Synthesis and application of a new isothiocyanate as a chiral derivatizing agent for the indirect resolution of chiral amino alcohols and amines

The synthesis of the optical pure trans-1,2-diaminocyclohexane (DACH)-based N-3,5-dinitrobenzoyl-DACH-isothiocyanate (DDITC) is straightforward and the compounds, available in R,R and S,S configurations, can serve as highly selective, stable and optically pure chiral derivatizing agents (CDA) for the indirect resolution of chiral primary and secondary amines and in particular of amino alcohols. The synthetic route to obtain DDITC is described and RP-HPLC separations of a number of pharmaceutically important amino alcohols including beta-blockers derivatized with DDITC are presented. The latter diastereomers were compared with the well established GITC-derivatized compounds by RP-HPLC. The separation factor (alpha) of the diastereomeric thioureas ranged between 1.05 and 2.00 and the peak resolution (R) ranged from 0.67 to 6.67 for the DDITC derivatives, and were usually higher than the values for the GITC derivatives. However, derivatization of secondary amines containing a tertiary butyl group at the amino function (e.g., timolol) is impossible using DDITC, a limitation not observed using GITC as CDA. The advantage of DDITC over other chiral isothiocyanates is the higher chromatographic selectivity and the high detection sensitivity, including the option of electrochemical detection due to the redox potential (-0.62 V) of the nitro group. UV detection of the DDITC-derivatized amino compounds shows excellent sensitivity because of the higher molar absorptivity (epsilon) deduced from the nitroaryl chromophor (e.g., DDITC derivative of metamphetamine, epsilon(242) = 26 000). The chemical stability of the DDITC derivatives is much higher than that of GITC derivatives owing to the absence of easily hydrolysable ester groups, which is considered a further advantage.