Hydrochloric Acid → 1-Ethoxycarbonyl-cis-3,5-dimethylpiperazine

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Reaction Steps

To a solution of 50 grams of cis-2,6-dimethylpiperazine in 130 ml. of water and containing bromphenol blue as indicator, there is added, with stirring and cooling, a solution of 100 ml. of concentrated hydrochloric acid in 500 ml. of water until the bromphenol blue just turns yellow. Then, 47.7 grams of ethyl chloroformate is introduced in 5 ml. portions by rapid, dropwise addition with stirring. After each 5 ml. addition, aqueous 25% sodium hydroxide solution is added dropwise until the indicator turns green. The addition of reactants is continued until thin layer chromatography shows that all of the piperazine has reacted. The reaction mixture is then made alkaline with aqueous 50% sodium hydroxide solution and then extracted with ethyl ether. The combined ether extracts are dried over anhydrous sodium sulfate and then chromatographed on a low pressure silica gel column using a mixture of 2% ethanol, 0.25% concentrated ammonium hydroxide and 97.75% methylene chloride to apply the reaction mixture to the column. Fractions are collected from the column by elution with this solvent and the solvent is evaporated to leave pure 1-ethoxycarbonyl-cis-3,5-dimethylpiperazine. The column is further eluted with a mixture of 5% ethanol, 0.25% concentrated ammonium hydroxide and 94.75% methylene chloride and the solvent is evaporated from the fractions collected to leave a residue which is 1-ethoxycarbonyl-cis-2,6-dimethylpiperazine.

Provenance & Evidence