title: 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).
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.
authors.affiliation: Goethe-University Frankfurt, Institute of Pharmaceutical Chemistry, Max-von-Laue-Str. 9, D-60438 Frankfurt/M., Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Gabler
authors.forename: Manfred
authors.initials: M
authors.lastname: Schubert-Zsilavecz
mesh_terms: D000588:Amines / Q000737:chemistry*; D006846:Hydrocarbons, Halogenated / Q000138:chemical synthesis / Q000737:chemistry*; D008956:Models, Chemical; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000302:isolation & purification
chemical_list: C548544:2-(4-chloro-6-(2,3-dimethylphenylamino)pyrimidin-2-ylthio)octanoic acid; D000588:Amines; D006846:Hydrocarbons, Halogenated; D011743:Pyrimidines; C006253:pirinixic acid