Investigation of Mechanistic Pathway for Trimethyl borate mediated Amidation of (R)-Mandelic Acid for the Synthesis of Mirabegron, an Antimuscarinic Agent

The present work describes investigation of mechanistic pathway for trimethyl borate mediated amidation of ( R )-mandelic acid ( 3 ) with 4-nitophenylethylamine ( 2 ) to provide (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide ( 4 ) during mirabegron synthesis. P lausible reaction mechanism is proposed by isolating and elucidat ing the active α -hydroxy ester intermediate 16 from the reaction mass. Trimethyl borate mediated approach proved to be selective in providing 4 without disturbing α -hydroxyl group and stereochemistry of chiral center, and is also a greener, economic and production friendly over the reported methods . The developed approach is rapid and efficient for the preparation of 4 with an overall yield of 85-87 % and around 99.0 % purity by HPLC at scale .