Efficient synthesis of enantiomerically pure thioester precursors of [11C]McN-5652 from racemic McN-5652

Abstract

An improved synthesis of the anantiomerically pure thioester precursors of [11C](+)-McN-5652 ([11C](+)−1]), and [11C](−)-McN5652 ([11C](−)−1]) starting from racemic McN-5652 ((±)−1) is described. The synthetic method includes the resolution of (±)−1 by repeated crystallization of the (+)- and (−)-di-p-toluoyltartrates yielding (+)-McN-5652 ((+)−1) and (−)-McN-5652 ((−)-1), each with >98% enantiomeric purity. S-Demethylation of (±)−1, (+)−1, and (−)-1, respectively was achieved by treatment with sodium amide at low temperatures (−78°C) followed by conversion of the intermediate thiols 2 with acetyl chloride to give the corresponding thioester precursors (±)−3, (+)−3 or (−)−3. This demethylation method almost completely suppressed the isomerization of the pharmacologically active trans diastereomer into the inactive cis form. Chiral HPLC analyses confirmed that the S-demethylation proceeded without any racemization. 11C-Labelling of (+)−3 or (−)−3, yields enantiomerically pure [11C](+)-McN-5652 or [11C](−)-McN5652, each in 22% radiochemical yield (decay-corrected, related to [11C]CO2) and a specific radioactivity of 74 GBq/μmol (2 Ci/μmol) at the end of synthesis (EOS) Copyright © 1999 John Wiley & Sons, Ltd.