Focusing on the step-by-step transformation of the traditional solid-phase peptide synthesis (SPPS) into an environmentally friendly process, we herein report the elimination of environmentally hazardous components (piperidine, DMF and DCM) from this technique.
Racemic 2-(2-trifluoromethyl)-1H-benzo[d]imidazol-1-yl)benzoic acid (TBBA) was synthesized in three steps from 1-fluoro-2-nitrobenzene. Target (P)-and (M)-TBBA atropisomers were stable with a racemization barrier above 30 kcal/mol. As a chiral derivatizing agent, TBBA showed much higher differences in chemical shifts (Δδ PM ) than the conventional Mosher's acid.
The methods for separation of R,S-tolterodine and R,S-methoxytolterodine enantiomers using sulfated α-, β-CD and phosphated-γ-CD by CE in acidic BGE based on Tris/phosphate pH 2.5 buffer were developed. Sulfated α- and β-CD allow anodic detection while phosphated-γ-CD allows only cathodic detection of the separated enantiomers. The influence of chiral selector (CS)'s concentration as well as the influence of composition and concentration of BGE on resolutions were studied. Reversal migration order of tolterodine and methoxytolterodine enantiomers was observed, when sulfated-α- and sulfated-β-CD were used. The developed methods with all three studied CSs, were validated and compared. All proposed methods enable determination of 0.2% of S-tolterodine as an optical impurity in pills, however the method with phosphated-γ-CD provided lower detection limit, better repeatability of peak areas and migration times, and also lower consumption of CS. Developed method employing phosphated-γ-CD that was applied for the determination of optical purity of R-tolterodine in commercial pills.
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