Preparation of (−)-(R)-2-(2,3,4,5,6-pentafluorophenoxy)-2-(phenyl-d5)acetic acid: an efficient 1H NMR chiral solvating agent for direct enantiomeric purity evaluation of quinoline-containing antimalarial drugs

The title compound was prepared as a racemate from (±)-mandelic acid-d5 in one step. The corresponding (−)-(R)-enantiomer (98% ee) was obtained by resolution with (−)-(R)-1-phenylethylamine and evaluated as a chiral solvating agent (CSA) for direct 1H NMR enantiomeric excess determination of mefloquine (Lariam®), chloroquine (Chloroquine Bayer®), and hydroxychloroquine (Plaquenil®) enantiomers. The displayed non-equivalence was high for signals in the aromatic region of all three antimalarials. Thus, the mandelic acid derivative described herein may be considered as the first efficient CSA ‘invisible’ in the aromatic region, useful for direct 1H NMR ee value determination of chiral quinoline-containing antimalarial drugs.

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(−)-(R)-2-(2,3,4,5,6-Pentafluorophenoxy)-2-(phenyl-d5)acetic acidC14H2D5F5O3Ee = 98%[α]D20 = −151 (c 2, CHCl3)Source of chirality: resolutionAbsolute configuration: (R)