Preparative Route to 2‐Ethoxycarbonylimidazole‐4‐phosphonate (V) and Diethyl Imidazole‐2,4‐dicarboxylate (XI).

Abstract

Practical synthesis of 2-ethoxycarbonylimidazole-4-phosphonate (1a) and diethyl imidazole-2,4-dicarboxylate (1b) are described.J. Heterocyclic Chem., 40, 159 (2003).Over the last twenty years, it has been well established that L-glutamate was the major excitatory neurotransmitter in the mammalian central nervous system (CNS) [1]. Glutamate plays an essential role in many physiological CNS functions through the activation of three major types of postsynaptic ionotropic receptors designated according to the non-natural substances that selectively activates them: NMDA (N-Methyl-D-Aspartate), AMPA 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid) and Kainate receptors. In addition, glutamate activates several types of metabotropic receptors signalling through a G-protein coupled [2]. In connection with our program aimed at the development of potent and selective AMPA antagonists as source of potential drugs for cerebral ischemia or epilepsy [3], we needed to develop easy and efficient methods leading to 2-ethoxycarbonylimidazole-4-phosphonate (1a, Scheme 1) and diethyl imidazole-2,4-dicarboxylate (1b, Scheme 2) [4].To our knowledge, few phosphorylated imidazoles were already described. Thus, the imidazol-2-ylphosphonic acids were prepared by direct action of the corresponding N-protected imidazoles with various phosphorus (V) acid chlorides following hydrolysis . Likewise, relatively few 1H-Imidazole-2,4-dicarboxylates have been synthesized to date. Thus, 1b was only prepared via the hydrogenation of diethyl 1-(p-methoxybenzyl)imidazole-2,4-dicarboxylate which was obtained in a two steps synthesis from 2-amino-2-cyano acetate and 1-ethoxycarbonylformimidate in a 25 % overall yield [6]. The corresponding dimethyl imidazole-2,4-dicarboxylate was synthesized by photolysis of methyl (E)-3-(5-methoxycarbonyltetrazol-1-yl) propenoate [7]. 2-Carboxy-4-carbomethoxyimidazole has been obtained by the condensation of ethyl amino-oximinoacetate with methylpropiolate followed by an in situ thermolysis reaction [8]. Finally, diethyl 4-amino-1-(H)imidazole-2,5-dicarboxylate has been prepared from carboxyethoxyformimidate [9].Preparation of 2-Ethoxycarbonylimidazole-4-phosphonate (1a).As outlined in Scheme 1 (Pathway A), our fist attempt was based on the simple 5-lithiation reaction [10]

Stable triazolylphosphonate analogues of phosphohistidine

“…Our synthetic endeavours began with the thermal Huisgen cycloaddition (Dondoni et al 2004) of the known phosphonate 10 (Vuilhorgne et al 2003) and serine-derived azide 9a (Boger et al 1994). Gratifyingly, this reaction gave both of the desired triazole regioisomers 11a and 12a (Scheme 1; Table 1), which were easily separable by column chromatography.…”