title: High enantioselective Novozym 435-catalyzed esterification of (R,S)-flurbiprofen monitored with a chiral stationary phase.
abstract: Lipases form Candida rugosa and Candida antarctica were tested for their application in the enzymatic kinetic resolution of (R,S)-flurbiprofen by enantioselective esterification. Successful chromatographic separation with well-resolved peaks of (R)- and (S)-flurbiprofen and their esters was achieved in one run on chiral stationary phases by high-performance liquid chromatography (HPLC). In this study screening of enzymes was performed, and Novozym 435 was selected as an optimal catalyst for obtaining products with high enantiopurity. Additionally, the influence of organic solvents (dichloromethane, dichloroethane, dichloropropane, and methyl tert-butyl ether), primary alcohols (methanol, ethanol, n-propanol, and n-butanol), reaction time, and temperature on the enantiomeric ratio and conversion was tested. The high values of enantiomeric ratio (E in the range of 51.3-90.5) of the esterification of (R,S)-flurbiprofen were obtained for all tested alcohols using Novozym 435, which have a great significance in the field of biotechnological synthesis of drugs. The optimal temperature range for the performed reactions was from 37 to 45 °C. As a result of the optimization, (R)-flurbiprofen methyl ester was obtained with a high optical purity, eep = 96.3 %, after 96 h of incubation. The enantiomeric ratio of the reaction was E = 90.5 and conversion was C = 35.7 %.
authors.affiliation: Department of Medicinal Chemistry, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Dr. A. Jurasza 2, 85-089, Bydgoszcz, Poland, tomasz.siodmiak@cm.umk.pl.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Siódmiak
authors.forename: Debby
authors.initials: D
authors.lastname: Mangelings
authors.forename: Yvan
authors.initials: Y
authors.lastname: Vander Heyden
authors.forename: Marta
authors.initials: M
authors.lastname: Ziegler-Borowska
authors.forename: Michał Piotr
authors.initials: MP
authors.lastname: Marszałł
mesh_terms: D055162:Biocatalysis; D002175:Candida / Q000737:chemistry / Q000201:enzymology*; D002851:Chromatography, High Pressure Liquid / Q000295:instrumentation; D004800:Enzymes, Immobilized; D004951:Esterification; D005480:Flurbiprofen / Q000737:chemistry / Q000378:metabolism*; D005656:Fungal Proteins / Q000737:chemistry* / Q000378:metabolism; D007700:Kinetics; D008049:Lipase / Q000737:chemistry* / Q000378:metabolism; D013237:Stereoisomerism; D013379:Substrate Specificity
chemical_list: D004800:Enzymes, Immobilized; D005656:Fungal Proteins; D005480:Flurbiprofen; C093667:Novozyme 435; D008049:Lipase