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
Studies 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 pe...
Published in: | Catalysts |
---|---|
Main Authors: | , , , |
Format: | Text |
Language: | English |
Published: |
Multidisciplinary Digital Publishing Institute
2022
|
Subjects: | |
Online Access: | https://doi.org/10.3390/catal12050546 |
id |
ftmdpi:oai:mdpi.com:/2073-4344/12/5/546/ |
---|---|
record_format |
openpolar |
spelling |
ftmdpi:oai:mdpi.com:/2073-4344/12/5/546/ 2023-08-20T04:01:50+02:00 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 Beata Zdun Piotr Cieśla Jan Kutner Paweł Borowiecki 2022-05-17 application/pdf https://doi.org/10.3390/catal12050546 EN eng Multidisciplinary Digital Publishing Institute Biocatalysis https://dx.doi.org/10.3390/catal12050546 https://creativecommons.org/licenses/by/4.0/ Catalysts; Volume 12; Issue 5; Pages: 546 biocatalysis lipases kinetic resolution chiral 2-arylpropanoic acids esterification non-steroidal anti-inflammatory drugs trialkyl orthoesters Text 2022 ftmdpi https://doi.org/10.3390/catal12050546 2023-08-01T05:04:42Z Studies 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. Text Antarc* Antarctica MDPI Open Access Publishing Catalysts 12 5 546 |
institution |
Open Polar |
collection |
MDPI Open Access Publishing |
op_collection_id |
ftmdpi |
language |
English |
topic |
biocatalysis lipases kinetic resolution chiral 2-arylpropanoic acids esterification non-steroidal anti-inflammatory drugs trialkyl orthoesters |
spellingShingle |
biocatalysis lipases kinetic resolution chiral 2-arylpropanoic acids esterification non-steroidal anti-inflammatory drugs trialkyl orthoesters Beata Zdun Piotr Cieśla Jan Kutner Paweł Borowiecki 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 |
topic_facet |
biocatalysis lipases kinetic resolution chiral 2-arylpropanoic acids esterification non-steroidal anti-inflammatory drugs trialkyl orthoesters |
description |
Studies 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. |
format |
Text |
author |
Beata Zdun Piotr Cieśla Jan Kutner Paweł Borowiecki |
author_facet |
Beata Zdun Piotr Cieśla Jan Kutner Paweł Borowiecki |
author_sort |
Beata Zdun |
title |
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 |
title_short |
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 |
title_full |
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 |
title_fullStr |
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 |
title_full_unstemmed |
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 |
title_sort |
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 |
publisher |
Multidisciplinary Digital Publishing Institute |
publishDate |
2022 |
url |
https://doi.org/10.3390/catal12050546 |
genre |
Antarc* Antarctica |
genre_facet |
Antarc* Antarctica |
op_source |
Catalysts; Volume 12; Issue 5; Pages: 546 |
op_relation |
Biocatalysis https://dx.doi.org/10.3390/catal12050546 |
op_rights |
https://creativecommons.org/licenses/by/4.0/ |
op_doi |
https://doi.org/10.3390/catal12050546 |
container_title |
Catalysts |
container_volume |
12 |
container_issue |
5 |
container_start_page |
546 |
_version_ |
1774712208925655040 |