Synthesis of carbon‐14 and stable isotope labeled Avagacestat: a novel gamma secretase inhibitor for the treatment of Alzheimer's disease

Bristol‐Myers Squibb and others are developing drugs that target novel mechanisms to combat Alzheimer's disease. γ ‐Secretase inhibitors are one class of potential therapies that have received considerable attention. ( R )‐2‐(4‐Chloro‐ N ‐(2‐fluoro‐4‐(1,2,4‐oxadiazol‐3‐yl)benzyl)phenylsulfonamido)‐5,5,5‐trifluoropentanamide (Avagacestat) is a γ ‐secretase‐inhibiting drug that has been investigated by Bristol‐Myers Squibb in preclinical and clinical studies. An important step in the development process was the synthesis of a carbon‐14‐labeled analog for use in a human absorption, distribution, metabolism, and excretion study and a stable isotope labeled analog for use as a standard in bioanalytical assays to accurately quantify the concentration of the drug in biological samples. Carbon‐14 labeled Avagacestat was synthesized in seven steps in a 33% overall yield from carbon‐14 labeled potassium cyanide. A total of 5.95 mCi was prepared with a specific activity of 0.81 μCi/mg and a radiochemical purity of 99.9%. 13 C 6 ‐Labeled Avagacestat was synthesized in three steps in a 15% overall yield from 4‐chloro[ 13 C 6 ]aniline. A total of 585 mg was prepared with a ultraviolet purity of 99.9%.