Lipase Catalyzed Synthesis of Enantiopure Precursors and Derivatives for β-Blockers Practolol, Pindolol and Carteolol
Sustainable methods for producing enantiopure drugs have been developed. Chlorohydrins as building blocks for several β-blockers have been synthesized in high enantiomeric purity by chemo-enzymatic methods. The yield of the chlorohydrins increased by the use of catalytic amount of base. The reason f...
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Online Access: | https://hdl.handle.net/11250/3029478 https://doi.org/10.3390/catal11040503 |
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ftntnutrondheimi:oai:ntnuopen.ntnu.no:11250/3029478 2023-05-15T13:53:35+02:00 Lipase Catalyzed Synthesis of Enantiopure Precursors and Derivatives for β-Blockers Practolol, Pindolol and Carteolol Gundersen, Morten Andre Austli, Guro Buaas Løvland, Sigrid Sløgedal Hansen, Mari Bergan Rødseth, Mari Jacobsen, Elisabeth Egholm 2021 application/pdf https://hdl.handle.net/11250/3029478 https://doi.org/10.3390/catal11040503 eng eng MDPI Catalysts. 2021, 11, 503-518. urn:issn:2073-4344 https://hdl.handle.net/11250/3029478 https://doi.org/10.3390/catal11040503 cristin:1917433 Navngivelse 4.0 Internasjonal http://creativecommons.org/licenses/by/4.0/deed.no CC-BY 503-518 11 Catalysts Peer reviewed Journal article 2021 ftntnutrondheimi https://doi.org/10.3390/catal11040503 2022-11-09T23:42:01Z Sustainable methods for producing enantiopure drugs have been developed. Chlorohydrins as building blocks for several β-blockers have been synthesized in high enantiomeric purity by chemo-enzymatic methods. The yield of the chlorohydrins increased by the use of catalytic amount of base. The reason for this was found to be the reduced formation of the dimeric by-products compared to the use of higher concentration of the base. An overall reduction of reagents and reaction time was also obtained compared to our previously reported data of similar compounds. The enantiomers of the chlorohydrin building blocks were obtained by kinetic resolution of the racemate in transesterification reactions catalyzed by Candida antarctica Lipase B (CALB). Optical rotations confirmed the absolute configuration of the enantiopure drugs. The β-blocker (S)-practolol ((S)-N-(4-(2-hydroxy-3-(isopropylamino)propoxy)phenyl)acetamide) was synthesized with 96% enantiomeric excess (ee) from the chlorohydrin (R)-N-(4-(3-chloro-2 hydroxypropoxy)phenyl)acetamide, which was produced in 97% ee and with 27% yield. Racemic building block 1-((1H-indol-4-yl)oxy)-3-chloropropan-2-ol for the β-blocker pindolol was produced in 53% yield and (R)-1-((1H-indol-4-yl)oxy)-3-chloropropan-2-ol was produced in 92% ee. The chlorohydrin 7-(3-chloro-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one, a building block for a derivative of carteolol was produced in 77% yield. (R)-7-(3-Chloro-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one was obtained in 96% ee. The S-enantiomer of this carteolol derivative was produced in 97% ee in 87% yield. Racemic building block 5-(3-chloro-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one, building block for the drug carteolol, was also produced in 53% yield, with 96% ee of the R-chlorohydrin (R)-5-(3-chloro-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one. (S)-Carteolol was produced in 96% ee with low yield, which easily can be improved. publishedVersion Article in Journal/Newspaper Antarc* Antarctica NTNU Open Archive (Norwegian University of Science and Technology) Catalysts 11 4 503 |
institution |
Open Polar |
collection |
NTNU Open Archive (Norwegian University of Science and Technology) |
op_collection_id |
ftntnutrondheimi |
language |
English |
description |
Sustainable methods for producing enantiopure drugs have been developed. Chlorohydrins as building blocks for several β-blockers have been synthesized in high enantiomeric purity by chemo-enzymatic methods. The yield of the chlorohydrins increased by the use of catalytic amount of base. The reason for this was found to be the reduced formation of the dimeric by-products compared to the use of higher concentration of the base. An overall reduction of reagents and reaction time was also obtained compared to our previously reported data of similar compounds. The enantiomers of the chlorohydrin building blocks were obtained by kinetic resolution of the racemate in transesterification reactions catalyzed by Candida antarctica Lipase B (CALB). Optical rotations confirmed the absolute configuration of the enantiopure drugs. The β-blocker (S)-practolol ((S)-N-(4-(2-hydroxy-3-(isopropylamino)propoxy)phenyl)acetamide) was synthesized with 96% enantiomeric excess (ee) from the chlorohydrin (R)-N-(4-(3-chloro-2 hydroxypropoxy)phenyl)acetamide, which was produced in 97% ee and with 27% yield. Racemic building block 1-((1H-indol-4-yl)oxy)-3-chloropropan-2-ol for the β-blocker pindolol was produced in 53% yield and (R)-1-((1H-indol-4-yl)oxy)-3-chloropropan-2-ol was produced in 92% ee. The chlorohydrin 7-(3-chloro-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one, a building block for a derivative of carteolol was produced in 77% yield. (R)-7-(3-Chloro-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one was obtained in 96% ee. The S-enantiomer of this carteolol derivative was produced in 97% ee in 87% yield. Racemic building block 5-(3-chloro-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one, building block for the drug carteolol, was also produced in 53% yield, with 96% ee of the R-chlorohydrin (R)-5-(3-chloro-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one. (S)-Carteolol was produced in 96% ee with low yield, which easily can be improved. publishedVersion |
format |
Article in Journal/Newspaper |
author |
Gundersen, Morten Andre Austli, Guro Buaas Løvland, Sigrid Sløgedal Hansen, Mari Bergan Rødseth, Mari Jacobsen, Elisabeth Egholm |
spellingShingle |
Gundersen, Morten Andre Austli, Guro Buaas Løvland, Sigrid Sløgedal Hansen, Mari Bergan Rødseth, Mari Jacobsen, Elisabeth Egholm Lipase Catalyzed Synthesis of Enantiopure Precursors and Derivatives for β-Blockers Practolol, Pindolol and Carteolol |
author_facet |
Gundersen, Morten Andre Austli, Guro Buaas Løvland, Sigrid Sløgedal Hansen, Mari Bergan Rødseth, Mari Jacobsen, Elisabeth Egholm |
author_sort |
Gundersen, Morten Andre |
title |
Lipase Catalyzed Synthesis of Enantiopure Precursors and Derivatives for β-Blockers Practolol, Pindolol and Carteolol |
title_short |
Lipase Catalyzed Synthesis of Enantiopure Precursors and Derivatives for β-Blockers Practolol, Pindolol and Carteolol |
title_full |
Lipase Catalyzed Synthesis of Enantiopure Precursors and Derivatives for β-Blockers Practolol, Pindolol and Carteolol |
title_fullStr |
Lipase Catalyzed Synthesis of Enantiopure Precursors and Derivatives for β-Blockers Practolol, Pindolol and Carteolol |
title_full_unstemmed |
Lipase Catalyzed Synthesis of Enantiopure Precursors and Derivatives for β-Blockers Practolol, Pindolol and Carteolol |
title_sort |
lipase catalyzed synthesis of enantiopure precursors and derivatives for β-blockers practolol, pindolol and carteolol |
publisher |
MDPI |
publishDate |
2021 |
url |
https://hdl.handle.net/11250/3029478 https://doi.org/10.3390/catal11040503 |
genre |
Antarc* Antarctica |
genre_facet |
Antarc* Antarctica |
op_source |
503-518 11 Catalysts |
op_relation |
Catalysts. 2021, 11, 503-518. urn:issn:2073-4344 https://hdl.handle.net/11250/3029478 https://doi.org/10.3390/catal11040503 cristin:1917433 |
op_rights |
Navngivelse 4.0 Internasjonal http://creativecommons.org/licenses/by/4.0/deed.no |
op_rightsnorm |
CC-BY |
op_doi |
https://doi.org/10.3390/catal11040503 |
container_title |
Catalysts |
container_volume |
11 |
container_issue |
4 |
container_start_page |
503 |
_version_ |
1766258789052317696 |