tert-butyl N-piperazin-1-ylcarbamate

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

Procedure: Using (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (29.8 g, 137 mmol) and tert-butyl piperazin-1-ylcarbamate (28.9 g, 144 mmol) gave tert-butyl (S)-{4-[3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl]piperazin-1-yl}carbamate (36.68 g, yield 64%) as a white powder in the same manner as in Example 496.

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

Procedure: Using (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (29.8 g, 137 mmol) and tert-butyl piperazin-1-ylcarbamate (28.9 g, 144 mmol) gave tert-butyl (S)-{4-[3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl]piperazin-1-yl}carbamate (36.68 g, yield 64%) as a white powder in the same manner as in Example 496.

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

Procedure: Using 2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 6 (4.36 g, 20.0 mmol) and tert-butyl piperazin-1-ylcarbamate (4.44 g, 22.0 mmol) gave tert-butyl{4-[3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl]piperazin-1-yl}carbamate (6.08 g, yield 72%) as a white powder in the same manner as in Example 365.

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

Procedure: Using 2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 6 (4.36 g, 20.0 mmol) and tert-butyl piperazin-1-ylcarbamate (4.44 g, 22.0 mmol) gave tert-butyl{4-[3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl]piperazin-1-yl}carbamate (6.08 g, yield 72%) as a white powder in the same manner as in Example 365.

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

Procedure: A mixture of (2-methyl-2-oxiranylmethyl) toluene-4-sufonate (9.75 g, 40.3 mmol), tert-butyl piperazin-1-yl-carbamate (6.75 g, 33.5 mmol) prepared in Reference Example 36, triethylamine (7 ml, 50.3 mmol) and potassium iodide (6.68 g, 33.5 mmol) in DMF (70 ml) was stirred at room temperature overnight. The reaction mixture was poured into water, and extracted with ethyl acetate. The extract was washed with water and brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/acetone=4/1) to afford tert-butyl[4-(2-methyl-2-oxiranylmethyl)piperazin-1-yl]carbamate (4.66 g, yield 51%) as a colorless crystalline powder. extracted with ethyl acetate The extract was washed with water and brine dried over sodium sulfate filtered The filtrate was concentrated under reduced pressure The residue was purified by silica gel column chromatography (hexane/acetone=4/1)

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

Procedure: A mixture of (2-methyl-2-oxiranylmethyl) toluene-4-sufonate (9.75 g, 40.3 mmol), tert-butyl piperazin-1-yl-carbamate (6.75 g, 33.5 mmol) prepared in Reference Example 36, triethylamine (7 ml, 50.3 mmol) and potassium iodide (6.68 g, 33.5 mmol) in DMF (70 ml) was stirred at room temperature overnight. The reaction mixture was poured into water, and extracted with ethyl acetate. The extract was washed with water and brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/acetone=4/1) to afford tert-butyl[4-(2-methyl-2-oxiranylmethyl)piperazin-1-yl]carbamate (4.66 g, yield 51%) as a colorless crystalline powder. extracted with ethyl acetate The extract was washed with water and brine dried over sodium sulfate filtered The filtrate was concentrated under reduced pressure The residue was purified by silica gel column chromatography (hexane/acetone=4/1)

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

Procedure: Tert-butyl piperazin-1-yl-carbamate (403 mg, 2.0 mmol) was suspended in methylene chloride (4 ml), to which trifluoroacetic acid (1.6 ml) was added, and the mixture was stirred at room temperature for 5 minutes. To which 4-(trifluoromethyl)benzaldehyde (0.3 ml, 2.2 mmol) was added, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into sodium hydrogencarbonate aqueous solution, and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=9/1) to afford piperazin-1-yl-(4-trifluoromethylbenzylidene)-amine (432 mg, yield 84%) as a colorless crystalline powder. was added the resulting mixture was stirred at room temperature for 1 hour extracted with ethyl acetate The extract was washed with brine dried over sodium sulfate concentrated under reduced pressure The residue was purified by silica gel column chromatography (methylene chloride/methanol=9/1)

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

Procedure: Tert-butyl(4-benzylpiperazin-1-yl)carbamate (42.22 g, 145 mmol) prepared in Reference Example 35 was dissolved in ethanol (300 ml). To which 20% palladium hydroxide/carbon (6.0 g) was added, and the mixture was stirred at room temperature under an atmospheric pressure of hydrogen for 20 minutes, and then at 50° C. for 30 minutes. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. Thus obtained solid was washed with IPE, collected by filtration, and dried under reduced pressure to afford tert-butyl piperazin-1-yl-carbamate (28.9 g, yield 99%) as a colorless crystalline powder. The catalyst was removed by filtration the filtrate was concentrated under reduced pressure Thus obtained solid was washed with IPE collected by filtration dried under reduced pressure

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

Procedure: The title compound 4.0 g (96%) was obtained in a manner similar to the Manufacturing Example 83 by use of benzyl 4-oxocyclohexylcarbamate and tert-butyl 1-piperazinecarbamate, instead of tetrahydro-4H-pyran-4-one and tert-butyl piperidin-4-ylcarbamate, respectively.

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The same reaction procedure used in the reference of Tetrahedron Letters. Vol 35 839-842, 1994 was made. 15.78 g (84.7 mmol) of 1-(t-butoxycarbonylamino)piperazine, 6.85 ml (84.7 mmol) of pyridine and 15.1 ml (84.7 mmol) of diisopropylethylarine were dissolved in 200 ml of anhydrous toluene and then carbonic acid gas was intromitted for 1 hour under -10° C. The reaction solution was added to 80 ml of toluene solution of 10.6 ml (84.7 mmol) of thionylchloride being cooled under -10° C. and stirred for 1 hour. The reaction solution was added to 0.1 N hydrochloric acid and the toluene layer was separated out. The reaction mixture was dried over anhydride sodium sulfate and concentrated under reduced pressure. These crystals thus obtained were washed with hexane, whereby 13.7 g of 4-(2-methyl-2-propyloxycarbonyl)piperazine-1-carbonylchloride was obtained. The same reaction procedure the toluene layer was separated out The reaction mixture was dried over anhydride sodium sulfate concentrated under reduced pressure These crystals thus obtained were washed with hexane

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

Procedure: To a solution of N-(1-piperazinyl)-tert-butoxycarboxamide (15 g) in dichloromethane (200 ml) was added acetic anhydride (7.74 ml) and pyridine (6.63 ml). The mixture was stirred at ambient temperature for 1 hour. The solution was washed with saturated aqueous solution of sodium hydrogen carbonate and brine. The organic layer was collected, dried over magnesium sulfate, and concentrated. The residue was triturated with n-hexane to give N-(4-acetyl-1-piperazinyl)-tert-butoxycarboxamide (16.4 g). The solution was washed with saturated aqueous solution of sodium hydrogen carbonate and brine The organic layer was collected dried over magnesium sulfate concentrated The residue was triturated with n-hexane

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

Procedure: To a solution of N-(4-benzyloxycarbonyl-1-piperazinyl)-tert-butoxycarboxamide (28 g) in methanol (250 ml) was added 10% palladium on carbon (5 g), and the mixture was stirred at ambient temperature under 3 atm of hydrogen for 1 hour. Palladium on carbon was filtered off and the filtrate was concentrated to give N-(1-piperazinyl)-tert-butoxycarboxamide (17.6 g). Palladium on carbon was filtered off the filtrate was concentrated