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‐ 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 H 8 ]‐( 7 ) was synthesized in three steps from 2‐cyanopyridine‐ 2 H 4 using Kulinkovich‐Szymonik aminocyclopropanation, followed by coupling to L ‐alanine‐2,3,3,3‐ 2 H 4 ‐ N ‐ t ‐BOC, and then removal of the BOC‐protecting group. Amide bond formation with acid ( 6 ) gave [ 2 H 8 ]‐( 2 ) in 36% overall yield. The amine [ 13 C 4 , 15 N]‐( 8 ) was obtained in two steps using L‐threonine‐ 14 C 4 , 15 N and then coupled to acid [ 13 C]‐( 6 ) to give [ 13 C 5 , 15 N]‐( 3 ) in 56% overall yield.