Working Paper Article Version 1 This version is not peer-reviewed

Lipase Catalysed Synthesis of Enantiopure Precursors and Derivatives for β-Blockers Practolol, Pindolol and Carteolol

Version 1 : Received: 3 March 2021 / Approved: 4 March 2021 / Online: 4 March 2021 (08:34:02 CET)

A peer-reviewed article of this Preprint also exists.

Gundersen, M.A.; Austli, G.B.; Løvland, S.S.; Hansen, M.B.; Rødseth, M.; Jacobsen, E.E. Lipase Catalyzed Synthesis of Enantiopure Precursors and Derivatives for β-Blockers Practolol, Pindolol and Carteolol. Catalysts 2021, 11, 503. Gundersen, M.A.; Austli, G.B.; Løvland, S.S.; Hansen, M.B.; Rødseth, M.; Jacobsen, E.E. Lipase Catalyzed Synthesis of Enantiopure Precursors and Derivatives for β-Blockers Practolol, Pindolol and Carteolol. Catalysts 2021, 11, 503.

Journal reference: Catalysts 2021, 11, 503
DOI: 10.3390/catal11040503

Abstract

The -blocker (S)-practolol ((S)-N-(4-(2-hydroxy (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 -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 99% ee of the R-chlorohydrin (R)-5-(3-chloro-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one. The yield of all four chlorohydrins increased by use of catalytic amounts of base. The reason for this was found to be less formation of the dimeric by-products compared to use of higher concentration of the base. An overall reduction of reagents and reaction time was also obtained compared to our previous 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) from SyncoZymes Co, Shanghai, China. Optical rotations confirmed the absolute configuration of the enantiopure drugs.

Keywords

(S)-Practolol; paracetamol; (S)-pindolol; (S)-carteolol; Candida antarctica Lipase B; chiral chromatography; dimer formation

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