Synthesis of (E)-3-(2-carboxy-2-pyridyl-vinyl)-4,6-dichloro-1H-indole-2-carboxylic acids, glycine-site NMDA receptor antagonists, utilizing the Knoevenagel condensation reaction

The Knoevenagel condensation of arylacetonitriles with ethyl 4,6-dichloro-3-formyl-1H-indole-2-carboxylate (2), followed by hydrolysis, provides a convenient entry into a series of analogs of MDL 105,519, 1, a selective glycine site N-methyl-d-aspartate (NMDA) receptor antagonist. Surprisingly, the hydrolysis of the indole arylpropenenitriles terminates at the formation of the corresponding carboxamide and does not proceed further to the desired dicarboxylic acid. However, when the aryl substituent is pyridine, hydrolysis proceeds via an azepinoindole unique to this series, which upon further hydrolysis converts smoothly to the desired dicarboxylic acid analog.