Triazolo piperazines

Treatment of 18 with ethylenediamine afforded the desired triazolo piperazine 3 at room temperature albeit in low yields. Attempts to improve the reaction revealed that when the oxadiazole was added to two equivalents of ethylenediamine in methanol at 0 °C, a new species crystallized directly from the reaction mixture. This solid was isolated, identified as the amidine 20, and was found to convert to 3 by refiuxing in methanol for 4h (Scheme 5.11). The formation of amidine 20 was curious since it suggested that initial attack of ethylenediamine did not occur at the carbon of the oxadiazole vicinal to the trifluoromethyl group. Of the three carbons of the oxadiazole which need to react with ethylenediamine, this would easily be rationalized as the most electrophilic. In order to understand the mecha-... 

Some piperazine-containing [l,2,4]triazolo[2,3-a][l,3,5]triazines, for example, 308 and 309, have been shown to be potent and selective adenosine A2a receptor antagonists <2004BML4831, 2004JME6218, 2005JME2009>. 

Trazodone Trazodone, 2-[3-[4-(m-chlorophenyl)-l-piperazineyl]propyl]-s-triazolo[4,3-a] piridine-3(2H)-one (7.3.8), is synthesized from 2-chloropiridine, the reaction of which with semicarbazide gives s-triazolo-3-one[4,3-a]pyridine (7.3.7). Alkylation of this product using l-(3-chloropropyl)-4-(3-chlorophenyl)piperazine gives trazodone (7.3.8) [61,62]. 

An alternahve method had been reported in the literature [12] to prepare [1,2,4] triazolo[4,3-a]piperazines (Route B, Scheme 5.9) via the condensahon of a chloromethyl oxadiazole with 1,2-phenylenediamine to afford the benzo fused compounds. The reachon condihons reported for this approach were harsh and the yields were low, presumably due to the poor nucleophilicity of 1,2-phenylenedi-amine. However, we felt that the synthesis of 3 could potentially be accomplished under milder reachon condihons because of the enhanced nucleophilicity of... 

Disposition in the Body. Rapidly and almost completely absorbed after oral administration. It is extensively metabolised by hydroxylation and oxidation. About 75% of a dose is excreted in the urine as metabolites and 15% is eliminated in the faeces, in 72 hours. Less than 1% of a dose is excreted in the urine as unchanged drug. The major urinary metabolites are a propionic acid derivative (3-oxo-l,2,4-triazolo[4,3- ]pyridine-2-propionic acid), /7-hydroxytrazodone, and a dihydrodiol derivative and its glucuronide and sulphate conjugates, which account for about 35%, 20%, and 15% of the urinary material respectively an N-oxide has also been identified. In plasma, the major metabolite is l-(3-chlorophenyl)piperazine (active), but this accounts for less than 1% of a dose in the urine. 

Oxadiazoles have been utilized in the synthesis of 1,2,4-triazoles. Condensation of highly reactive chloromethyloxadiazoles 171 with ethylenediamines 172 afforded amidines 173, which under reflux in methanol, gave [l,2,4]triazolo[4,3-a]piperazines 174 <050L1039>. Reaction of... 

The synthesis of piperazine-derived 2-furan-2-yl[l,2,4]triazolo[l,5-n ]pyrazines was carried out using 3-amino-2-pyrazine carboxylate. The introduction of the piperazine to the pyrazine template was achieved through a pteridin-4-one intermediate <05H2321>. 

Y Steele, R D Chirico, S E Knipmeyer, A Nguyen, N K Smith. Thermodynsmic properties and ideal-gas enthalpies of formation of dicyclohexyl sulfide, diethyl-enetriamine, di-n-octyl sulfide, dimethyl carbonate, piperazine, hexachloroprop-1-ene, tetrakis (dimethylaminojethylene, N,N -bis(2-hydroxyethyl)ethylenediamine, and l,2,4-triazolo l,5-a pyrimidine. J Chem Eng Data42 1031-1052,1997. 

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