1-(3-phenylpropyl)piperidin-4-amine;dihydrochloride

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

Procedure: Triethylamine (1.34 ml) was added dropwise to a suspension of 4-amino-1-(3-phenylpropyl)piperidine dihydrochloride (1.40 g) and dimethylformamide (10 ml). Into the mixture which was stirred for 10 minutes, 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid (1.00 g) and diethyl cyanophosphonate (0.81 ml) were added. The mixture was stirred for 1 hour at room temperature, and 2 hours at 55° C. Ethyl acetate:tetrahydrofuran=4:1 (1.75 ml) and 1N-sodium hydroxide (30 ml) were added into the reaction mixture. The organic layer which was washed with sodium hydroxide (30 ml×3) and water (30 ml×2) was concentrated. The residual crystal which was added acetate (4 ml) was stirred for 1 hour at room temperature. This was dried under reduced pressure to obtain N-[1-(3-phenylpropan-1-yl)piperidin-4-yl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide (1.07 g, 63.6%). The mixture was stirred for 1 hour at room temperature 2 hours at 55° C The organic layer which was washed with sodium hydroxide (30 ml×3) and water (30 ml×2) was concentrated The residual crystal which was added acetate (4 ml) was stirred for 1 hour at room temperature This was dried under reduced pressure

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

Procedure: Triethylamine (6.7 ml) was added dropwise to a suspension of 4-amino-1-(3-phenylpropyl)piperidine dihydrochloride (7.01 g) and dimethylformamide (40 ml). The mixture was stirred for 10 minutes. 5-Thia-1,8b-diazaacenaphthylene-4-carboxylic acid (5.00 g), 1-hydroxy-1H-benzotriazole monohydrate (0.710 g) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (4.61 g) were added into the reaction mixture. This was stirred for 2 hours at 68-70° C. (inner temperature). Ethyl acetate:tetrahydrofuran=4:1 (380 ml), 1N-sodium hydroxide (50 ml) and water (80 ml) were added into the reaction solution. The aqueous layer was extracted by ethyl acetate:tetrahydrofuran=4:1 (120 ml×2). The organic layer was washed with water (130 ml×3), and then concentrated. The residue which was added ethyl acetate (15 ml) was stirred for 2 hours at room temperature. The reaction mixture was dried under reduced pressure to obtain N-[1-(3-phenylpropan-1-yl)piperidin-4-yl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide (8.87 g, 92.5%). This was stirred for 2 hours at 68-70° C. (inner temperature) The aqueous layer was extracted by ethyl acetate The organic layer was washed with water (130 ml×3) concentrated The residue which was added ethyl acetate (15 ml) was stirred for 2 hours at room temperature The reaction mixture was dried under reduced pressure

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid (1.2 g), 4-amino-1-(3-phenylpropan-1-yl)piperidine dihydrochloride (1.5 g), triethylamine (1.5 ml), 1-hydroxy-1H-benzotriazole monohydrate (0.8 g), and 1-ethyl-3-(3-diethylaminopropyl)carbodiimide hydrochloride (1.0 g) in N,N-dimethylformamide (15 ml) was stirred at 50° C. for 2 hours. After spontaneous cooling, this reaction mixture was extracted with ethyl acetate/tetrahydrofuran (4/1; 90 ml). The organic layer was washed with 1N-aqueous solution of sodium hydroxide (10 ml) and water (30 ml) and concentrated. The resulting crystal crop was rinsed with diisopropyl ether (20 ml) and dried to provide the title compound (2.0 g, 95%). After spontaneous cooling, this reaction mixture was extracted with ethyl acetate/tetrahydrofuran (4/1; 90 ml) The organic layer was washed with 1N-aqueous solution of sodium hydroxide (10 ml) and water (30 ml) concentrated The resulting crystal crop was rinsed with diisopropyl ether (20 ml) dried

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

Procedure: To a suspension of 4.21 g (24.03 mmol.) of N-tert-butoxycarbonyl glycine and 5.51 g (35.98 mmol.) of 1-hydroxybenzotriazole monohydrate in acetonitrile (30 ml) was added, at room temperature, 6.90 g (36.0 mmol.) of N-ethyl-N′-3-(N,N-dimethylamino)propylcarboxiimide hydrochloride. The mixture was stirred for one hour. To the reaction system was then added a solution of 7.00 g (24.03 mmol.) of 4-amino-1-(3-phenylpropan-1-yl)piperidine dihydrochloride, 7.32 g (48.08 mmol.) of 1,8-bicyclo[5.4.0]unde-7-cene (DBU) and 3.4 ml (24.4 mmol.) of triethylamine in acetonitrile (20 ml). The mixture was stirred for 2 hours at room temperature. The solvent was distilled off under reduced pressure. To the residue was added chloroform. The mixture was washed with water and a saturated aqueous saline solution, followed by drying over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by means of a column chromatography (methanol/ethyl acetate 30%). The solvent was distilled off under reduced pressure to give the object compound as a yellowish orange liquid product. The yield was 5.35 g (59%). was added, at room temperature The mixture was stirred for 2 hours at room temperature The solvent was distilled off under reduced pressure To the residue was added chloroform The mixture was washed with water by drying over magnesium sulfate The solvent was distilled off under reduced pressure The residue was purified by means of a column chromatography (methanol/ethyl acetate 30%) The solvent was distilled off under reduced pressure