Labeling of Cp-105,191. Unusual findings on triphenyltin hydride reduction of an aryl iodide

CP-105,191 (1) is a potent, selective and systemically-available inhibitor of acyl-coenzyme A:cholesterol acyl transferase. We needed to make tritium-labeled 1 in order to facilitate the preclinical evaluation of the pharmacokinetics and systemic anti-atherosclerosis effects of 1. Desiring to introduce the tritium as the last step in the synthesis, we opted for introduction of the tritium into the quinoline nucleus via reduction of an 8-iodo species (8, synthesis to be described). To our surprise, treatment of 8 with distilled triphenyltin deuteride and catalytic AIBN in diglyme at reflux for 2 hours gave 67-72% yield of 1 with no deuterium incorporation. Consideration of these results and others to be presented suggests that the solvent is participating in radical chain propagation and that this reaction was unsuitable for tritium labeling. After these results, we found that reduction of 8 with atmospheric pressure of deuterium catalyzed by palladium on carbon in ethanol and triethylamine gave 75-95% yield of 1 with complete deuterium incorporation at C8 of the quinoline ring. The same reaction using 4 Ci of tritium gas gave 1.8 Ci of tritium-labeled 1 with specific activity of 20 Ci/mmole and 97% radiochemical purity.