Practical synthesis of N-alkyl-N-alkyloxycarbonylaminomethyl prodrug derivatives of acetaminophen, theophylline, and 6-mercaptopurine

We report a novel synthesis of N-alkyl-N-alkyloxycarbonylaminomethyl (NANAOCAM) prodrugs of acetaminophen, theophylline, and 6-mercaptopurine by alkylation of the corresponding drug molecule with N-alkyl-N- alkyloxycarbonylaminomethyl chlorides in good yield. Most of the alkylating agents were efficiently synthesized by chloromethylation of N-alkyl carbamic acid alkyl esters, which in turn were made from alkyl amines and alkyl chloroformates. In cases where the alkyl chloroformates were not available, synthesis of N-alkyl carbamic acid alkyl esters was accomplished by converting an alcohol to a chloroformate or to an activated acylating agent such as acyl imidazoles or p-nitrophenylcarbonate esters, followed by their reaction with alkyl amines.