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New Phosphine Reagents to Functionalize C-H Bonds

At a Glance

Researchers at Colorado State University have developed a new set of bench-stable phosphine reagents through a novel and distinct chemical process that directly converts C–H bonds in pyridine building blocks, drug-like fragments, and pharmaceuticals into fluoralkyl derivatives. The novel reagents and chemical process is suitable for medicinal and agrochemical discovery programs, drug and agrochemical scale up (for clinical trials, etc.) and manufacture.

Background

Fluoroalkyl groups profoundly affect the physical properties of pharmaceuticals and influence virtually all metrics associated with their pharmacokinetic and pharmacodynamic profile. Drug candidates increasingly contain CF3 and CF2H groups, and the same trend in agrochemical development shows that the effect of fluoroalkylation translates across human, insect, and plant life. New fluoroalkylation reactions have undoubtedly stimulated this uptake; however, methods that directly convert C–H bonds into C–CF2X (X = F or H) groups in complex drug-like molecules are rare. For pyridine, the most common aromatic heterocycle in pharmaceuticals, only one approach, via fluoroalkyl radicals, is viable for pyridyl C–H fluoroalkylation in the elaborate structures encountered during drug development.

It is well understood that new methods are needed to advance both pharmaceutical and agrochemical discovery.

Benefits

  • Mechanistically distinct process
  • Reaction has a unique regiochemical profile and functions on complex pyridine-containing substrates
  • The novel set of bench-stable phosphine reagents directly functionalize C-H bonds
  • No pre-installed functional groups or directing groups are required
  • Suitable methods for late-stage functionalization
  • Method reliably fluoroalkylates pyridine building blocks from C-H precursors

Applications

  • Medicinal and Agrochemical discovery programs
  • Drug and Agrochemical scale up (for clinical trials, etc.) and manufacture
  • Potential for compounds to be sold by chemical manufacture
  • Widely applicable in the pharmaceutical and agrochemical sciences

Publications

Phosphorus-mediated sp2 -sp3 couplings for C–H fluoroalkylation of azines. Nature https://doi.org/10.1038/s41586-021-03567-3 (2021).

Zhang, X.; et al. (2021): Phosphorus-Mediated sp2-sp3 Couplings for Selective C–H Fluoroalkylation of Complex Azines. ChemRxiv. Preprint. https://doi.org/10.26434/chemrxiv.13635206.v1 

Last Updated: October 2022
Opportunity

Available for Licensing
TRL: 3

IP Status

US Patent 17/634,140
US Continuation Pending

Inventors

​Andrew McNally
Kyle Nottingham
Chirag Patel
Jeffrey Levy
Xuan Zhang

Reference Number
2021-016
Licensing Manager

Steve Foster
Steve.Foster@colostate.edu
970-491-7100

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