TY - JOUR
T1 - Multi-carbon labelling of active pharmaceutical ingredients enabled by a three-gas surrogate hydroformylation
AU - Hammershøj, Hans Christian Dahl
AU - Guðmundsson, Haraldur Gunnar
AU - Kjærsgaard, Samuel
AU - Bønnelykke, Jonas
AU - Kolodiazhnaia, Iuliia
AU - Skrydstrup, Troels
PY - 2023/2/6
Y1 - 2023/2/6
N2 - 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.]
AB - 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.]
U2 - 10.1038/s44160-022-00223-0
DO - 10.1038/s44160-022-00223-0
M3 - Journal article
SN - 2731-0582
VL - 2
SP - 243
EP - 250
JO - Nature Synthesis
JF - Nature Synthesis
ER -