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

Research output: Contribution to journalArticle

1 Citation (Scopus)

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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Pharmaceutical Chemistry
Chromatography
Silicon Dioxide
Toxicology
Modulators
Oxidation
Communication
pyridine
picolinamide

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., ... 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
David, Thomas K. ; Prashanth, Nayak K. ; Rajendraswami, M. ; Pallalu, Devendrareddy ; Castelhano, Arlindo L. ; Kates, Michael J. ; Blobaum, Anna L. ; Jones, Carrie K. ; Emmitte, Kyle A. ; Conn, P. Jeffrey ; Lindsley, Craig W. / Development and kilogram-scale synthesis of mGlu5 negative allosteric modulator VU0424238 (auglurant). In: Tetrahedron Letters. 2017 ; Vol. 58, No. 36. pp. 3554-3558.
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David, TK, Prashanth, NK, Rajendraswami, M, Pallalu, D, Castelhano, AL, Kates, MJ, Blobaum, AL, Jones, CK, Emmitte, KA, Conn, PJ & Lindsley, CW 2017, 'Development and kilogram-scale synthesis of mGlu5 negative allosteric modulator VU0424238 (auglurant)', Tetrahedron Letters, vol. 58, no. 36, pp. 3554-3558. https://doi.org/10.1016/j.tetlet.2017.07.100

Development and kilogram-scale synthesis of mGlu5 negative allosteric modulator VU0424238 (auglurant). / David, Thomas K.; Prashanth, Nayak K.; Rajendraswami, M.; Pallalu, Devendrareddy; Castelhano, Arlindo L.; Kates, Michael J.; Blobaum, Anna L.; Jones, Carrie K.; Emmitte, Kyle A.; Conn, P. Jeffrey; Lindsley, Craig W.

In: Tetrahedron Letters, Vol. 58, No. 36, 06.09.2017, p. 3554-3558.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Development and kilogram-scale synthesis of mGlu5 negative allosteric modulator VU0424238 (auglurant)

AU - David, Thomas K.

AU - Prashanth, Nayak K.

AU - Rajendraswami, M.

AU - Pallalu, Devendrareddy

AU - Castelhano, Arlindo L.

AU - Kates, Michael J.

AU - Blobaum, Anna L.

AU - Jones, Carrie K.

AU - Emmitte, Kyle A.

AU - Conn, P. Jeffrey

AU - Lindsley, Craig W.

PY - 2017/9/6

Y1 - 2017/9/6

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AB - 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%).

KW - Pyridine N-oxide

KW - Recrystallization

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JO - Tetrahedron Letters

JF - Tetrahedron Letters

SN - 0040-4039

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David TK, Prashanth NK, Rajendraswami M, Pallalu D, Castelhano AL, Kates MJ et al. Development and kilogram-scale synthesis of mGlu5 negative allosteric modulator VU0424238 (auglurant). Tetrahedron Letters. 2017 Sep 6;58(36):3554-3558. https://doi.org/10.1016/j.tetlet.2017.07.100