Synthesis of highly potent lymphocyte function‐associated antigen‐1 antagonists labeled with carbon‐14 and with stable isotopes, part 3

The drug candidates (2) and (3) are highly potent LFA‐1 inhibitors. They were efficiently prepared labeled with carbon‐14 using a palladium‐catalyzed carboxylation of an iodo‐precursor (5) and sodium formate‐14C to afford acid [14C]‐(6), which was coupled via an amide bond to chiral amines (7) and (8) in 52% and 48% overall yield, respectively, and with specific activities higher than 56 mCi/mmol and radiochemical purities of 99%. For stable isotopes synthesis, the amine [2H8]‐(7) was synthesized in three steps from 2‐cyanopyridine‐2H4 using Kulinkovich‐Szymonik aminocyclopropanation, followed by coupling to L‐alanine‐2,3,3,3‐2H4‐N‐t‐BOC, and then removal of the BOC‐protecting group. Amide bond formation with acid (6) gave [2H8]‐(2) in 36% overall yield. The amine [13C4,15N]‐(8) was obtained in two steps using L‐threonine‐14C4,15N and then coupled to acid [13C]‐(6) to give [13C5,15N]‐(3) in 56% overall yield. Two highly potent LFA‐1 inhibitors (2) and (3) were efficiently prepared labeled with carbon‐14 using a palladium‐catalyzed carboxylation of an iodo‐precursor (5) and sodium formate‐14C followed by amide bond formation with chiral amines (7) and (8). These two drug candidates were also labeled with stable isotopes by first preparing the chiral amines [2H8]‐(7) and [13C4,15N]‐(8) and then coupling them to (6) and [13C]‐(6).