tert-butyl 4-(cyclopropylmethyl)piperazine-1-carboxylate

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

Procedure: 1-Tertbutoxycarbonylpiperazine (6a) (1.86 g, 10 mmol) was dissolved in dichloromethane (20 mL), and anhydrous potassium carbonate (829 mg, 6 mmol) was added. The dichloromethane solution of chloromethyl cyclopropane (7a) (1.1 mL, 12 mmol) was added dropwise, and reacted overnight at room temperature, after that, the reaction mixture was washed with water. The water layer was extracted with dichloromethane for twice, the organic phases were combined, washed successively with 50 mL saturated sodium bicarbonate solution and saturated sodium chloride solution for three times, dried with anhydrous sodium sulfate. Column chromatography (petroleum ether:ethyl acetate 2:1) was performed to isolate white solid powder 1-tertbutoxycarbonyl-4-(cyclopropylmethyl)piperazine (7b), 2.01 g white solid (yield 79.0%). ESI-MS m/z calculated for: 240.18. found: 241.05 [M+H]+. reacted overnight at room temperature after that, the reaction mixture was washed with water The water layer was extracted with dichloromethane for twice, the organic phases washed successively with 50 mL saturated sodium bicarbonate solution and saturated sodium chloride solution for three times dried with anhydrous sodium sulfate

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

Procedure: 1-Tertbutoxycarbonylpiperazine (6a) (1.86 g, 10 mmol) was dissolved in dichloromethane (20 mL), and anhydrous potassium carbonate (829 mg, 6 mmol) was added. The dichloromethane solution of chloromethyl cyclopropane (7a) (1.1 mL, 12 mmol) was added dropwise, and reacted overnight at room temperature, after that, the reaction mixture was washed with water. The water layer was extracted with dichloromethane for twice, the organic phases were combined, washed successively with 50 mL saturated sodium bicarbonate solution and saturated sodium chloride solution for three times, dried with anhydrous sodium sulfate. Column chromatography (petroleum ether:ethyl acetate 2:1) was performed to isolate white solid powder 1-tertbutoxycarbonyl-4-(cyclopropylmethyl)piperazine (7b), 2.01 g white solid (yield 79.0%). ESI-MS m/z calculated for: 240.18. found: 241.05 [M+H]+. reacted overnight at room temperature after that, the reaction mixture was washed with water The water layer was extracted with dichloromethane for twice, the organic phases washed successively with 50 mL saturated sodium bicarbonate solution and saturated sodium chloride solution for three times dried with anhydrous sodium sulfate

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

Procedure: Tert-butyl 4-(cyclopropylmethyl)piperazine-1-carboxylate 31a (2 g, 8.30 mmol) was dissolved in 40 mL of dichloromethane followed by the addition of 20 mL of a 4 M solution of hydrogen chloride in dioxane. The reaction solution was stirred for 0.5 hours. The reaction solution was concentrated under reduced pressure followed by the addition of 40 mL of dichloromethane and dropwise with 20 mL of triethylamine to adjust pH to 10 to 11. The resulting solution was concentrated under reduced pressure. The residue was added with 50 mL of ethyl acetate and filtered. The filtrate was concentrated under reduced pressure, added with 50 mL of ethyl acetate and 20 mL of water, then added with (R)-2-chloromethyl-oxirane (0.92 g, 9.96 mmol) and sodium hydroxide (0.66 g, 16.60 mmol). The reaction solution was stirred for 12 hours. The reaction solution was concentrated under reduced pressure, added with 50 mL of water and extracted with dichloromethane (50 mL×3). The combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 1-(cyclopropylmethyl)-4-[[(2R)-oxiran-2-yl]methyl]piperazine 31b (0.91 g, yield: 57.0%) as a yellow oil. The reaction solution was concentrated under reduced pressure followed by the addition of 40 mL of dichloromethane and dropwise with 20 mL of triethylamine The resulting solution was concentrated under reduced pressure The residue was added with 50 mL of ethyl acetate filtered The filtrate was concentrated under reduced pressure added with 50 mL of ethyl acetate and 20 mL of water The reaction solution was stirred for 12 hours The reaction solution was concentrated under reduced pressure added with 50 mL of water extracted with dichloromethane (50 mL×3) The combined organic phase was washed with saturated sodium chloride solution (50 mL) dried over anhydrous magnesium sulfate The filtrate was concentrated under reduced pressure The resulting residue was purified by silica gel column chromatography

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

Procedure: Tert-butyl piperazine-1-carboxylate 7a (6.14 g, 33 mmol), bromomethyl-cyclopropane (4.05 g, 30 mmol) and triethylamine (6.06 g, 60 mmol) were dissolved in 70 mL of dichloromethane. The reaction solution was stirred for 12 hours. The resulting solution was added with 50 mL of aqeuous saturated sodium bicarbonate solution and extracted with dichloromethane (50 mL×3). The combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound tert-butyl 4-(cyclopropylmethyl)piperazine-1-carboxylate 31a (4.50 g, yield: 62.5%) as a yellow oil. extracted with dichloromethane (50 mL×3) The combined organic phase was washed with saturated sodium chloride solution (50 mL) dried over anhydrous magnesium sulfate The filtrate was concentrated under reduced pressure The resulting residue was purified by silica gel column chromatography

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

Procedure: Tert-butyl piperazine-1-carboxylate 7a (6.14 g, 33 mmol), bromomethyl-cyclopropane (4.05 g, 30 mmol) and triethylamine (6.06 g, 60 mmol) were dissolved in 70 mL of dichloromethane. The reaction solution was stirred for 12 hours. The resulting solution was added with 50 mL of aqeuous saturated sodium bicarbonate solution and extracted with dichloromethane (50 mL×3). The combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound tert-butyl 4-(cyclopropylmethyl)piperazine-1-carboxylate 31a (4.50 g, yield: 62.5%) as a yellow oil. extracted with dichloromethane (50 mL×3) The combined organic phase was washed with saturated sodium chloride solution (50 mL) dried over anhydrous magnesium sulfate The filtrate was concentrated under reduced pressure The resulting residue was purified by silica gel column chromatography

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

Procedure: Tert-butyl piperazine-1-carboxylate 7a (6.14 g, 33 mmol), bromomethyl-cyclopropane (4.05 g, 30 mmol) and triethylamine (6.06 g, 60 mmol) were dissolved in 70 mL of dichloromethane. The reaction solution was stirred for 12 hours. The resulting solution was added with 50 mL of aqeuous saturated sodium bicarbonate solution and extracted with dichloromethane (50 mL×3). The combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound tert-butyl 4-(cyclopropylmethyl)piperazine-1-carboxylate 31a (4.50 g, yield: 62.5%) as a yellow oil. extracted with dichloromethane (50 mL×3) The combined organic phase was washed with saturated sodium chloride solution (50 mL) dried over anhydrous magnesium sulfate The filtrate was concentrated under reduced pressure The resulting residue was purified by silica gel column chromatography

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-tert-butyloxycarbonylpiperazine (2.24 g, 12.0 mmol) in THF (10 ml) were added water (0.15 ml), acetic acid (3.60 ml), formylcyclopropane (1.35 ml, 18.1 mmol), and sodium cyanoborohydride (18 ml of a 1M solution in THF, 18 mmol). The mixture was stirred at 20° C. for 14 hours. The mixture is concentrated under reduced pressure, and the residue is mixed with water (80 ml) and 1 N aqueous hydrochloric acid (40 ml). After washing with ethyl acetate (20 ml) the aqueous phase is made basic by addition of potassium carbonate (approx. 20 g) and extracted with ethyl acetate (4×30 ml). The combined extracts were dried with magnesium sulphate and concentrated under reduced pressure, to yield 2.3 g (80%) of the title compound as a colourless oil. The mixture is concentrated under reduced pressure the residue is mixed with water (80 ml) and 1 N aqueous hydrochloric acid (40 ml) After washing with ethyl acetate (20 ml) the aqueous phase is made basic by addition of potassium carbonate (approx. 20 g) extracted with ethyl acetate (4×30 ml) The combined extracts were dried with magnesium sulphate concentrated under reduced pressure

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

Procedure: 1-Tertbutoxycarbonylpiperazine (6a) (1.86 g, 10 mmol) was dissolved in dichloromethane (20 mL), and anhydrous potassium carbonate (829 mg, 6 mmol) was added. The dichloromethane solution of chloromethyl cyclopropane (7a) (1.1 mL, 12 mmol) was added dropwise, and reacted overnight at room temperature, after that, the reaction mixture was washed with water. The water layer was extracted with dichloromethane for twice, the organic phases were combined, washed successively with 50 mL saturated sodium bicarbonate solution and saturated sodium chloride solution for three times, dried with anhydrous sodium sulfate. Column chromatography (petroleum ether:ethyl acetate 2:1) was performed to isolate white solid powder 1-tertbutoxycarbonyl-4-(cyclopropylmethyl)piperazine (7b), 2.01 g white solid (yield 79.0%). ESI-MS m/z calculated for: 240.18. found: 241.05 [M+H]+. reacted overnight at room temperature after that, the reaction mixture was washed with water The water layer was extracted with dichloromethane for twice, the organic phases washed successively with 50 mL saturated sodium bicarbonate solution and saturated sodium chloride solution for three times dried with anhydrous sodium sulfate