Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2011 Dec 5;16(12):10013-28.
doi: 10.3390/molecules161210013.

Tertiary alkylamines as nucleophiles in substitution reactions at heteroaromatic halide during the synthesis of the highly potent pirinixic acid derivative 2-(4-chloro-6-(2,3-dimethylphenylamino)pyrimidin-2-ylthio)octanoic acid (YS-121)

Matthias Gabler  1 , Manfred Schubert-Zsilavecz
Affiliations

Tertiary alkylamines as nucleophiles in substitution reactions at heteroaromatic halide during the synthesis of the highly potent pirinixic acid derivative 2-(4-chloro-6-(2,3-dimethylphenylamino)pyrimidin-2-ylthio)octanoic acid (YS-121)

Matthias Gabler et al. Molecules. .

Abstract

YS-121 [2-(4-chloro-6-(2,3-dimethylphenylamino)pyrimidin-2-ylthio)octanoic acid] is the result of target-oriented structural derivatization of pirinixic acid. It is a potent dual PPARα/γ-agonist, as well as a potent dual 5-LO/mPGES-1-inhibitor. Additionally, recent studies showed an anti-inflammatory efficacy in vivo. Because of its interference with many targets, YS-121 is a promising drug candidate for the treatment of inflammatory diseases. Ongoing preclinical studies will thus necessitate huge amounts of YS-121. To cope with those requirements, we have optimized the synthesis of YS-121. Surprisingly, we isolated and characterized byproducts during the resulting from nucleophilic aromatic substitution reactions by different tertiary alkylamines at a heteroaromatic halide. These amines should actually serve as assisting bases, because of their low nucleophilicity. This astonishing fact was not described in former publications concerning that type of reaction and, therefore, might be useful for further reaction improvement in general. Furthermore, we could develop a proposal for the mechanism of that byproduct formation.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Chemical structure of pirinixic acid.
Figure 2
Figure 2
Chemical structure of YS-121.
Scheme 1
Scheme 1
Synthesis of YS-121 2 including byproduct formation and optimization step.
Figure 3
Figure 3
Chemical structure of the isolated byproduct 8.
Figure 4
Figure 4
Chemical structure of the isolated byproduct 9.
Figure 5
Figure 5
Chemical structure of the Meisenheimer complex intermediate 10.
Figure 6
Figure 6
Chemical structure of the isolated byproduct 11.
Figure 7
Figure 7
Chemical structure of the isolated byproduct 12.
Figure 8
Figure 8
Chemical structures of not isolated hypothetical intermediates of the respective intermediate stages during reaction with N-methylpyrrolidine.
Scheme 2
Scheme 2
Postulated mechanism of byproduct formation.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Santilli A.A., Scotese A.C., Tomarelli R.M. A potent antihypercholesterolemic agent: [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid (Wy-14643) Experientia. 1974;30:1110–1111. - PubMed
    1. Reddy J.K., Moody D.E., Azarnoff D.L., Tomarelli R.M. Hepatic effects of some [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio] acetic acid (WY-14,643) analogs in the mouse. Arch. Int. Pharmacodyn. Ther. 1977;225:51–57. - PubMed
    1. Issemann I., Green S. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature. 1990;347:645–650. doi: 10.1038/347645a0. - DOI - PubMed
    1. Kliewer S.A., Forman B.M., Blumberg B., Ong E.S., Borgmeyer U., Mangelsdorf D.J., Umesono K., Evans R.M. Differential expression and activation of a family of murine peroxisome proliferator-activated receptors. Proc. Natl. Acad. Sci. USA. 1994;91:7355–7359. - PMC - PubMed
    1. Willson T.M., Brown P.J., Sternbach D.D., Henke B.R. The PPARs: From orphan receptors to drug discovery. J. Med. Chem. 2000;43:527–550. doi: 10.1021/jm990554g. - DOI - PubMed

MeSH terms

Substances

LinkOut - more resources