Synthesis of isotopically labelled [14C]ZT‐1 (Debio‐9902), [d3]ZT‐1 and (−)‐[d3]huperzine A, a new generation of acetylcholinesterase inhibitors

A method has been developed for the synthesis of two isotopically labelled forms of a pro‐drug of the acetylcholinesterase inhibitor (−)‐huperzine A. These labelled compounds,[ 14 C]ZT‐1 (Debio‐9902) and [d 3 ]ZT‐1, were used in clinical studies to evaluate a potential treatment for Alzheimer's disease. The pro‐drug [ 14 C]ZT‐1 was isolated with a radiochemical purity of >98% and a gravimetric specific activity of 129 μCi/mg in a seven‐step synthesis starting from [U‐ 14 C]phenol in 7% yield. Subsequently, the deuterium labelled target (−)‐[d 3 ]huperzine A was achieved in six steps with an overall yield of 15% and gave an isotopic distribution of d 2 (1.65% huperzine A) and d 3 (97.93% huperzine A) with a chemical purity of 98.5%. Condensation of the substrate (−)‐[d 3 ]huperzine A with 5‐chloro‐ o ‐vanillin gave the Schiff base [d 3 ]ZT‐1 in a chemical yield of 80%. Reduction of the Schiff base gave reduced‐[d 3 ]ZT‐1, which was converted into the hydrochloride salt with an isotopic distribution of d 2 (1.60%) and d 3 (98.02%). Copyright © 2011 John Wiley & Sons, Ltd.