Microwave‐Assisted Synthesis of (±)‐Mandelic Acid‐d₅, Optical Resolution, and Absolute Configuration Determination

Abstract

An efficient microwave-assisted synthesis of(±)-mandelic acid-d5was developed. The racemic mixture was resolved by diastereomeric salt formation using 1-phenylethylamine enantiomers as resolving agents. At each step, the resolution process was checked by determining mandelic acid-d5enantiomer ee values directly on fractional crystallized diastereomeric salts by chiral capillary electrophoresis analysis. Highly enriched (−)- and (+)-mandelic acid-d5(95% and 90% ee, resp.) were obtained and their absolute configurations—RandS, respectively—were determined by correlation of the (−)-mandelic acid-d5circular dichroism spectrum to the (R)-mandelic acid one.

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

“…4.1.1. (RS)-2-Hydroxy-2-(D 5 )phenylacetic acid (RS)-8Prepared as reported in the literature 26. Yield: 82%.…”

“…Racemic O-pentafluorophenyl mandelic acid-d 5 (RS)-5 [2-(2,3,4,5,6-pentafluorophenoxy)-2-(phenyl-d 5 )acetic acid] was prepared via the synthetic route shown in Scheme 1. (RS)-2-Hydroxy-2-(D 5 )phenylacetic acid (RS)-8 was prepared as previously described, 26 by submitting hexadeuterobenzene 6 to Friedel-Crafts acylation with 2,2-dichloroacetyl chloride to give dichloroacetophenone-d 5 7. Treatment of 7 with NaOH gave (RS)-8, which underwent a copper-catalyzed coupling with hexafluorobenzene 25,27 to afford the desired compound (RS)-5.…”