Synthesis of carbon-14 and stable isotope labelled NN414: a potent potassium channel opener

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 [14C]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 [13C,2H3]iodomethane and [2H2]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 [13C,2H5]NN414 in 8.6% overall yield. Copyright © 2004 John Wiley & Sons, Ltd.