Carbon 14 synthesis of glycine transporter 1 inhibitor Iclepertin (BI 425809) and its major metabolites

Abstract

Carbon 14 labeled Iclepertin (BI 425809, 1) and its major metabolites were needed for ADME and several other studies necessary for the advancement of this drug candidate in clinical trials. Iclepertin is composed of two main chemical blocks, (R)‐5‐(methylsulfonyl)‐2‐([1,1,1‐trifluoropropan‐2‐yl]oxy)benzoic acid (2), and 3‐[(1R,5R)‐3‐azabicyclo[3.1.0]hexan‐5‐yl]‐5‐(trifluoromethyl)isoxazole (3) linked to each other via an amide bond. In the first synthesis of carbon 14 labeled 1, 2‐fluorobenzoic acid, carboxyl‐14C was converted to [14C]‐2 in three steps and then coupled to 3 to provide [14C]‐1a in 45% overall yield. In the second synthesis, [14C]‐3 was prepared in six radioactive steps and coupled to the acid 2 to furnish [14C]‐1b in 20% overall yield. Both synthetic routes provided [14C]‐1a and [14C]‐1b with specific activities higher than 53 mCi/mmol and radiochemical, chemical, and enantiomeric purities above 98%. Two major metabolites of 1, BI 761036 and BI 758790, were also prepared labeled with carbon 14 using intermediates already available from the synthesis of [14C]‐1.