Synthesis of Quaternary Ammonium Salts of Tricyclic Cationic Drugs: A One-Pot Synthesis for the Bioorganic Chemistry Laboratory

A one-pot conversion of tricyclic cationic drugs to their quaternary ammonium forms is described for a widely used bioactive drug: chlorpromazine, a phenothiazine-based antipsychotic. After conversion to its free base, the parent drug was methylated using substoichiometric amounts of methyl iodide dissolved in ether; the charged quaternary ammonium derivative precipitated and parent drug was removed by successive washes with ether. The synthesis is quick, simple, and yields a single methylated product that is readily analyzed by IR, NMR, and TLC. In addition to these standard analytical protocols, the conversion of parent drug to the methylated form was evaluated in a simple biological system by qualitatively measuring the ability of the drug to induce alterations in the shape of mammalian erythrocytes via light microscopy of treated cells. The experiment successfully links aspects of synthetic organic chemistry and biology and is thus suitable for second-year organic chemistry and upper-division bioorganic chemistry laboratory courses. (Contains 1 scheme.)