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.

Regioselective Control of the SNAr Amination of 5-Substituted-2,4-Dichloropyrimidines Using Tertiary Amine Nucleophiles

“…Notwithstanding the use of 2 equiv of NEt 3 , the reaction did not proceed further to give 4a . The implicit N -dealkylation that occurred from a cationic quaternary amine intermediate, presumably involving the liberated halide as the nucleophile, is a phenomenon observed previously in selected azine S N Ar chemistry, − as well as in less related synthetic transformations. , To our knowledge, our study is the first study to emphasize the regiochemical advantage of this S N Ar approach to pyrimidine functionalization. The identity of 3a as the product of this S N Ar reaction with NEt 3 was confirmed by X-ray analysis (Figure ).…”

Multi-gram Preparation of 7-Nitroquinoxalin-2-amine

“…10 This methodology uses higher amounts of amine and the removal of DMF was a time demanding issue. To circumvent these issues, a more environment friendly methodology was employed using 1.05 equivalent of amine and 3 equivalent of triethylamine in ethanol under refluxing conditions, 11 see Table 1. Corresponding p-methoxybenzylamine derivative (5) was obtained after solvent removal and water washing by filtration in good yields (> 90%).…”