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Labelling of the guanylate cyclase activator cinaciguat (BAY 58‐2667) with carbon‐14, tritium and stable isotopes
Author(s) -
Seidel D.,
Pleiß U.
Publication year - 2010
Publication title -
journal of labelled compounds and radiopharmaceuticals
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.432
H-Index - 47
eISSN - 1099-1344
pISSN - 0362-4803
DOI - 10.1002/jlcr.1738
Subject(s) - chemistry , tritium , carbon 14 , bibenzyl , methyl iodide , benzene , carboxylation , cyanation , chemical synthesis , radiosynthesis , medicinal chemistry , radiochemistry , organic chemistry , catalysis , biochemistry , physics , quantum mechanics , nuclear physics , microbiology and biotechnology , in vivo , biology , in vitro
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‐phenylethyl)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. Copyright © 2010 John Wiley & Sons, Ltd.