(2R,5S)-1-benzyl-2,5-dimethylpiperazine

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (2R,5S)-1-benzyl-2,5-dimethylpiperazine (3.52 g, 17.2 mmol) in tetrahydrofuran (50 mL), trimethylamine (2.12 g, 20.9 mmol) and di-tert-butylcarbonate (4.56 g, 20.9 mmol) were added under ice-cold conditions, and the mixture was stirred for 15 minutes. Then, the mixture was stirred at room temperature for 5.5 hours. The reaction solution was added water, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/ethyl acetate), and the title compound (3.16 g, 60%) was obtained as a pale yellow oil. Then, the mixture was stirred at room temperature for 5.5 hours extracted with ethyl acetate washed with brine dried over sodium sulfate concentrated in vacuo The obtained residue was purified by silica-gel column chromatography (hexane/ethyl acetate)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (2R,5S)-1-benzyl-2,5-dimethylpiperazine (3.52 g, 17.2 mmol) in tetrahydrofuran (50 mL), trimethylamine (2.12 g, 20.9 mmol) and di-tert-butylcarbonate (4.56 g, 20.9 mmol) were added under ice-cold conditions, and the mixture was stirred for 15 minutes. Then, the mixture was stirred at room temperature for 5.5 hours. The reaction solution was added water, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/ethyl acetate), and the title compound (3.16 g, 60%) was obtained as a pale yellow oil. Then, the mixture was stirred at room temperature for 5.5 hours extracted with ethyl acetate washed with brine dried over sodium sulfate concentrated in vacuo The obtained residue was purified by silica-gel column chromatography (hexane/ethyl acetate)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 15 ml portion of pyridine solution containing 0.63 g of (2R,5S)-1-benzyl-2,5-dimethylpiperazine was mixed with 0.7 g of 4-fluoro-2-trifluoromethylbenzonitrile and stirred at 90° C. for 2 days. The reaction mixture was concentrated and the residue was purified by a silica gel column chromatography to obtain the title compound from n-hexane-ethyl acetate (9:2, v/v) as a white solid. The reaction mixture was concentrated the residue was purified by a silica gel column chromatography

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In an atmosphere of argon, 0.57 g of lithium aluminum hydride was added at 0° C. to 30 ml of THF solution containing 1.0 g of (3S,6R)-1-benzyl-3,6-dimethylpiperazine-2,5-dione, and the mixture was stirred overnight with heating under reflux. The reaction mixture was cooled to 0° C., 1.0 ml of water was added dropwise thereto and 1.0 ml of 10% aqueous sodium hydroxide was added dropwise thereto, and then the mixture was further mixed with 1.0 ml of water and stirred for 30 minutes. The precipitate was separated by filtration and washed with ethyl acetate, and the filtrate was washed with 10% aqueous potassium carbonate and saturated brine, dried over anhydrous magnesium sulfate, filtered and then concentrated. The residue was subjected to a silica gel column chromatography and eluted with chloroform-methanol-28% aqueous ammonia (25:1:0.1, v/v/v) to obtain 0.75 g of the title compound as a yellow oily substance. with heating under reflux stirred for 30 minutes The precipitate was separated by filtration washed with ethyl acetate the filtrate was washed with 10% aqueous potassium carbonate and saturated brine dried over anhydrous magnesium sulfate filtered concentrated eluted with chloroform-methanol-28% aqueous ammonia (25:1:0.1, v/v/v)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2(R),5(S)-Dimethyl-1-N-benzyl-piperazine (6.0 g, 29 mmol) was dissolved in dimethylformamide (100 mL), and triethylamine (6.4 mL, 44 mmol) and the mixture was placed under nitrogen. To the solution was added 2-fluoro-nitrobenzene (3.5 mL, 31 mmol). The reaction was heated at 100° C. for 72 hours The solution was evaporated in vacuo and redissolved in ethyl acetate (100 mL). The solution was then washed with saturated sodium bicarbonate solution (100 mL) and saturated brine solution (100 mL). The separated organic phase was dried over magnesium sulfate, filtered and the filtrate was evaporated in vacuo. The crude product was then purified by flash chromatography, eluting with ethyl acetate/methanol/triethylamine 85:10:5. The product (8.2 g) was dissolved in ethanol (250 mL). Palladium on charcoal catalyst (10% w/w, 2.2 g) was added to the solution and the solution was hydrogenated in a Parr apparatus at 3 bar for 3 hours. The solution was filtered and evaporated to give the aniline product. Yield (5.2 g, 87%) was evaporated in vacuo redissolved in ethyl acetate (100 mL) The solution was then washed with saturated sodium bicarbonate solution (100 mL) and saturated brine solution (100 mL) The separated organic phase was dried over magnesium sulfate filtered the filtrate was evaporated in vacuo The crude product was then purified by flash chromatography eluting with ethyl acetate/methanol/triethylamine 85:10:5 The product (8.2 g) was dissolved in ethanol (250 mL) Palladium on charcoal catalyst (10% w/w, 2.2 g) was added to the solution The solution was filtered evaporated

Conditions: temp:210.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3.81 g of (2R,5S)-1-benzyl-2,5-dimethylpiperazine in 20 ml of DMI were added 3.80 g of 4-fluoro-2-methylbenzonitrile and 7.27 g of diisopropylethylamine, followed by 2 days of stirring in a sealed tube at 210° C. After the addition of ethyl acetate to the reaction solution, the mixture was washed with water and the organic layer was dried over anhydrous sodium sulfate. The solvent was removed by evaporation and the resulting residue was purified by silica gel column chromatography to obtain 1.50 g of the title compound as a solid from an eluate eluted with hexane-ethyl acetate (85:15, v/v). the mixture was washed with water the organic layer was dried over anhydrous sodium sulfate The solvent was removed by evaporation the resulting residue was purified by silica gel column chromatography

Conditions: temp:210.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3.81 g of (2R,5S)-1-benzyl-2,5-dimethylpiperazine in 20 ml of DMI were added 3.80 g of 4-fluoro-2-methylbenzonitrile and 7.27 g of diisopropylethylamine, followed by 2 days of stirring in a sealed tube at 210° C. After the addition of ethyl acetate to the reaction solution, the mixture was washed with water and the organic layer was dried over anhydrous sodium sulfate. The solvent was removed by evaporation and the resulting residue was purified by silica gel column chromatography to obtain 1.50 g of the title compound as a solid from an eluate eluted with hexane-ethyl acetate (85:15, v/v). the mixture was washed with water the organic layer was dried over anhydrous sodium sulfate The solvent was removed by evaporation the resulting residue was purified by silica gel column chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (2R,5S)-1-benzyl-2,5-dimethylpiperazine (3.52 g, 17.2 mmol) in tetrahydrofuran (50 mL), trimethylamine (2.12 g, 20.9 mmol) and di-tert-butylcarbonate (4.56 g, 20.9 mmol) were added under ice-cold conditions, and the mixture was stirred for 15 minutes. Then, the mixture was stirred at room temperature for 5.5 hours. The reaction solution was added water, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/ethyl acetate), and the title compound (3.16 g, 60%) was obtained as a pale yellow oil. Then, the mixture was stirred at room temperature for 5.5 hours extracted with ethyl acetate washed with brine dried over sodium sulfate concentrated in vacuo The obtained residue was purified by silica-gel column chromatography (hexane/ethyl acetate)