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

An on-column stopped-flow multidimensional HPLC (sfMDHPLC) procedure using two chiral stationaryphases (CSPs) and one achiral C18 column was developed for the determination of rateconstants and free energy barriers of enantiomerization of (±)(R,S)-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazine 5,5-dioxide. Moreover, a stopped-flow HPLC (sfHPLC) method previouslydeveloped was applied to the determination of kinetic parameters of enantiomerization of the abovecompound in the presence of a CSP. The individual enantiomers of the studied compound were isolatedin parallel by preparative HPLC and the rate constants and free energy barriers of enantiomerizationweredetermined in different solvents (off-column method). The data obtained by sfMDHPLC, sfHPLC and offcolumnmethods were compared. The (S) enantiomer of the studied compound (S18986) was preparedby asymmetric synthesis and subsequently purified by preparative HPLC, followed by the determinationof rate constants and free energy barriers of enantiomerization in different buffer solutions at pH 2–9.3.