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

doi:10.1016/j.tetlet.2017.07.100

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 journal › Article › peer-review

3 Scopus citations

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 S_NAr 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 language	English
Pages (from-to)	3554-3558
Number of pages	5
Journal	Tetrahedron Letters
Volume	58
Issue number	36
DOIs	https://doi.org/10.1016/j.tetlet.2017.07.100
State	Published - 6 Sep 2017

Keywords

Pyridine N-oxide
Recrystallization
SAr
mGlu NAM

Access to Document

10.1016/j.tetlet.2017.07.100

Cite this

@article{883a08f9b19f4781b0a256abe73c1a58,

title = "Development and kilogram-scale synthesis of mGlu5 negative allosteric modulator VU0424238 (auglurant)",

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%).",

keywords = "Pyridine N-oxide, Recrystallization, SAr, mGlu NAM",

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

year = "2017",

month = sep,

day = "6",

doi = "10.1016/j.tetlet.2017.07.100",

language = "English",

volume = "58",

pages = "3554--3558",

journal = "Tetrahedron Letters",

issn = "0040-4039",

publisher = "Elsevier Ltd",

number = "36",

}

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

N2 - 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%).

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

KW - SAr

KW - mGlu NAM

UR - http://www.scopus.com/inward/record.url?scp=85026815116&partnerID=8YFLogxK

U2 - 10.1016/j.tetlet.2017.07.100

DO - 10.1016/j.tetlet.2017.07.100

M3 - Article

AN - SCOPUS:85026815116

SN - 0040-4039

VL - 58

SP - 3554

EP - 3558

JO - Tetrahedron Letters

JF - Tetrahedron Letters

IS - 36

ER -

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

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this