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<p>A six-step synthesis to (+)-nebivolol ((<i>S,R,R,R</i>)-nebivolol or <i>d</i>-nebivolol) in a cumulative yield of 32% has been developed. Conventional use of diazo compounds has been replaced with a novel approach of sulphur ylide for a safer one-carbon chain extension of methyl 6-fluorochromane-2-carboxylate, which entailed the formation of racemic 2-[dimethyl(oxido)-λ6-sulfanylidene]-1-(6-fluoro-3,4-dihydro-2H-chromen-2-yl)ethenone from methyl 6-fluorochromane-2-carboxylate in high yield. Subsequently the β-keto sulfoxonium ylide was converted into 2-chloro-1-(6-fluorochroman-2-yl)ethanone. Reduction of 2-chloro-1-(6-fluorochroman-2-yl)ethanone to 2-chloro-1-(6-fluorochroman-2-yl)ethanol was catalyzed by Ketoreductase 228 from Syncozymes and resulted in halohydrins (<i>R</i>)-2-chloro-1-((<i>S</i>)-6-fluorochroman-2-yl)ethanol and (<i>S</i>)<i>-</i>2-chloro-1-((<i>S</i>)-6-fluorochroman-2-yl)ethanol in 92% yield. The halohydrins were separated by preparative HPLC. (<i>S</i>)-2-Chloro-1-((<i>S</i>)-6-fluorochroman-2-yl)ethanol underwent amination to produce (<i>R</i>)-2-amino-1-((<i>S</i>)-6-fluorochroman-2-yl)ethanol. The final synthesis step involved reaction of (<i>R</i>)-2-amino-1-((<i>S</i>)-6-fluorochroman-2-yl)ethanol and (<i>R</i>)-2-chloro-1-((<i>S</i>)-6-fluorochroman-2-yl)ethanol forming (+)-nebivolol with &gt; 99% enantiomeric excess (<i>ee</i>).</p>

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Synthesis of Enantiopure Beta-Blocker (+)-Nebivolol by Enzyme Catalyzed Asymmetrization Reaction

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月25日

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  • Fredrik Bjørnes,
  • Sara Aasen,
  • Marcin Krzysztof Makosa-Szczygiel,
  • Zoe Palmyre Thieffry,
  • Juliette Lefebvre,
  • Eline Flo Hoem,
  • Elisabeth Egholm Jacobsen

摘要

A six-step synthesis to (+)-nebivolol ((S,R,R,R)-nebivolol or d-nebivolol) in a cumulative yield of 32% has been developed. Conventional use of diazo compounds has been replaced with a novel approach of sulphur ylide for a safer one-carbon chain extension of methyl 6-fluorochromane-2-carboxylate, which entailed the formation of racemic 2-[dimethyl(oxido)-λ6-sulfanylidene]-1-(6-fluoro-3,4-dihydro-2H-chromen-2-yl)ethenone from methyl 6-fluorochromane-2-carboxylate in high yield. Subsequently the β-keto sulfoxonium ylide was converted into 2-chloro-1-(6-fluorochroman-2-yl)ethanone. Reduction of 2-chloro-1-(6-fluorochroman-2-yl)ethanone to 2-chloro-1-(6-fluorochroman-2-yl)ethanol was catalyzed by Ketoreductase 228 from Syncozymes and resulted in halohydrins (R)-2-chloro-1-((S)-6-fluorochroman-2-yl)ethanol and (S)-2-chloro-1-((S)-6-fluorochroman-2-yl)ethanol in 92% yield. The halohydrins were separated by preparative HPLC. (S)-2-Chloro-1-((S)-6-fluorochroman-2-yl)ethanol underwent amination to produce (R)-2-amino-1-((S)-6-fluorochroman-2-yl)ethanol. The final synthesis step involved reaction of (R)-2-amino-1-((S)-6-fluorochroman-2-yl)ethanol and (R)-2-chloro-1-((S)-6-fluorochroman-2-yl)ethanol forming (+)-nebivolol with > 99% enantiomeric excess (ee).