1-methylpiperazin-2-one;hydrochloride

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: DIPEA (0.52 ml, 2.96 mmol) and 1-methylpiperazin-2-one hydrochloride (0.22 g, 1.48 mmol) were sequentially added to a solution of ethyl 2-bromo-2-phenylacetate (0.22 ml, 1.23 mmol) in acetonitrile (4 ml). The reaction was stirred at room temperature for 1.5 hours. DIPEA (0.13 ml, 0.74 mmol) was added again and the reaction was stirred at room temperature overnight. The solvent was evaporated and the crude was purified by flash chromatography (DCM/Acetone=9/1) to obtain ethyl 2-(4-methyl-3-oxopiperazin-1-yl)-2-phenylacetate (256 mg, 75% yield) as a yellow oil. the reaction was stirred at room temperature overnight The solvent was evaporated the crude was purified by flash chromatography (DCM/Acetone=9/1)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Starting materials: Ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and 1-methylpiperazin-2-one hydrochloride.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Starting materials: Ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and 1-methylpiperazin-2-one hydrochloride.

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Methyl-2-piperazinone hydrochloride (1:1) (300 mg, 1.99 mmol) was combined with dichloromethane (20 mL) to give a light yellow suspension. N,N-Diisopropylethylamine (309 mg, 417 μl, 2.39 mmol) was added at 0° C. Subsequently 3-(4-cyanophenyl)-2-oxaziridinecarboxylic acid 1,1-dimethylethyl ester (441 mg, 1.79 mmol) in dichloromethane (10 mL) was added during 35 min at 0° C. and the reaction mixture was stirred for 1 h at 0° C. Afterwards the reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (silica gel, 20 g, 0% to 100% ethyl acetate in n-heptane) to deliver an oil contaminated with 4-cyano-benzaldehyde. This material was purified by a second chromatography (aminophase 5 g, ethyl acetate/n-heptane 1/1) to give the title compound (67 mg, 15%) as white solid; GC-MS (EI) 229.0 (M)+. to give a light yellow suspension Afterwards the reaction mixture was concentrated in vacuo the residue was purified by flash chromatography (silica gel, 20 g, 0% to 100% ethyl acetate in n-heptane) This material was purified by a second chromatography (aminophase 5 g, ethyl acetate/n-heptane 1/1)

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Methyl-2-piperazinone hydrochloride (1:1) (300 mg, 1.99 mmol) was combined with dichloromethane (20 mL) to give a light yellow suspension. N,N-Diisopropylethylamine (309 mg, 417 μl, 2.39 mmol) was added at 0° C. Subsequently 3-(4-cyanophenyl)-2-oxaziridinecarboxylic acid 1,1-dimethylethyl ester (441 mg, 1.79 mmol) in dichloromethane (10 mL) was added during 35 min at 0° C. and the reaction mixture was stirred for 1 h at 0° C. Afterwards the reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (silica gel, 20 g, 0% to 100% ethyl acetate in n-heptane) to deliver an oil contaminated with 4-cyano-benzaldehyde. This material was purified by a second chromatography (aminophase 5 g, ethyl acetate/n-heptane 1/1) to give the title compound (67 mg, 15%) as white solid; GC-MS (EI) 229.0 (M)+. to give a light yellow suspension Afterwards the reaction mixture was concentrated in vacuo the residue was purified by flash chromatography (silica gel, 20 g, 0% to 100% ethyl acetate in n-heptane) This material was purified by a second chromatography (aminophase 5 g, ethyl acetate/n-heptane 1/1)

反応条件: temp:105.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 1,4-dibromobenzene (470 mg, 2.0 mmol), 1-methylpiperazin-2-one hydrochloride (150 mg, 1.0 mmol, from J&W PharmLab), palladium acetate (6.7 mg, 0.030 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.035 g, 0.060 mmol), and cesium carbonate (0.98 g, 3.0 mmol) in toluene (5.0 mL) was evacuated and refilled with nitrogen three times and then the reaction was stirred at 105° C. overnight. The mixture was diluted with ethyl acetate, washed with water, brine, then dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexane (0-60%) to afford the desired product (0.26 g, 49%). LCMS calculated for C11H14BrN2O (M+H)+: m/z=269.0. Found 269.0. was evacuated refilled with nitrogen three times The mixture was diluted with ethyl acetate washed with water, brine dried over Na2SO4 filtered concentrated The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexane (0-60%)

反応条件: temp:105.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 1,4-dibromobenzene (470 mg, 2.0 mmol), 1-methylpiperazin-2-one hydrochloride (150 mg, 1.0 mmol, from J&W PharmLab), palladium acetate (6.7 mg, 0.030 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.035 g, 0.060 mmol), and cesium carbonate (0.98 g, 3.0 mmol) in toluene (5.0 mL) was evacuated and refilled with nitrogen three times and then the reaction was stirred at 105° C. overnight. The mixture was diluted with ethyl acetate, washed with water, brine, then dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexane (0-60%) to afford the desired product (0.26 g, 49%). LCMS calculated for C11H14BrN2O (M+H)+: m/z=269.0. Found 269.0. was evacuated refilled with nitrogen three times The mixture was diluted with ethyl acetate washed with water, brine dried over Na2SO4 filtered concentrated The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexane (0-60%)

反応条件: temp:35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 14 ml of 3M hydrogen chloride in ethyl acetate were added to 3.0 g of the product obtained in step (1) above, and the mixture was stirred at 35° C. for one hour. Diethyl ether was added to the reaction mixture, and the crystals which precipitated out were collected by filtration, washed with diethyl ether and dried, to give 2.1 g of the title compound. the crystals which precipitated out were collected by filtration washed with diethyl ether dried

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Starting materials: Ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and 1-methylpiperazin-2-one hydrochloride.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: DIPEA (0.52 ml, 2.96 mmol) and 1-methylpiperazin-2-one hydrochloride (0.22 g, 1.48 mmol) were sequentially added to a solution of ethyl 2-bromo-2-phenylacetate (0.22 ml, 1.23 mmol) in acetonitrile (4 ml). The reaction was stirred at room temperature for 1.5 hours. DIPEA (0.13 ml, 0.74 mmol) was added again and the reaction was stirred at room temperature overnight. The solvent was evaporated and the crude was purified by flash chromatography (DCM/Acetone=9/1) to obtain ethyl 2-(4-methyl-3-oxopiperazin-1-yl)-2-phenylacetate (256 mg, 75% yield) as a yellow oil. the reaction was stirred at room temperature overnight The solvent was evaporated the crude was purified by flash chromatography (DCM/Acetone=9/1)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: DIPEA (0.52 ml, 2.96 mmol) and 1-methylpiperazin-2-one hydrochloride (0.22 g, 1.48 mmol) were sequentially added to a solution of ethyl 2-bromo-2-phenylacetate (0.22 ml, 1.23 mmol) in acetonitrile (4 ml). The reaction was stirred at room temperature for 1.5 hours. DIPEA (0.13 ml, 0.74 mmol) was added again and the reaction was stirred at room temperature overnight. The solvent was evaporated and the crude was purified by flash chromatography (DCM/Acetone=9/1) to obtain ethyl 2-(4-methyl-3-oxopiperazin-1-yl)-2-phenylacetate (256 mg, 75% yield) as a yellow oil. the reaction was stirred at room temperature overnight The solvent was evaporated the crude was purified by flash chromatography (DCM/Acetone=9/1)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Starting materials: Ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and 1-methylpiperazin-2-one hydrochloride.