On‐Column Hydrolysis Kinetics Determination of Boronic Pinacol Ester Intermediates for Use in Optimization of Fast HPLC Methods

Abstract

Boronic acid and boronic ester intermediates are the basis for Suzuki coupling and Petasis reactions that are widely used in pharmaceutical synthetic schemes. The analysis of these compounds utilizing traditional reversed phase liquid chromatography (RPLC) is complicated by the potential of on‐column hydrolysis. In order to effectively develop and optimize RPLC methods for accurate analysis of these compounds, a better understanding of the potential on‐column hydrolysis needs to be achieved. Kinetic studies of this type of on‐column hydrolysis were performed utilizing a stop flow kinetic approach. The rate of on‐column hydrolysis was determined as a function of initial organic composition, mobile phase pH, and column temperature. In addition, the Arrhenius activation energy was calculated. A fast reversed phase liquid chromatography method was then developed and optimized to minimize on‐column hydrolysis effects based on the garnered information. The method was applied to successfully resolve ten different boronic acid and boronic pinacol ester functionalized compounds within five minutes. Thus, the wide range applicability of fast RPLC technology for accurate analysis of this specific class of compounds was demonstrated.

Keywords:

• On‐column hydrolysis kinetics
• Boronic acid
• Boronic pinacol ester intermediates

Acknowledgment

The authors would like to thank Dr. Naijun Wu for valuable discussions.