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Synthesis of carbon‐14 and stable isotope labelled NN414: a potent potassium channel opener
Author(s) -
Johansen Steen K.,
Kristensen Jesper B.,
Müller Lars K.,
Jessen Claus U.,
Foged Christian
Publication year - 2004
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.805
Subject(s) - chemistry , yield (engineering) , labelling , curtius rearrangement , carbon 14 , potassium channel opener , deamination , radiochemistry , deuterium , carbon fibers , medicinal chemistry , organic chemistry , potassium , biochemistry , materials science , physics , quantum mechanics , metallurgy , composite number , composite material , enzyme
Currently, NN414, a potent β ‐cell selective potassium channel opener, is undergoing clinical trials for the treatment of type 2 diabetes. Here, we report the synthesis of carbon‐14 and stable isotope labelled NN414 for use in metabolic studies and as an internal standard in pharmacokinetic assays, respectively. The carbon‐14 labelling was performed in two steps starting from an advanced intermediate. This provided [ 14 C]NN414 in 60% overall radiochemical yield with a specific activity of 58mCi/mmol. The stable isotope labelling was accomplished from benzyl tert ‐butyl malonate in eight steps using [ 13 C, 2 H 3 ]iodomethane and [ 2 H 2 ]dibromomethane as the source of carbon‐13/deuterium. The synthetic sequence, which included a Mannich reaction followed by deamination, a Simmons–Smith‐type cyclopropanation and a modified Curtius reaction, provided [ 13 C, 2 H 5 ]NN414 in 8.6% overall yield. Copyright © 2004 John Wiley & Sons, Ltd.