Enantiomerization of chiral 2,3,3a,4-tetrahydro-1 H-pyrrolo[2,1- c][1,2,4]benzothiadiazine 5,5-dioxide by stopped-flow multidimensional HPLC

Abstract

An on-column stopped-flow multidimensional HPLC (sfMDHPLC) procedure using two chiral stationary phases (CSPs) and one achiral C 18 column was developed for the determination of rate constants and free energy barriers of enantiomerization of (±)( R, S)-2,3,3a,4-tetrahydro-1 H-pyrrolo[2,1- c][1,2,4]benzothiadiazine 5,5-dioxide. Moreover, a stopped-flow HPLC (sfHPLC) method previously developed was applied to the determination of kinetic parameters of enantiomerization of the above compound in the presence of a CSP. The individual enantiomers of the studied compound were isolated in parallel by preparative HPLC and the rate constants and free energy barriers of enantiomerization were determined in different solvents (off-column method). The data obtained by sfMDHPLC, sfHPLC and off-column methods were compared. The ( S) enantiomer of the studied compound (S18986) was prepared by asymmetric synthesis and subsequently purified by preparative HPLC, followed by the determination of rate constants and free energy barriers of enantiomerization in different buffer solutions at pH 2–9.3.