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Molecules 2011, 16(12), 10013-10028; doi:10.3390/molecules161210013
Communication

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)

 and *
Received: 18 November 2011; Accepted: 30 November 2011 / Published: 5 December 2011
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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.
Keywords: YS-121; pirinixic acid; reaction improvement; nucleophilic aromatic substitution reaction at heteroaromatic halide by tertiary alkylamines; byproduct formation mechanism YS-121; pirinixic acid; reaction improvement; nucleophilic aromatic substitution reaction at heteroaromatic halide by tertiary alkylamines; byproduct formation mechanism
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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MDPI and ACS Style

Gabler, M.; Schubert-Zsilavecz, M. 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). Molecules 2011, 16, 10013-10028.

AMA Style

Gabler M, Schubert-Zsilavecz M. 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). Molecules. 2011; 16(12):10013-10028.

Chicago/Turabian Style

Gabler, Matthias; Schubert-Zsilavecz, Manfred. 2011. "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)." Molecules 16, no. 12: 10013-10028.


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