Development and kilogram-scale synthesis of mGlu5 negative allosteric modulator VU0424238 (auglurant)

Thomas K. David, Nayak K. Prashanth, M. Rajendraswami, Devendrareddy Pallalu, Arlindo L. Castelhano, Michael J. Kates, Anna L. Blobaum, Carrie K. Jones, Kyle A. Emmitte, P. Jeffrey Conn, Craig W. Lindsley

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Abstract

This communication details the kilogram-scale synthesis of N-(5-fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide (VU0424238, auglurant), a novel mGlu5 negative allosteric modulator (NAM) developed as an alternative treatment for depression. The process highlights a challenging pyridine N-oxidation sequence, an SNAr reaction, and the elimination of all chromatography steps (required in the medicinal chemistry route) with replacement by highly efficient recrystallizations (save one silica plug). The improved process was utilized for the preparation of a 1.2 kg toxicology batch, as well as a 2.82 kg GMP batch to support the Phase I trial, in very high purity (99.8%).

Original languageEnglish
Pages (from-to)3554-3558
Number of pages5
JournalTetrahedron Letters
Volume58
Issue number36
DOIs
StatePublished - 6 Sep 2017

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Keywords

  • Pyridine N-oxide
  • Recrystallization
  • SAr
  • mGlu NAM

Cite this

David, T. K., Prashanth, N. K., Rajendraswami, M., Pallalu, D., Castelhano, A. L., Kates, M. J., Blobaum, A. L., Jones, C. K., Emmitte, K. A., Conn, P. J., & Lindsley, C. W. (2017). Development and kilogram-scale synthesis of mGlu5 negative allosteric modulator VU0424238 (auglurant). Tetrahedron Letters, 58(36), 3554-3558. https://doi.org/10.1016/j.tetlet.2017.07.100