2-hydroxy-2-methyl-1-piperazin-1-ylpropan-1-one

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: Benzyl 4-(2-hydroxy-2-methylpropionyl)piperazine-1-carbamate (2.82 g, 9.20 mmol) synthesized in Production example 28-1 was dissolved in methanol (100 ml) under nitrogen atmosphere; 10% palladium on carbon (50% wet, 1.96 g) was added thereto, the reaction system was purged with hydrogen at atmospheric pressure; and the reaction mixture was stirred overnight. After the reaction system was purged with nitrogen, the catalyst was filtered out, and washed with methanol, then the solvent, together with the filtrate and the washing solution, was distilled off. The residue was dried under reduced pressure to yield the title compound (1.58 g, 9.20 mmol, quantitative) as a colorless oil. the reaction system was purged with hydrogen at atmospheric pressure After the reaction system was purged with nitrogen the catalyst was filtered out washed with methanol the solvent, together with the filtrate and the washing solution, was distilled off The residue was dried under reduced pressure

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

Procedure: N1-Methyl-5-(2-amino-4-pyridyl)oxy-1H-1-indolecarboxamide (150 mg, 0.53 mmol) synthesized in Production example 5-1 was dissolved in tetrahydrofuran (3 ml). Triethylamine (0.37 ml, 2.66 mmol) and phenyl chlorocarbonate (0.15 ml, 1.2 mmol) were sequentially added dropwise at room temperature, and the reaction mixture was stirred for 30 minutes. 1-(2-Hydroxy-2-methylpropionyl)piperazine (412 mg, 2.39 mmol) and N,N-dimethylformamide (3 ml) were added and the reaction mixture was stirred for 3 days. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate:methanol=95:5). The crystals were precipitated from diethyl ether-hexane (1:2), filtered off, and dried under aeration to yield the title compound (189.4 mg, 0.39 mmol, 74.2%) as white crystals. the reaction mixture was stirred for 3 days The reaction mixture was partitioned between ethyl acetate and water The organic layer was washed with water and brine dried over anhydrous sodium sulfate The solvent was distilled off the residue was purified by silica gel column chromatography (eluent; ethyl acetate:methanol=95:5) The crystals were precipitated from diethyl ether-hexane (1:2) filtered off dried under aeration

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

Procedure: N1-Methyl-5-(2-amino-4-pyridyl)oxy-1H-1-indolecarboxamide (150 mg, 0.53 mmol) synthesized in Production example 5-1 was dissolved in tetrahydrofuran (3 ml). Triethylamine (0.37 ml, 2.66 mmol) and phenyl chlorocarbonate (0.15 ml, 1.2 mmol) were sequentially added dropwise at room temperature, and the reaction mixture was stirred for 30 minutes. 1-(2-Hydroxy-2-methylpropionyl)piperazine (412 mg, 2.39 mmol) and N,N-dimethylformamide (3 ml) were added and the reaction mixture was stirred for 3 days. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate:methanol=95:5). The crystals were precipitated from diethyl ether-hexane (1:2), filtered off, and dried under aeration to yield the title compound (189.4 mg, 0.39 mmol, 74.2%) as white crystals. the reaction mixture was stirred for 3 days The reaction mixture was partitioned between ethyl acetate and water The organic layer was washed with water and brine dried over anhydrous sodium sulfate The solvent was distilled off the residue was purified by silica gel column chromatography (eluent; ethyl acetate:methanol=95:5) The crystals were precipitated from diethyl ether-hexane (1:2) filtered off dried under aeration

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

Procedure: N1-Methyl-5-(2-amino-4-pyridyl)oxy-1H-1-indolecarboxamide (150 mg, 0.53 mmol) synthesized in Production example 5-1 was dissolved in tetrahydrofuran (3 ml). Triethylamine (0.37 ml, 2.66 mmol) and phenyl chlorocarbonate (0.15 ml, 1.2 mmol) were sequentially added dropwise at room temperature, and the reaction mixture was stirred for 30 minutes. 1-(2-Hydroxy-2-methylpropionyl)piperazine (412 mg, 2.39 mmol) and N,N-dimethylformamide (3 ml) were added and the reaction mixture was stirred for 3 days. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate:methanol=95:5). The crystals were precipitated from diethyl ether-hexane (1:2), filtered off, and dried under aeration to yield the title compound (189.4 mg, 0.39 mmol, 74.2%) as white crystals. the reaction mixture was stirred for 3 days The reaction mixture was partitioned between ethyl acetate and water The organic layer was washed with water and brine dried over anhydrous sodium sulfate The solvent was distilled off the residue was purified by silica gel column chromatography (eluent; ethyl acetate:methanol=95:5) The crystals were precipitated from diethyl ether-hexane (1:2) filtered off dried under aeration

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

Procedure: Benzyl 4-(2-hydroxy-2-methylpropionyl)piperazine-1-carbamate (2.82 g, 9.20 mmol) synthesized in Production example 28-1 was dissolved in methanol (100 ml) under nitrogen atmosphere; 10% palladium on carbon (50% wet, 1.96 g) was added thereto, the reaction system was purged with hydrogen at atmospheric pressure; and the reaction mixture was stirred overnight. After the reaction system was purged with nitrogen, the catalyst was filtered out, and washed with methanol, then the solvent, together with the filtrate and the washing solution, was distilled off. The residue was dried under reduced pressure to yield the title compound (1.58 g, 9.20 mmol, quantitative) as a colorless oil. the reaction system was purged with hydrogen at atmospheric pressure After the reaction system was purged with nitrogen the catalyst was filtered out washed with methanol the solvent, together with the filtrate and the washing solution, was distilled off The residue was dried under reduced pressure

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

Procedure: N1-Methyl-5-(2-amino-4-pyridyl)oxy-1H-1-indolecarboxamide (150 mg, 0.53 mmol) synthesized in Production example 5-1 was dissolved in tetrahydrofuran (3 ml). Triethylamine (0.37 ml, 2.66 mmol) and phenyl chlorocarbonate (0.15 ml, 1.2 mmol) were sequentially added dropwise at room temperature, and the reaction mixture was stirred for 30 minutes. 1-(2-Hydroxy-2-methylpropionyl)piperazine (412 mg, 2.39 mmol) and N,N-dimethylformamide (3 ml) were added and the reaction mixture was stirred for 3 days. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate:methanol=95:5). The crystals were precipitated from diethyl ether-hexane (1:2), filtered off, and dried under aeration to yield the title compound (189.4 mg, 0.39 mmol, 74.2%) as white crystals. the reaction mixture was stirred for 3 days The reaction mixture was partitioned between ethyl acetate and water The organic layer was washed with water and brine dried over anhydrous sodium sulfate The solvent was distilled off the residue was purified by silica gel column chromatography (eluent; ethyl acetate:methanol=95:5) The crystals were precipitated from diethyl ether-hexane (1:2) filtered off dried under aeration

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

Procedure: N1-Methyl-5-(2-amino-4-pyridyl)oxy-1H-1-indolecarboxamide (150 mg, 0.53 mmol) synthesized in Production example 5-1 was dissolved in tetrahydrofuran (3 ml). Triethylamine (0.37 ml, 2.66 mmol) and phenyl chlorocarbonate (0.15 ml, 1.2 mmol) were sequentially added dropwise at room temperature, and the reaction mixture was stirred for 30 minutes. 1-(2-Hydroxy-2-methylpropionyl)piperazine (412 mg, 2.39 mmol) and N,N-dimethylformamide (3 ml) were added and the reaction mixture was stirred for 3 days. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate:methanol=95:5). The crystals were precipitated from diethyl ether-hexane (1:2), filtered off, and dried under aeration to yield the title compound (189.4 mg, 0.39 mmol, 74.2%) as white crystals. the reaction mixture was stirred for 3 days The reaction mixture was partitioned between ethyl acetate and water The organic layer was washed with water and brine dried over anhydrous sodium sulfate The solvent was distilled off the residue was purified by silica gel column chromatography (eluent; ethyl acetate:methanol=95:5) The crystals were precipitated from diethyl ether-hexane (1:2) filtered off dried under aeration

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

Procedure: 7H-Indolo[2,1-a][2]benzazepine-10-carboxamide, 13-cyclohexyl-N-[(dimethylamino)sulfonyl]-6-[[4-(2-hydroxy-2-methyl-l-oxopropyl)-1-piperazinyl]carbonyl]-3-methoxy-. To a solution of tert-butyl piperazine-1-carboxylate (372 mg, 2.0 mmol), 2-hydroxy-2-methylpropanoic acid (229 mg, 2.2 mmol) and triethylamine (1.1 mL) in DMF (7 mL) was added HATU (988 mg, 2.6 mmol). The reaction mixture was stirred at rt for 2 h, then diluted with H2O, neutralized with 1N aqueous HCl (8 mL), concentrated, and the residue was partitioned between EtOAc and H2O. The organic phase was separated, washed with brine and concentrated to a white solid (1.1 g). The solid was dissolved into ClCH2CH2Cl (10 mL) and treated with trifluoroacetic acid (5 mL). The reaction mixture was stirred at rt for 2 h, and concentrated to yield crude 2-hydroxy-2-methyl-1-(piperazin-1-yl)propan-1-one (1.1 g) as yellow semi-solid. concentrated the residue was partitioned between EtOAc and H2O The organic phase was separated washed with brine concentrated to a white solid (1.1 g) The solid was dissolved into ClCH2CH2Cl (10 mL) treated with trifluoroacetic acid (5 mL) The reaction mixture was stirred at rt for 2 h concentrated