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)

  • 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.

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Metadaten
Author:Matthias Gabler, Manfred Schubert-ZsilaveczGND
URN:urn:nbn:de:hebis:30:3-253130
DOI:https://doi.org/10.3390/molecules161210013
ISSN:1420-3049
Parent Title (English):Molecules
Publisher:Molecular Diversity Preservation International (MDPI)
Place of publication:Basel
Document Type:Article
Language:English
Date of Publication (online):2012/06/27
Date of first Publication:2011/12/05
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2012/06/27
Volume:16
Issue:12
Page Number:16
First Page:10013
Last Page:10028
HeBIS-PPN:357590783
Institutes:Biochemie, Chemie und Pharmazie / Biochemie und Chemie
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 54 Chemie / 540 Chemie und zugeordnete Wissenschaften
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 3.0