Preparation of 1‐methyl‐4‐[4‐(7‐chloro‐4‐quinolyl‐[3‐14C]‐amino)benzoyl]piperazine

Abstract 1‐Methyl‐4‐[4‐(7‐chloro‐4‐quninolyl‐[3‐14C]amino)‐benzoyl]piperazine (V) was prepared for pharmacokinetic and pharmacodynamic evaluation. The synthesis of V was accomplished first by a modified Claisen ester condensation reaction of diethyl‐[2‐14C]‐malonate, triethyl orthoformate, and acetic anhydride in the presence of ZnCl2 to form ethyl ethoxymethylene‐[2‐14C]‐malonate (I), which was further condensed with m‐chloroaniline to yield 7‐chloro‐4‐hydroxy‐3‐[14C]‐quinoline‐ethylcarboxylate (II). Saponification of II yielded the corresponding carboxylic acid (III). Decarboxylation of the acid group upon heating and a substitution of the 4‐OH group of compound III into chlorine atom with POCl3 produced 4,7‐dichloro‐[3‐14C]‐quinoline (IV), which then was reacted with 1‐methyl‐4‐(pamino‐benzoyl)piperazine to form the title compound V. There were a total of five steps of reaction, with a overall yield of 34.3%. The specific activity was 1.74 mCi/mmol.