Labelling of the guanylate cyclase activator cinaciguat (BAY 58-2667) with carbon-14, tritium and stable isotopes

For studies of pharmacokinetics and drug metabolism of the new soluble guanylate cyclase activator cinaciguat (BAY 58-2667) the (14)C-labelled compound was synthesized. The tritiated compound was required to elucidate the mode of action and the stable labelled compound was required for bio-analytical studies by quantitative mass spectrometry as well. Two radiosyntheses are described with different formation of the labelled intermediate 1-(chloro[(14)C]methyl)-4-(2-pheny-lethyl)benzene. The first one started with (14)C-carboxylation of 1-bromo-4-(2-phenylethyl)benzene yielding the desired product in 5 steps. In the second synthesis intermediate 1-(chloro[(14)C]methyl)-4-(2-phenylethyl)benzene was formed by chloromethylation of bibenzyl with [(14)C]paraformaldehyde/hydrochloric acid subsequently resulting in the final product in three steps. Tritium labelling was performed by tritium exchange of the diester intermediate using an organo-iridium catalyst and subsequent saponification. The stable labelled compound was synthesized via a convergent synthesis starting with (13)C,(15)N-cyanation of 1-(chloromethyl)-2-{[4-(2-phenylethyl)benzyl]oxy}benzene and (13)C-cyanation of methyl 4-bromobenzoate, respectively. The labelled product was obtained after 7 chemical steps.