Multi-carbon labelling of active pharmaceutical ingredients enabled by a three-gas surrogate hydroformylation

Hans Christian Dahl Hammershøj, Haraldur Gunnar Guðmundsson*, Samuel Kjærsgaard, Jonas Bønnelykke, Iuliia Kolodiazhnaia, Troels Skrydstrup*

*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

4 Citations (Scopus)

Abstract

Drug metabolism and pharmacokinetic studies play a crucial role in drug discovery and development programmes, assessing a lead drug candidate’s efficacy and safety profile. Quantitative bioanalytical assessment of analytes with mass spectrometry requires the use of stable carbon-13-labelled compounds with a molecular mass difference of ≥3 daltons. The incorporation of three or more carbon isotopes into drug candidates is not trivial, often requiring lengthy and costly syntheses. Here we report a dual catalytic strategy for the synthesis of multi-carbon-labelled isotopologues of active pharmaceutical ingredients. This approach uses isotopically labelled gas surrogates in a three-chamber reactor for sequential release of alkenes, carbon monoxide and hydrogen followed by low-pressure hydroformylation to generate multi-labelled alkyl aldehydes. The method’s utility has been demonstrated through the synthesis of multiple labelled N-alkyl bioactive compounds, site-selective carbon-13 and deuterium introduction and for triple-carbon labelling of small molecules combined with α-functionalization. [Figure not available: see fulltext.]

Original languageEnglish
JournalNature Synthesis
Volume2
Pages (from-to)243-250
Number of pages8
ISSN2731-0582
DOIs
Publication statusPublished - 6 Feb 2023

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