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Elucidation of Synthetic Mechanism Involved in the Conversion of Zwitterionic Clonixin to Carboxamide Side-Product

S. Sudalai Kumar, N. Ramkumar, D. Kodimunthiri


N-(3-Chloro-2-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide is obtained as a by-product during the synthesis and crystallization of Clonixin (2-(3-chloro-2-methylanilino)nicotinic acid) and its polymorphs, respectively. This conversion was unexpected and it changed the usual investigation path way enabling the formation of neutral and zwitterionic polymorphs in our study on Clonixin in contrary to studies of 2-(p-tolylamino) nicotinic acid investigation. The same conversion is checked in the other synthesized analogs such as 2-(phenylamino)nicotinic acid (PNA), 2-(methyl(phenyl)amino)nicotinic acid (MPNA), 2-(p-tolylamino)nicotinic acid (TNA) and 2-(methyl(p-tolyl)amino)nicotinic acid (MTNA) but they were all not going to any other side product formation like Clonixin. These ampholites were synthesized by the aromatic nucleophilic substitution reactions of respective aryl amines and 2-chloronicotinic acid in the presence of p-tolylsulfonic acid and pyridine in this report. However, the side product was separated from the crystallization of Clonixin in acetic acid during polymorph hunt. All other analogs were failed in giving this side product as those crystal structures of compounds were analyzed thoroughly by single crystal X-ray determination method. On comparison of this molecule with other ampholites, a new mechanism was proposed for the conversion of Clonixin to this by product in this study and the other molecules are under investigation for no conversion even though they are similar in structures.

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