Application | 1-BOC-(2S,6R)-2, 6-dimethylpiperazine is a commonly used drug design fragment, which can be selectively protected by (2S,6R)-2, 6-dimethylpiperazine via CbzCl, the remaining secondary amine was again protected with Boc anhydride and the Cbz protection was finally removed to give the title compound. |
preparation | [step 1](3S,5R)-3, benzyl 5-dimethylpiperazine-1-carboxylate (2S,6R)-2, 6-dimethylpiperazine (10.000g,87.573mmol) and triethylamine (18.309mL,131.360mmol) the solution in dichloromethane (300mL) was mixed with benzyl chloroformate (13.752mL,96.331mmol) at 0 °c and stirred at the same temperature for 2 hours. Next, a saturated aqueous solution of potassium bicarbonate was added to the reaction mixture followed by extraction with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. Benzyl (3S,5R)-3, 5-dimethylpiperazine-1-carboxylate was used without further purification (11.000g,50.6%, pale yellow oil). [Step 2]4-benzyl 1-tert-butyl (2R,6S)-2, 6-dimethylpiperazine-1, 4-dicarboxylate (3S,5R) prepared at room temperature-Benzyl 3, 5-dimethylpiperazine-1-carboxylate (11.000g,44.296mmol), di-tert-butyl dicarbonate (10.634g,48.725mmol) and triethylamine (9.261mL,66.444mmol) in dichloromethane (300mL) The solution was stirred at the same temperature for 18 hours. Next, water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The concentrate was purified by column chromatography and concentrated (SiO2,12G cartridge; Ethyl acetate/hexane = 0 to 20%), 4-benzyl 1-tert-butyl (2R,6S)-2, 6-dimethylpiperazine-1, 4-dicarboxylate (6.350g,41.2%) was obtained as a pale yellow oil. [Step 3]1-BOC-(2S,6R)-2, 6-dimethylpiperazine to 4-benzyl 1-tert-butyl (2R,6S)-2, 6-dimethylpiperazine -1, 4-dicarboxylate A stirred solution of (6.350g,18.224mmol) in ethanol (10% ml) was slowly added dropwise 2, 4-pd/C(1g) at room temperature. The reaction mixture was stirred at the same temperature for a further 17 hours under hydrogen atmosphere (H2 balloon), filtered through a Celite pad to remove solids, and concentrated under reduced pressure. (2R,6S)-2, 6-dimethylpiperazine-1-carboxylic acid tert-butyl ester was used without further purification (3.820g,97.8%, yellow oil). |