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

Abstract

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.

Keywords

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