Synthesis of lead LFA‐1 antagonist [14C]spyrocyclic hydantoin

Radiolabelled drug lead candidate leukocyte function‐associated antigen 1 antagonist ¹⁴C]spyrocyclic hydantoin: 5‐(((5S,9R)‐9‐(4‐¹⁴C]‐cyanophenyl)‐3‐(3,5‐dichlorophenyl)‐1‐methyl‐2,4‐dioxo‐1,3,7‐triazaspiro4.4]nonan‐7‐yl)methyl)thiophene‐3‐carboxylic acid, 12 , was conveniently prepared in three radiochemical steps from (5S,9R)‐tert‐butyl 9‐(4‐bromophenyl)‐3‐(3,5‐dichlorophenyl)‐1‐methyl‐2,4‐dioxo‐1,3,7‐triazaspiro4.4]nonane‐7‐carboxylate 9 . The radiochemical yield of 12 was 28.5% from the resolved bromide 9 . The preparation of the racemic spyrocyclic hydantoin 3 was obtained via a 3+2]dipolar cycloaddition reaction between 2 and N‐benzyl‐N‐(methoxymethyl)trimethylsilylmethylamine. The introduction of ¹⁴C] cyanide was completed via a palladium (0) catalyzed reaction by the addition of Zn(¹⁴CN)₂ to aryl bromide 9 . The radiochemical and chiral purities of 12 determined by high‐performance liquid chromatography were 98.7 and 99.7%, respectively. The specific activity of 12 was 87.5 µCi/mg (48.6 mCi/mmol). Copyright © 2009 John Wiley & Sons, Ltd.