N-ethyl-2-methyl-N-(2-methylpropyl)propan-1-amine

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

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

Procedure: 1.6 g (2.7 mmol) of 3-[(2S)-3-[4-(1-benzyloxycarbonyl-4-piperidyloxy)phenyl]-2-(t-butoxycarbonylamino)propoxy]-4-iodobenzonitrile was dissolved in 4 N solution of hydrogen chloride in dioxane, and the solution was stirred at room temperature overnight. The solvent was distilled off, and the residue was dissolved in dimethylformamide. 1 ml (6 mmol) of N,N-diisobutylethylamine and 0.34 ml (2.7 mmol) of benzenesulfonyl chloride were added to the solution under cooling with ice, and they were stirred for 2 hours. After the isolation process with ethyl acetate as the extractant in the same manner as that of step 1 in Example 1, the crude product was obtained, which was purified by the silica gel column chromatography to obtain the title compound. The solvent was distilled off the residue was dissolved in dimethylformamide under cooling with ice, and they were stirred for 2 hours which was purified by the silica gel column chromatography

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

Procedure: To a solution of 6-fluoro-3-(1-(3-cyanopropyl)-4-piperidyl)indole (453 mg, 1.6 mmol) in ethanol (30 mL) was added platinum oxide (110 mg) and a concentrated hydrochloric acid (0.8 mL), and the resulting mixture was stirred under hydrogen atmosphere at room temperature overnight. After filtrating the reaction mixture through Celite, the filtrate was concentrated, and a saturated aqueous sodium hydrogencarbonate was added to pH of 10, and the resulting mixture was extracted with chloroform. After drying over anhydrous sodium sulfate, the chloroform layer was concentrated to afford 6-fluoro-3-(1-(4-aminobutyl)-4-piperidyl)indole (470 mg, yield: 100%) as a pale yellow solid. To a solution of this amine (68 mg, 0.23 mmol) in DMF (0.22 mL) was added lH-pyrazole-1-carboxamidine hydrochloride (35 mg, 0.23 mmol) and diisobutylethylamine (31 mg, 0.23 mmol), and the mixture was stirred at room temperature overnight. After washing with diethyl ether, the reaction mixture was purified by column chromatography on a silica gel (silica gel NH-DM 1020 produced by Fuji Silysia Chemical Ltd., eluent; chloroform:methanol=4:1) to afford a free form (61 mg, yield: 77%) of the title compound as a yellow viscous oil. After adding hydrochloric acid/methanol to a solution of the free form (61 mg) in methanol was concentrated and was then freeze-dried to afford the title compound (53 mg) as a white amorphous solid. After washing with diethyl ether the reaction mixture was purified by column chromatography on a silica gel (silica gel NH-DM 1020 produced by Fuji Silysia Chemical Ltd., eluent; chloroform:methanol=4:1)

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

Procedure: In N,N-dimethylformamide (10 ml) was dissolved trans- 7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid (0.5 g) obtained in Example 2. To the solution were added pivaloyloxymethyl chloride (0.43 ml), N,N-diisobutyl ethylamine (0.52 ml) and KI (0.2 g). The mixture was stirred at room temperature overnight. To the reaction mixture were added water (100 ml) and ethyl acetate (100 ml), followed by extraction. The ethyl acetate layer was washed with an aqueous solution of potassium hydrogensulfate, an aqueous solution of sodium hydrogencarbonate and water, successively, which was dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography (hexane:ethyl acetate=10:1 to 5:1) to afford trans-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid pivaloyloxymethyl ester (0.55 g). followed by extraction The ethyl acetate layer was washed with an aqueous solution of potassium hydrogensulfate an aqueous solution of sodium hydrogencarbonate and water, successively, which was dried over anhydrous magnesium sulfate The solvent was then distilled off under reduced pressure The residue was purified by means of a silica gel column chromatography (hexane:ethyl acetate=10:1 to 5:1)

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

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

Procedure: In N,N-dimethylformamide (10 ml) was dissolved trans- 7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid (0.5 g) obtained in Example 2. To the solution were added pivaloyloxymethyl chloride (0.43 ml), N,N-diisobutyl ethylamine (0.52 ml) and KI (0.2 g). The mixture was stirred at room temperature overnight. To the reaction mixture were added water (100 ml) and ethyl acetate (100 ml), followed by extraction. The ethyl acetate layer was washed with an aqueous solution of potassium hydrogensulfate, an aqueous solution of sodium hydrogencarbonate and water, successively, which was dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography (hexane:ethyl acetate=10:1 to 5:1) to afford trans-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid pivaloyloxymethyl ester (0.55 g). followed by extraction The ethyl acetate layer was washed with an aqueous solution of potassium hydrogensulfate an aqueous solution of sodium hydrogencarbonate and water, successively, which was dried over anhydrous magnesium sulfate The solvent was then distilled off under reduced pressure The residue was purified by means of a silica gel column chromatography (hexane:ethyl acetate=10:1 to 5:1)

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

Procedure: In N,N-dimethylformamide (10 ml) was dissolved trans-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid (0.5 g) obtained in Example 2. To the solution were added pivaloyloxymethyl chloride (0.43 ml), N,N-diisobutyl ethylamine (0.52 ml) and KI (0.2 g). The mixture was stirred at room temperature overnight. To the reaction mixture were added water (100 ml) and ethyl acetate (100 ml), followed by extraction. The ethyl acetate layer was washed with an aqueous solution of potassium hydrogensulfate, an aqueous solution of sodium hydrogencarbonate and water, successively, which was dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography (hexane:ethyl acetate=10:1 to 5:1) to afford trans-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid pivaloyloxymethyl ester (0.55 g). followed by extraction The ethyl acetate layer was washed with an aqueous solution of potassium hydrogensulfate an aqueous solution of sodium hydrogencarbonate and water, successively, which was dried over anhydrous magnesium sulfate The solvent was then distilled off under reduced pressure The residue was purified by means of a silica gel column chromatography (hexane:ethyl acetate=10:1 to 5:1)

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

Procedure: 1.6 g (2.7 mmol) of 3-[(2S)-3-[4-(1-benzyloxycarbonyl-4-piperidyloxy)phenyl]-2-(t-butoxycarbonylamino)propoxy]-4-iodobenzonitrile was dissolved in 4 N solution of hydrogen chloride in dioxane, and the solution was stirred at room temperature overnight. The solvent was distilled off, and the residue was dissolved in dimethylformamide. 1 ml (6 mmol) of N,N-diisobutylethylamine and 0.34 ml (2.7 mmol) of benzenesulfonyl chloride were added to the solution under cooling with ice, and they were stirred for 2 hours. After the isolation process with ethyl acetate as the extractant in the same manner as that of step 1 in Example 1, the crude product was obtained, which was purified by the silica gel column chromatography to obtain the title compound. The solvent was distilled off the residue was dissolved in dimethylformamide under cooling with ice, and they were stirred for 2 hours which was purified by the silica gel column chromatography

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

Procedure: To a solution of 6-fluoro-3-(1-(3-cyanopropyl)-4-piperidyl)indole (453 mg, 1.6 mmol) in ethanol (30 mL) was added platinum oxide (110 mg) and a concentrated hydrochloric acid (0.8 mL), and the resulting mixture was stirred under hydrogen atmosphere at room temperature overnight. After filtrating the reaction mixture through Celite, the filtrate was concentrated, and a saturated aqueous sodium hydrogencarbonate was added to pH of 10, and the resulting mixture was extracted with chloroform. After drying over anhydrous sodium sulfate, the chloroform layer was concentrated to afford 6-fluoro-3-(1-(4-aminobutyl)-4-piperidyl)indole (470 mg, yield: 100%) as a pale yellow solid. To a solution of this amine (68 mg, 0.23 mmol) in DMF (0.22 mL) was added lH-pyrazole-1-carboxamidine hydrochloride (35 mg, 0.23 mmol) and diisobutylethylamine (31 mg, 0.23 mmol), and the mixture was stirred at room temperature overnight. After washing with diethyl ether, the reaction mixture was purified by column chromatography on a silica gel (silica gel NH-DM 1020 produced by Fuji Silysia Chemical Ltd., eluent; chloroform:methanol=4:1) to afford a free form (61 mg, yield: 77%) of the title compound as a yellow viscous oil. After adding hydrochloric acid/methanol to a solution of the free form (61 mg) in methanol was concentrated and was then freeze-dried to afford the title compound (53 mg) as a white amorphous solid. After washing with diethyl ether the reaction mixture was purified by column chromatography on a silica gel (silica gel NH-DM 1020 produced by Fuji Silysia Chemical Ltd., eluent; chloroform:methanol=4:1)

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

Procedure: In N,N-dimethylformamide (10 ml) was dissolved trans- 7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid (0.5 g) obtained in Example 2. To the solution were added pivaloyloxymethyl chloride (0.43 ml), N,N-diisobutyl ethylamine (0.52 ml) and KI (0.2 g). The mixture was stirred at room temperature overnight. To the reaction mixture were added water (100 ml) and ethyl acetate (100 ml), followed by extraction. The ethyl acetate layer was washed with an aqueous solution of potassium hydrogensulfate, an aqueous solution of sodium hydrogencarbonate and water, successively, which was dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography (hexane:ethyl acetate=10:1 to 5:1) to afford trans-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid pivaloyloxymethyl ester (0.55 g). followed by extraction The ethyl acetate layer was washed with an aqueous solution of potassium hydrogensulfate an aqueous solution of sodium hydrogencarbonate and water, successively, which was dried over anhydrous magnesium sulfate The solvent was then distilled off under reduced pressure The residue was purified by means of a silica gel column chromatography (hexane:ethyl acetate=10:1 to 5:1)