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Ir C–H Activation and Other Catalysis Applied to a Complex Drug Candidate

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Abstract

Transition metal catalysis by Cu (CF3Cu), Ir (C–H activation), and Ru (ring-closing metathesis) were applied to prepare a complicated tetra substituted pyrazolopyridine drug candidate at GlaxoSmithKline. CuI/FSO2CF2CO2Me was utilized to install a CF3 group in a position otherwise difficult to access. IrOMe(COD)/bipyridine was utilized to activate the remote C5 position of a pyrazolopyridine, and Ru (Hoveyda–Grubbs catalyst) was utilized to prepare a chiral aminocyclopentenone for oxysulfonium cyclopropanation. These methods were employed to synthesize a drug candidate, where previous syntheses were considered insufficiently safe by process safety to scale. The synthesis is presented in three parts: CF3 installation in a complicated heterocycle; C–H activation at a remote site; enantioselective cyclopropanation and aminoketone reduction.

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Notes

  1. MSH onset reported to be 41.5 °C, see [1].

  2. Storage incident, see [2].

  3. For reviews on CF3SiR3 as nucleophilic trifluoromethylating reagents, see [3].

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Acknowledgments

We gratefully acknowledge assistance from Will Canoy, Analytical Science group, and from Nicole Deschamps, Automation group, for work done previously on catalyst optimization.

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Authors and Affiliations

  1. Product Development, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC, 27709, USA

    K. Bullock, R. Davis, V. Elitzin, M. Hatcher, M. Jackson, B. Liu, D. Patterson, J. Powers, M. Salmons, E. Tabet & M. Toczko

  2. Medicinal Chemistry, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC, 27709, USA

    P. Chong

Authors
  1. K. Bullock
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  2. P. Chong
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  3. R. Davis
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  4. V. Elitzin
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  5. M. Hatcher
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  6. M. Jackson
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  7. B. Liu
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  8. D. Patterson
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  9. J. Powers
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  10. M. Salmons
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  11. E. Tabet
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  12. M. Toczko
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Correspondence to R. Davis.

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Bullock, K., Chong, P., Davis, R. et al. Ir C–H Activation and Other Catalysis Applied to a Complex Drug Candidate. Top Catal 55, 446–452 (2012). https://doi.org/10.1007/s11244-012-9809-z

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