(R)-1-BENZYL-3-METHYLPIPERAZINE

反应条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 0.20 g (0.38 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, 93 mg (0.49 mmol) (R)-1-benzyl-3-methyl-piperazine, 0.01 g (0.03 mmol) cetyltrimethyl-ammonium bromide, 0.038 g (0.074 mmol) bis(tri-t-butylphosphine)palladium(0), 0.05 ml NaOH 50% and 2 ml toluene was degassed by two freeze-thaw cycles. The reaction mixture was heated under argon at 90° C. for 48 h. After cooling to room temperature the mixture was diluted with water and brine and extracted with three portions of tert-butyl methyl ether. The combined organic layers were dried over sodium sulphate and concentrated in vacuo. Flash column chromatography gave 95 mg (37%) of the title compound as a light yellow solid. was degassed by two freeze-thaw cycles After cooling to room temperature the mixture was diluted with water and brine extracted with three portions of tert-butyl methyl ether The combined organic layers were dried over sodium sulphate concentrated in vacuo

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 1.0 g (10 mmol) (R)-2-methylpiperazine, 1.3 g (10 mmol) benzyl chloride and 4.1 g (30 mmol) potassium carbonate in 10 ml ethanol was heated at reflux over night. After cooling to room temperature the reaction mixture was diluted with a 0.5 M aqueous solution of sodium hydroxide and extracted with three portions of dichloromethane. The combined organic extracts were dried over sodium sulfate and concentrated. Flash column chromatography gave 0.93 g (49%) of the title compound as an off-white solid. was heated at reflux over night extracted with three portions of dichloromethane The combined organic extracts were dried over sodium sulfate concentrated

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 1.0 g (10 mmol) (R)-2-methylpiperazine, 1.3 g (10 mmol) benzyl chloride and 4.1 g (30 mmol) potassium carbonate in 10 ml ethanol was heated at reflux over night. After cooling to room temperature the reaction mixture was diluted with a 0.5 M aqueous solution of sodium hydroxide and extracted with three portions of dichloromethane. The combined organic extracts were dried over sodium sulfate and concentrated. Flash column chromatography gave 0.93 g (49%) of the title compound as an off-white solid. was heated at reflux over night extracted with three portions of dichloromethane The combined organic extracts were dried over sodium sulfate concentrated

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Tert-butyl 2-chloropyrimidine-4-carboxylate (4.12 g, 19.2 mmol) and (R)-1-benzyl-3-methylpiperazine (1.83 g, 9.6 mmol) were suspended in acetonitrile (50 ml), followed by addition of N,N-diisopropylethylamine (3.34 ml, 19.2 mmol), and then the resulting liquid was heated at reflux under nitrogen stream for 15 hours. The resulting reaction liquid was concentrated, followed by addition of distilled water (50 ml), and then extracted with MC (100 ml×2). The organic layer was dried over anhydrous sodium sulfate, followed by filtration and concentration, and then the residue thus obtained was subjected to MPLC (1% MeOH/MC), to obtain 3.34 g of yellow solid (94%). the resulting liquid was heated at reflux under nitrogen stream for 15 hours The resulting reaction liquid was concentrated followed by addition of distilled water (50 ml) extracted with MC (100 ml×2) The organic layer was dried over anhydrous sodium sulfate followed by filtration and concentration the residue thus obtained

反应条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 0.20 g (0.38 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, 93 mg (0.49 mmol) (R)-1-benzyl-3-methyl-piperazine, 0.01 g (0.03 mmol) cetyltrimethyl-ammonium bromide, 0.038 g (0.074 mmol) bis(tri-t-butylphosphine)palladium(0), 0.05 ml NaOH 50% and 2 ml toluene was degassed by two freeze-thaw cycles. The reaction mixture was heated under argon at 90° C. for 48 h. After cooling to room temperature the mixture was diluted with water and brine and extracted with three portions of tert-butyl methyl ether. The combined organic layers were dried over sodium sulphate and concentrated in vacuo. Flash column chromatography gave 95 mg (37%) of the title compound as a light yellow solid. MS m/e (%): 687 (M+H+, 100) was degassed by two freeze-thaw cycles After cooling to room temperature the mixture was diluted with water and brine extracted with three portions of tert-butyl methyl ether The combined organic layers were dried over sodium sulphate concentrated in vacuo

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 1.0 g (10 mmol) (R)-2-methylpiperazine, 1.3 g (10 mmol) benzyl chloride and 4.1 g (30 mmol) potassium carbonate in 10 ml ethanol was heated at reflux over night. After cooling to room temperature the reaction mixture was diluted with a 0.5 M aqueous solution of sodium hydroxide and extracted with three portions of dichloromethane. The combined organic extracts were dried over sodium sulfate and concentrated. Flash column chromatography gave 0.93 g (49%) of the title compound as an off-white solid. MS m/e (%): 191 (M+H+, 100) was heated at reflux over night extracted with three portions of dichloromethane The combined organic extracts were dried over sodium sulfate concentrated

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: (2R)-4-Benzyl-2-methyl-1-(2-methylthiophenyl) piperazine was prepared in 26% yield from ortho-bromothioanisole and (R)-3-methyl-1-benzylpiperazine in a manner similar to Preparation 1A. LRMS (ESI+): 223.2 (M+1)

反应条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 0.20 g (0.38 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, 93 mg (0.49 mmol) (R)-1-benzyl-3-methyl-piperazine, 0.01 g (0.03 mmol) cetyltrimethyl-ammonium bromide, 0.038 g (0.074 mmol) bis(tri-t-butylphosphine)palladium(0), 0.05 ml NaOH 50% and 2 ml toluene was degassed by two freeze-thaw cycles. The reaction mixture was heated under argon at 90° C. for 48 h. After cooling to room temperature the mixture was diluted with water and brine and extracted with three portions of tert-butyl methyl ether. The combined organic layers were dried over sodium sulphate and concentrated in vacuo. Flash column chromatography gave 95 mg (37%) of the title compound as a light yellow solid. was degassed by two freeze-thaw cycles After cooling to room temperature the mixture was diluted with water and brine extracted with three portions of tert-butyl methyl ether The combined organic layers were dried over sodium sulphate concentrated in vacuo

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 1.0 g (10 mmol) (R)-2-methylpiperazine, 1.3 g (10 mmol) benzyl chloride and 4.1 g (30 mmol) potassium carbonate in 10 ml ethanol was heated at reflux over night. After cooling to room temperature the reaction mixture was diluted with a 0.5 M aqueous solution of sodium hydroxide and extracted with three portions of dichloromethane. The combined organic extracts were dried over sodium sulfate and concentrated. Flash column chromatography gave 0.93 g (49%) of the title compound as an off-white solid. was heated at reflux over night extracted with three portions of dichloromethane The combined organic extracts were dried over sodium sulfate concentrated

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of (R)-1-benzyl-3-methylpiperazine (10 g, 52.6 mmol) in dichloromethane (30 mL) at room temperature was added triethylamine (10.6 g, 106 mmol) and the reaction mixture was stirred for 1 h. To the reaction mixture was added (BOC)2O (13.7 g, 62.8 mmol) and the contents were stirred for further 4 h. The reaction mixture was quenched in water and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the crude product. The crude product was purified by silica gel (100-200 mesh) column chromatography eluting with 10% ethyl acetate in n-hexanes to afford 13.0 g of (R)-tert-butyl 4-benzyl-2-methylpiperazine-1-carboxylate. the contents were stirred for further 4 h The reaction mixture was quenched in water extracted with dichloromethane The organic layer was dried over anhydrous sodium sulfate concentrated under reduced pressure to afford the crude product The crude product was purified by silica gel (100-200 mesh) column chromatography eluting with 10% ethyl acetate in n-hexanes

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of (R)-2-methylpiperazine (10 g, 100 mmol) in ethanol at room temperature was added K2CO3 (27.6 g, 200 mmol). The reaction mixture was cooled to 0° C., benzyl bromide (15.3 g, 89.5 mmol) was added and the reaction mixture was heated to 60° C. and stirred for 8 h. The reaction mixture was allowed to cool to room temperature, filtered through a filtration funnel and the filtrate was concentrated under reduced pressure to remove ethanol. The residue was washed with water and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude product. The crude product was purified by silica gel (100-200 mesh) column chromatography eluting with 5% methanol in chloroform to afford pure 12.0 g of (R)-1-benzyl-3-methylpiperazine. the reaction mixture was heated to 60° C. to cool to room temperature filtered through a filtration funnel the filtrate was concentrated under reduced pressure to remove ethanol The residue was washed with water extracted with dichloromethane The organic layer was dried over anhydrous sodium sulfate concentrated under reduced pressure to afford crude product The crude product was purified by silica gel (100-200 mesh) column chromatography eluting with 5% methanol in chloroform

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Tert-butyl 2-chloropyrimidine-4-carboxylate (4.12 g, 19.2 mmol) and (R)-1-benzyl-3-methylpiperazine (1.83 g, 9.6 mmol) were suspended in acetonitrile (50 ml), followed by addition of N,N-diisopropylethylamine (3.34 ml, 19.2 mmol), and then the resulting liquid was heated at reflux under nitrogen stream for 15 hours. The resulting reaction liquid was concentrated, followed by addition of distilled water (50 ml), and then extracted with MC (100 ml×2). The organic layer was dried over anhydrous sodium sulfate, followed by filtration and concentration, and then the residue thus obtained was subjected to MPLC (1% MeOH/MC), to obtain 3.34 g of yellow solid (94%). the resulting liquid was heated at reflux under nitrogen stream for 15 hours The resulting reaction liquid was concentrated followed by addition of distilled water (50 ml) extracted with MC (100 ml×2) The organic layer was dried over anhydrous sodium sulfate followed by filtration and concentration the residue thus obtained