Synthesis of highly potent lymphocyte function-associated antigen-1 antagonists labeled with carbon-14 and with...

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-¹⁴ C to afford acid [¹⁴ C]-(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 [² H₈ ]-(7) was synthesized in three steps from 2-cyanopyridine-² H₄ using Kulinkovich-Szymonik aminocyclopropanation, followed by coupling to L-alanine-2,3,3,3-² H₄ -N-t-BOC, and then removal of the BOC-protecting group. Amide bond formation with acid (6) gave [² H₈ ]-(2) in 36% overall yield. The amine [¹³ C₄ ,¹⁵ N]-(8) was obtained in two steps using L-threonine-¹⁴ C₄ ,¹⁵ N and then coupled to acid [¹³ C]-(6) to give [¹³ C₅ ,¹⁵ N]-(3) in 56% overall yield.