Synthesis of enantiomerically pure [14C]-labelled morpholine derivatives for a class of trace amine-associate receptor 1 agonists

Various agonists of the trace amine‐associate receptor 1, under consideration as potential clinical development candidates, were labelled with carbon‐14 for use in preclinical in vitro and in vivo drug metabolism studies. Herein, the [14C]‐radiosynthesis of 2‐phenyl‐substituted morpholines 1 is described. After evaluating and optimizing different synthetic routes, 4‐iodonitrobenzene 3 was selected as starting material for the 14‐step synthesis. Incorporation of carbon‐14 into the acetyl moiety allowed a safe and efficient synthesis of [14C]‐labelled 4‐nitroacetophenone 2 in five steps and 38% yield. Further transformation of 2 to the target compounds 1 was achieved in a 9‐step synthesis. In a representative example, [14C]‐labelled 1 was obtained in an overall yield of 11% and was isolated in >99% radiochemical purity and a specific activity of 47 mCi/mmol. An efficient synthesis for a class of carbon‐14 labelled trace amine‐associate receptor 1 agonists is described starting from [14C]‐potassium cyanide. The 14‐step asymmetric synthesis includes an enzymatic reduction using an alcohol dehydrogenase (ADH).