The fully protected Methyl N-4-Boc-N-1-Cbz-2-piperazinecarboxylate was prepared from 2-piperazinecarboxylic acid as shown in the below figure. Using a sequential one-pot protection procedure similar to that used to protect lysine, a solution of 2-piperazinecarboxylic acid (24.1 g, 0.185 mol) in 1:1 dioxane-water (1.2 L) was maintained at pH 11 with 50% aqueous sodium hydroxide during the addition of a solution of 2-(t-butyloxycarbonyloxyimino)-2-phenylacetonitrile (BOC-ON, 51 g, 0.21 mol) in dioxane (0.3 L). After 3 h, the reaction mixture was cooled in an ice bath and the pH was adjusted to pH 9.5 with 6 N HCl. Benzylchloroformate was added dropwise to the cold solution while maintaining the pH with 50% aqueous sodium hydroxide. The reaction was warmed to room temperature and stirred for 24 h. The solution was washed with diethyl ether (4 x 250 mL), the aqueous layer was acidified to pH 2 and extracted with ethyl acetate (4 x 250 mL) . The organic layer was dried over magnesium sulfate, filtered and evaporated to give a pale yellow oil.
The methyl ester 5(Methyl N-4-Boc-N-1-Cbz-2-piperazinecarboxylate) was obtained by treatment of a tetrahydrofuran solution of the crude acid with excess diazomethane. Alternatively, the methyl ester could be obtained on large scale by treatment of a saturated sodium bicarbonate solution of the intermediate carboxylic acid 4 with a methylene chloride solution of methyl iodide and Adogen 464, or preferably by refluxing an acetone solution of the carboxylic acid, dimethyisulfate and potassium carbonate.
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