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Expanding Access to Optically Active Non-Steroidal Anti-Inflammatory Drugs via Lipase-Catalyzed KR of Racemic Acids Using Trialkyl Orthoesters as Irreversible Alkoxy Group Donors

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dc.abstract.enStudies into the enzymatic kinetic resolution (EKR) of 2-arylpropanoic acids (‘profens’), as the active pharmaceutical ingredients (APIs) of blockbuster non-steroidal anti-inflammatory drugs (NSAIDs), by using various trialkyl orthoesters as irreversible alkoxy group donors in organic media, were performed. The enzymatic reactions of target substrates were optimized using several different immobilized preparations of lipase type B from the yeast Candida antarctica (CAL-B). The influence of crucial parameters, including the type of enzyme and alkoxy agent, as well as the nature of the organic co-solvent and time of the process on the conversion and enantioselectivity of the enzymatic kinetic resolution, is described. The optimal EKR procedure for the racemic profens consisted of a Novozym 435-STREM lipase preparation suspended in a mixture of 3 equiv of trimethyl or triethyl orthoacetate as alkoxy donor and toluene or n-hexane as co-solvent, depending on the employed racemic NSAIDs. The reported biocatalytic system provided optically active products with moderate-to-good enantioselectivity upon esterification lasting for 7–48 h, with most promising results in terms of enantiomeric purity of the pharmacologically active enantiomers of title APIs obtained on the analytical scale for: (S)-flurbiprofen (97% ee), (S)-ibuprofen (91% ee), (S)-ketoprofen (69% ee), and (S)-naproxen (63% ee), respectively. In turn, the employment of optimal conditions on a preparative-scale enabled us to obtain the (S)-enantiomers of: flurbiprofen in 28% yield and 97% ee, ibuprofen in 45% yield and 56% ee, (S)-ketoprofen in 23% yield and 69% ee, and naproxen in 42% yield and 57% ee, respectively. The devised method turned out to be inefficient toward racemic etodolac regardless of the lipase and alkoxy group donor used, proving that it is unsuitable for carboxylic acids possessing tertiary chiral centers.
dc.affiliationUniwersytet Warszawski
dc.contributor.authorBorowiecki, Paweł
dc.contributor.authorKutner, Jan
dc.contributor.authorCieśla, Piotr
dc.contributor.authorZdun, Beata
dc.date.accessioned2024-01-25T00:07:30Z
dc.date.available2024-01-25T00:07:30Z
dc.date.copyright2022-05-17
dc.date.issued2022
dc.description.accesstimeAT_PUBLICATION
dc.description.financeNie dotyczy
dc.description.number5
dc.description.versionFINAL_PUBLISHED
dc.description.volume12
dc.identifier.doi10.3390/CATAL12050546
dc.identifier.issn2073-4344
dc.identifier.urihttps://repozytorium.uw.edu.pl//handle/item/106725
dc.identifier.weblinkhttps://www.mdpi.com/2073-4344/12/5/546/pdf
dc.languageeng
dc.pbn.affiliationchemical sciences
dc.relation.ispartofCatalysts
dc.relation.pages546
dc.rightsCC-BY
dc.sciencecloudnosend
dc.subject.enbiocatalysis
dc.subject.enlipases
dc.subject.enkinetic resolution
dc.subject.enchiral 2-arylpropanoic acids
dc.subject.enesterification
dc.subject.ennon-steroidal anti-inflammatory drugs
dc.subject.entrialkyl orthoesters
dc.titleExpanding Access to Optically Active Non-Steroidal Anti-Inflammatory Drugs via Lipase-Catalyzed KR of Racemic Acids Using Trialkyl Orthoesters as Irreversible Alkoxy Group Donors
dc.typeJournalArticle
dspace.entity.typePublication