New Iridium-catalysed Methods for the Direct Preparation of Isotopically-labelled Compounds of Pharmaceutical Importance

New Iridium-catalysed Methods for the Direct Preparation of Compounds of Pharmaceutical Importance

Within the global pharmaceutical industry, there is considerable importance placed upon the area of isotopic labelling.  Specifically, pharmaceutical companies use labelled compounds extensively in both metabolism and toxicology studies throughout the drug discovery process.  Labelled compounds often retain the conformation and physical properties of the original drug candidate while incorporating a tracer moiety.  Moreover, the FDA approval for Deutetrabenazine, a drug molecule useful in treating symptoms associated with Huntington’s disease, constitutes the first deuterium-containing pharmaceutical to be approved for market, offering greater overall tolerability compared its non-deuterated analogue, Tetrabenazine.1  Despite the demand, incorporation of hydrogen isotopes into compounds can be a challenging and time-consuming task.  Previous work within the Kerr group has developed a range of iridium-based hydrogen isotope exchange (HIE) catalysts (such as 1, Figure 1), which allow the selective activation and exchange of a C—H bond, and reaction with deuterium or tritium, under very mild conditions.2  Kerr group catalysts are directed by a broad range of common functional groups and reliably label sp2 carbon centres.  Indeed, these catalysts have become some of the most active species in this area of labelling chemistry.
Within the past decade, the pharmaceutical industry has begun to explore more conformationally diverse sp3-rich structures occupying chemical space3 that is currently underexplored, as shown in the top right of the PMI plot in Figure 2.4  The inherent pharmaceutical properties such as increased solubility and lower toxicity of conformationally diverse sp3-rich molecules, makes them desirable targets despite their increased difficulty in synthesis.  This new focus requires reliable and robust HIE techniques viable for Csp3—H bonds.  Specifically, the ability to label sp3 carbon centres using amide or carbonyl directing groups, ubiquitous functionality in pharmaceuticals, would allow the synthesis of isotopically labelled compounds for metabolic and toxicology studies or even the synthesis of a deuterated pharmaceutical with improved ADME properties.
References

  1. DeWitt, S. H.; Maryanoff B. E., Biochemistry, 2018, 57, 472.
  2. Brown, J. A.; Irvine, S.; Kennedy, A. R.; Kerr, W. J.; Andersson, S.; Nilsson, G. N., Commun. 2008, 1115.
  3. Lovering, F.; Bikker, J.; Humblet, C. , Med. Chem. 2009, 52, 6752.
  4. Brown, D. G.; Boström, J., Med. Chem. 2015, 59, 4443-4458.

For more information about the project contact William Kerr (w.kerr@strath.ac.uk), Professor at the Department of Pure and Applied Chemistry at the University of Strathclyde, or Dr David Lindsay (), Research Associate at the Department of Pure and Applied Chemistry at the University of Strathclyde.
 
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