MANNICH REACTION’S MESMERIZING MANIFESTATIONS

After introduction of a new natural or synthetic chemical entity as a drug, the focus of research has always shifted to the modification of this chemical entity with the objective of improving ADMET properties, formulations for its efficient delivery, solubility, stability, organoleptic properties, reduction of toxicity, expansion of pharmacological range, formation of precursors, condensation products, complexation, prevention of formation of trace impurities and more. For example, the analgesic and antipyretic drug antipyrine, one of the earliest synthetic drugs, forms an intermolecular hydrogen bond with salicylic acid to give the stable compound antipyrine salicylate, also known as salipyrin. During the development of an aqueous drug formulation containing salipyrin and hexamine, 112 years ago, the unusual formation of a precipitate after some time did not go unnoticed by the young pharmacist and chemist Carl Mannich at Berlin University. Mannich then went on to explain the possible mechanism of formation of the condensation product, later to be known as the first Mannich compound or Mannich base, in a seminal, 21-page publication along with his student Krösche. The explanation was as much brilliant as it was accurate. He recognised that it was a generally applicable reaction, which would open the doors to the then difficult-to- synthesize 1,3-ketamines and which would allow the formation of open and cyclic compounds containing nitrogen – and to the world of natural product chemistry. An artistic view of the first Mannich base, which also happened to be tris-symmetrical, is reproduced below.