Chemical Development of MDL 103371: An <i>N</i>-Methyl-<scp>d</scp>-Aspartate-Type Glycine Receptor Antagonist for the Treatment of Stroke

Abstract

MDL 103371 is a N-methyl-d-aspartate (NMDA)-type glycine receptor antagonist for the potential treatment of stroke. Evaluation of five different synthetic routes, which included Stille, Suzuki, enol ether, Knoevenagel, and the Mukaiyama coupling reactions, revealed the Knoevenagel approach superior for preparing large quantities of drug substance for evaluation. The overall process utilized some classical chemistry. Fischer indole cyclization, followed by a Vilsmeier−Haack formylation and a Knoevenagel condensation gave immediate access into the proper carbon framework of the target molecule. A unique hydrogenation cataylst and solvent system for a nitro reduction, followed by a two step acid−base hydrolysis of a nitrile gave the crude product. Purification was accomplished by a potassium salt crystallization followed by a Schiff base formation to give MDL 103371 in nine steps in an overall yield of 38%.