4-[[4-(aminomethyl)piperidin-1-yl]methyl]oxan-4-ol

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

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: To a solution of tert-butyl ({1-[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]piperidin-4-yl}methyl)carbamate as prepared in 1(3) (50.28 g, 153 mmol) in methanol (100 mL) was added 4N hydrochloric acid dioxane solution (200 mL, 800 mmol) at room temperature. After 4 h, the volatile materials were removed by evaporation. The resulting amorphous was precipitated with diethyl ether/methanol (v/v=5/1). The precipitate was collected and added to the ice cooled 6N aqueous sodium hydroxide solution (200 mL) gradually. The mixture was extracted with dichloromethane/methanol (v/v=10/1, 500 mL×4). The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated in vacuo to give 24.90 g (99%) of the title compound as a pale brown amorphous solid. the volatile materials were removed by evaporation The resulting amorphous was precipitated with diethyl ether/methanol (v/v=5/1) The precipitate was collected added to the ice cooled 6N aqueous sodium hydroxide solution (200 mL) gradually The mixture was extracted with dichloromethane/methanol (v/v=10/1, 500 mL×4) The combined organic layers were washed with brine dried over magnesium sulfate concentrated in vacuo

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

Procedure: A mixture of benzyl ({1-[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]piperidin-4-yl}methyl)carbamate as prepared in 1(1) (5.60 g, 15.5 mmol) and palladium on activated carbon (10 wt. %, 1.20 g) in methanol (250 mL) was hydrogenated at room temperature for 20 h. Then, the mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo to give 3.30 g (94%) of the title compound as slightly yellow oil. Then, the mixture was filtered through a pad of Celite the filtrate was concentrated in vacuo

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

Procedure: To a stirred mixture of 6-fluoro-1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one (Step 2 of Example 9, 0.58 g, 3 mmol) and p-nitrophenylchloroformate (0.66 g, 3.3 mmol) in dichloromethane (15 mL) was added triethylamine (1.25 mL, 9.0 mmol) at room temperature. After being stirred for 2 h, a solution of 4-{[4-(aminomethyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-ol (Step 2 of Example 1, 0.75 g, 3.3 mmol) in dichloromethane (15 mL) was added to the mixture. After being stirred for 4 h, the mixture was diluted with ethyl acetate (100 mL). Then, the organic layer was washed with 0.5 N NaOH aq. (10 mL) for 5 times and brine, dried over MgSO4 and concentrated. The residue was chromatographed on a column of aminopropyl-silica gel eluting with hexane/ethyl acetate (3:1) to give 0.97 g (79%) of the title compound as a white solid. After being stirred for 4 h Then, the organic layer was washed with 0.5 N NaOH aq. (10 mL) for 5 times and brine dried over MgSO4 concentrated The residue was chromatographed on a column of aminopropyl-silica gel eluting with hexane/ethyl acetate (3:1)

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

Procedure: A mixture of benzyl({1-[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]piperidin-4-yl}methyl)carbamate (5.60 g, 15.5 mmol, step 1) and palladium on activated carbon (10 wt. %, 1.20 g) in methanol (250 mL) was hydrogenated at room temperature for 20 h. Then, the mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo to give 3.30 g (94%) of the title compound as slightly yellow oil. Then, the mixture was filtered through a pad of Celite the filtrate was concentrated in vacuo

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred mixture of 1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one (J. Med. Chem. 1999, 42, 2870-2880) (23.0 g, 130 mmol) and triethylamine (54.6 mL, 392 mmol) in tetrahydrofuran (300 mL) was added triphosgen (38.8 g, 130 mmol) in tetrahydrofuran (200 mL) gradually at room temperature. Then, the mixture was heated at 80° C. for 4 h. After cooling, a solution of 4-{[4-(aminomethyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-ol (step 2 of Example 1) (24.9 g, 109 mmol) and triethylamine (45 mL, 109 mmol) in tetrahydrofuran (500 mL) was added to the mixture. Then, the mixture was heated at 80° C. for 6 h. After cooling, sat. NaHCO3 aq was added to the mixture. The mixture was extracted with ethyl acetate (500 mL×4). The extracts were washed with brine, dried over MgSO4 and concentrated. The residue was chromatographed on a column of aminopropyl-silica gel eluting with hexane/ethyl acetate (3:1) to give 31.3 g (67%) of the title compound as a white solid. After cooling Then, the mixture was heated at 80° C. for 6 h After cooling The mixture was extracted with ethyl acetate (500 mL×4) The extracts were washed with brine dried over MgSO4 concentrated The residue was chromatographed on a column of aminopropyl-silica gel eluting with hexane/ethyl acetate (3:1)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred mixture of 1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one (J. Med. Chem. 1999, 42, 2870-2880) (23.0 g, 130 mmol) and triethylamine (54.6 mL, 392 mmol) in tetrahydrofuran (300 mL) was added triphosgen (38.8 g, 130 mmol) in tetrahydrofuran (200 mL) gradually at room temperature. Then, the mixture was heated at 80° C. for 4 h. After cooling, a solution of 4-{[4-(aminomethyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-ol (step 2 of Example 1) (24.9 g, 109 mmol) and triethylamine (45 mL, 109 mmol) in tetrahydrofuran (500 mL) was added to the mixture. Then, the mixture was heated at 80° C. for 6 h. After cooling, sat. NaHCO3 aq was added to the mixture. The mixture was extracted with ethyl acetate (500 mL×4). The extracts were washed with brine, dried over MgSO4 and concentrated. The residue was chromatographed on a column of aminopropyl-silica gel eluting with hexane/ethyl acetate (3:1) to give 31.3 g (67%) of the title compound as a white solid. After cooling Then, the mixture was heated at 80° C. for 6 h After cooling The mixture was extracted with ethyl acetate (500 mL×4) The extracts were washed with brine dried over MgSO4 concentrated The residue was chromatographed on a column of aminopropyl-silica gel eluting with hexane/ethyl acetate (3:1)

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

Procedure: To a solution of tert-butyl({1-[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]piperidin-4-yl}methyl)carbamate (50.28 g, 153 mmol) in methanol was added 4N HCl in dioxane (200 mL, 800 mmol) at room temperature. After 4 h, the volatile materials were removed by evaporation. The resulting amorphous was precipitated with diethyl ether/methanol (5:1). The precipitate was collected and added to the ice cooled 6N NaOH aq. (200 mL) gradually. The mixture was extracted with dichloromethane/methanol (10:1) for 4 times. The combined organic phase was washed with brine, dried over MgSO4 and concentrated to give 24.90 g (99%) of the title compound as pale brown amorphous. the volatile materials were removed by evaporation The resulting amorphous was precipitated with diethyl ether/methanol (5:1) The precipitate was collected added to the ice cooled 6N NaOH aq. (200 mL) gradually The mixture was extracted with dichloromethane/methanol (10:1) for 4 times The combined organic phase was washed with brine dried over MgSO4 concentrated

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

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