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Synthesis of diastereomeric anhydrides of (RS)-ketorolac and (RS)-etodolac, semipreparative HPLC enantioseparation, establishment of molecular asymmetry and recovery of pure enantiomers

Abstract

Enantioseparation of two anti-inflammatory drugs, namely, (RS)-ketorolac and (RS)- etodolac, marketed and administered commonly as racemates has been achieved by RPHPLC. The method provided very low limits of detection values (as 3.69 and 3.02 ng/mL for diastereomeric derivatives of (R)- and (S)-Ket, respectively) in comparison to literature reports. (S)-Naproxen benzotriazole ester, to be used as the chiral reagent, was synthesized and it was characterized by UV, IR, 1HNMR, elemental analysis and polarimetry. The diastereomeric derivatives were synthesized under microwave irradiation. The diastereomeric derivatives were separated on analytical scale by RPHPLC and then these were isolated by preparative HPLC; mobile phase in isocratic mode containing methanol and aqueous triethylaminephosphate (TEAP) was successful and separation conditions with respect to pH, flow rate, and buffer concentration were optimized. The diastereomeric derivatives were characterized and their absolute configuration was established. Hydrolysis of the derivatives provided native enantiomers under mild reaction conditions. It is a successful report on semipreparative HPLC enantioseparation of the two analytes with easy recovery of native enantiomers without racemization and with establishment of molecular asymmetry.

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Publication details

The article was received on 13 Aug 2017, accepted on 05 Oct 2017 and first published on 06 Oct 2017


Article type: Paper
DOI: 10.1039/C7NJ02898A
Citation: New J. Chem., 2017, Accepted Manuscript
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    Synthesis of diastereomeric anhydrides of (RS)-ketorolac and (RS)-etodolac, semipreparative HPLC enantioseparation, establishment of molecular asymmetry and recovery of pure enantiomers

    P. Malik and R. Bhushan, New J. Chem., 2017, Accepted Manuscript , DOI: 10.1039/C7NJ02898A

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