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

✍ Scribed by Loïc Leman; Sean L Kitson; Rodney T Brown; Jana Cairns; William Watters; Austin McMordie; Victor L Murrell; Judith Marfurt

Publisher
John Wiley and Sons
Year
2011
Tongue
French
Weight
515 KB
Volume
54
Category
Article
ISSN
0022-2135

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✦ Synopsis

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.

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