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

Vijayavitthal Thippannachar Mathad, Dattatray G. Deshmukh, Mukund N. Bangal, Mukunda R. Patekar, Vijay J. Medhane


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.Plausible reaction mechanism is proposedby isolating and elucidating the active α-hydroxy ester intermediate 16 from the reaction mass. Trimethylborate 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 of4with an overall yield of 85-87% and around 99.0% purity by HPLC at scale.


Trimethyl borate; amidation; α-hydroxy ester; antimuscarinic drug; mirabegron

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