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To a solution of (2i?,65)-2,6-dimethylpiperazine (8.0 g, 70.1 mmol) in DCM (70 niL) was added triethylamine (9.78 niL, 70.1 mmol). The reaction mixture was cooled to 0 0C and benzyl chlorocarbonate (9.86 mL, 70.1 mmol) was added. After stirring at 0 0C for 1 hour, the reaction was warmed to rt. The reaction mixture was washed with brine, dried (Na2SO4), concentrated and the residue purified with silica chromatography (Hex:EtOAc 1 :1 to EtOAc to EtOAc:MeOH 10:1) to give 13.48g (77 percent) of a colorless oil
50.6%
With triethylamine In dichloromethane at 0℃; for 2 h;
[5013] A solution of (2S,6R)-2,6-dimethylpiperazine (10.000 g, 87.573 mmol) and tri- ethylamine ( 18.309 mL, 131.360 mmol) in dichloromethane (300 inL) was mixed at 0 °C with benzyl chloroformate ( 13.752 mL, 96.331 mmol) and stirred at the same temperature for 2 hr. Then, saturated aqueous potassium bicarbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with aqueous saturated sodium chloride solution, dried with anhydrous MgS0 , filtered, and concentrated in vacuo. Benzyl (3S,5R)-3,5-dimethylpiperazine- l -carboxylate was used without further purification ( 1 1.000 g, 50.6 percent, pale yellow oil).
With triethylamine; In dichloromethane; at 0 - 20℃;
To a solution of (2i?,65)-2,6-dimethylpiperazine (8.0 g, 70.1 mmol) in DCM (70 niL) was added triethylamine (9.78 niL, 70.1 mmol). The reaction mixture was cooled to 0 0C and benzyl chlorocarbonate (9.86 mL, 70.1 mmol) was added. After stirring at 0 0C for 1 hour, the reaction was warmed to rt. The reaction mixture was washed with brine, dried (Na2SO4), concentrated and the residue purified with silica chromatography (Hex:EtOAc 1 :1 to EtOAc to EtOAc:MeOH 10:1) to give 13.48g (77 %) of a colorless oil
50.6%
With triethylamine; In dichloromethane; at 0℃; for 2.0h;
[5013] A solution of (2S,6R)-2,6-dimethylpiperazine (10.000 g, 87.573 mmol) and tri- ethylamine ( 18.309 mL, 131.360 mmol) in dichloromethane (300 inL) was mixed at 0 C with benzyl chloroformate ( 13.752 mL, 96.331 mmol) and stirred at the same temperature for 2 hr. Then, saturated aqueous potassium bicarbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with aqueous saturated sodium chloride solution, dried with anhydrous MgS0 , filtered, and concentrated in vacuo. Benzyl (3S,5R)-3,5-dimethylpiperazine- l -carboxylate was used without further purification ( 1 1.000 g, 50.6 %, pale yellow oil).
With tetra-(n-butyl)ammonium iodide; potassium carbonate; In ISOPROPYLAMIDE; at 120℃; for 20.0h;
To a solution of (3i?,55)-benzyl 3,5-dimethylpiperazine-l-carboxylate (Method 108, 5.0 g, 20.1 mmol) in DMA (25 mL) was added tetrabutylammonium iodide (7.44 g, 20.1 mmol), potassium carbonate (5.57 g, 40.3 mmol) and (2-bromoethoxy)(te/t- butyl)dimethylsilane (8.67 g, 36.2 mmol). The reaction mixture was stirred at 120 0C for 20 hours, then concentrated. DCM (5OmL) was added, and the organic layer was washed with H2O, dried (Na2SO4), concentrated and purified with silica chromatography to give 7.2g (88 %) of a brown oil
tert-butyl (2S,6R)-4-(4-(N-(2-fluoro-4-(methoxycarbonyl)benzyl)-1,1-dioxidothiomorpholine-4-carboxamido)benzyl)-2,6-dimethylpiperazine-1-carboxylate[ No CAS ]
4-benzyl 1-(tert-butyl) (2R,6S)-2,6-dimethylpiperazine-1,4-dicarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
41.2%
With triethylamine; In dichloromethane; at 20℃; for 18.0h;
[5016] A solution of benzyl (3S,5R)-3,5-dimethylpiperazine- l -carboxylate ( 1 1.000 g, 44.296 mmol), di-tert-butyl dicarbonate ( 10.634 g, 48.725 mmol) and triethylamine (9.261 mL, 66.444 mmol) in dichloromethane (300 mL) prepared at the room temperature was stirred at the same temperature for 18 hr. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with aqueous saturated sodium chloride solution, dried with anhydrous MgS04 , filtered, and concentrated in vacuo. The concentrate was purified and concentrated by column chromatography (Si02, 12 g cartridge; ethyl acetate / hexane = 0 % to 20 %) to give 4-benzyl l -(tert-butyl ) (2R,6S )-2,6-dimethylpiperazine- l ,4-dicarboxylate as pale yellow oil (6.350 g, 41.2 % ).
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