precursor protein-cleaving enzyme 1 inhibitors BI 1147560 and BI 1181181 labeled with carbon-14 and deuterium

The generation of amyloid beta peptides that aggregate in the brain is believed to play a major role in Alzheimer's disease. In theory, the inhibition of beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1), which catalyzes the initial rate-limiting step in amyloid beta production, may slow or stop Alzheimer's disease. Herein, we report the preparation of two potent BACE1 inhibitors, BI 1147560 (1) and BI 1181181 (2), labeled with carbon-14 and with deuterium. The use of advanced key chiral intermediates like 3 and 5 shortened the carbon-14 syntheses of these two compounds to five and six steps, respectively, and helped in preparing them with very high chemical purity and enantiomeric excess without deviating from the process chemistry route. For the deuterium synthesis, oxetan-3-ylmethanamine [²H₆]-7 and 2-fluoro-2-methylpropan-1-amine [²H₆]-9 were prepared then used with the chiral intermediate 5 to furnish deuterium labeled 1 and 2, respectively.