methyl (3R)-3-hydroxypentanoate

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

Procedure: To a stirred solution of (R)-methyl 3-hydroxypentanoate (49.4 mg, 48 μl, 0.374 mmol) in dioxane (3 ml) was added at room temperature potassium trimethylsilanolate (63.9 mg, 0.5 mmol) and the mixture was allowed to stir for additional 23 h. Afterwards N,N-diisopropylethyl-amine (177 mg, 1.37 mmol), trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and TBTU (120 mg, 0.374 mmol) were added, and the mixture was allowed to stir for 3 h at room temperature. The reaction mixture was poured into saturated NaHCO3 solution (20 ml) and extracted with dichloromethane (2×40 ml). The combined organic layers were washed with brine (20 ml), dried (MgSO4) and evaporated. The crude material (140 mg) was further purified by flash chromatography on silica gel (dichloromethane/MeOH 9:1) to yield the title compound as white solid (58 mg, 54%), MS (ISP) m/z=429.4 [(M+H)+], mp 201° C. to stir for 3 h at room temperature extracted with dichloromethane (2×40 ml) The combined organic layers were washed with brine (20 ml) dried (MgSO4) evaporated The crude material (140 mg) was further purified by flash chromatography on silica gel (dichloromethane/MeOH 9:1)

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

Procedure: Into a 200-ml autoclave (made of Hastelloy) were introduced 50 g of methyl 3-oxopentanoate (manufactured by Wacker Chemicals Co., Ltd.) and 75 ml of methanol. The atmosphere in the autoclave was replaced with nitrogen gas. Thereto was added a solution prepared by dissolving 325 mg of Ru2Cl4 ((+)-(T)BINAP)2Et3N as a ruthenium-optically active phosphine complex in 3.8 ml of methylene chloride. Asymmetric hydrogenation was conducted at a reaction temperature of 30° C. and a hydrogen pressure of 30 atm. After the reaction mixture was thus reacted for 50 hours, it was taken out of the autoclave. The methanol was distilled off, and the residue was subjected to vacuum distillation to obtain 49.8 g of methyl (R)-3-hydroxypentanoate. Yield, 98%. Thereto was added a solution prepared was conducted at a reaction temperature of 30° C. After the reaction mixture was thus reacted for 50 hours The methanol was distilled off the residue was subjected to vacuum distillation

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

Procedure: To a stirred solution of (R)-methyl 3-hydroxypentanoate (49.4 mg, 48 μl, 0.374 mmol) in dioxane (3 ml) was added at room temperature potassium trimethylsilanolate (63.9 mg, 0.5 mmol) and the mixture was allowed to stir for additional 23 h. Afterwards N,N-diisopropylethyl-amine (177 mg, 1.37 mmol), trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and TBTU (120 mg, 0.374 mmol) were added, and the mixture was allowed to stir for 3 h at room temperature. The reaction mixture was poured into saturated NaHCO3 solution (20 ml) and extracted with dichloromethane (2×40 ml). The combined organic layers were washed with brine (20 ml), dried (MgSO4) and evaporated. The crude material (140 mg) was further purified by flash chromatography on silica gel (dichloromethane/MeOH 9:1) to yield the title compound as white solid (58 mg, 54%), MS (ISP) m/z=429.4 [(M+H)+], mp 201° C. to stir for 3 h at room temperature extracted with dichloromethane (2×40 ml) The combined organic layers were washed with brine (20 ml) dried (MgSO4) evaporated The crude material (140 mg) was further purified by flash chromatography on silica gel (dichloromethane/MeOH 9:1)

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

Procedure: To a stirred solution of (R)-methyl 3-hydroxypentanoate (49.4 mg, 48 μl, 0.374 mmol) in dioxane (3 ml) was added at room temperature potassium trimethylsilanolate (63.9 mg, 0.5 mmol) and the mixture was allowed to stir for additional 23 h. Afterwards N,N-diisopropylethyl-amine (177 mg, 1.37 mmol), trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and TBTU (120 mg, 0.374 mmol) were added, and the mixture was allowed to stir for 3 h at room temperature. The reaction mixture was poured into saturated NaHCO3 solution (20 ml) and extracted with dichloromethane (2×40 ml). The combined organic layers were washed with brine (20 ml), dried (MgSO4) and evaporated. The crude material (140 mg) was further purified by flash chromatography on silica gel (dichloromethane/MeOH 9:1) to yield the title compound as white solid (58 mg, 54%), MS (ISP) m/z=429.4 [(M+H)+], mp 201° C. to stir for 3 h at room temperature extracted with dichloromethane (2×40 ml) The combined organic layers were washed with brine (20 ml) dried (MgSO4) evaporated The crude material (140 mg) was further purified by flash chromatography on silica gel (dichloromethane/MeOH 9:1)

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

Procedure: The title compound, white solid (58 mg, 54%), MS (ISP) m/z=431.5 [(M+H)+], mp 161° C., was prepared in accordance with the general method of example 2 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and methyl (R)-3-hydroxy-pentanoate.

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

Procedure: To a stirred solution of (R)-methyl 3-hydroxypentanoate (49.6 mg, 48.2 μl) in dioxane (3 ml) was added at room temperature potassium trimethylsilanolate (64.2 mg, 0 5 mmol) and the mixture was allowed to stir for additional 18 h. Afterwards N,N-diisopropylethylamine (178 mg, 1.38 mmol), trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and TBTU (121 mg, 0.376 mmol) were added, and the mixture was allowed to stir for 3 h at room temperature. The reaction mixture was poured into saturated NaHCO3 solution (20 ml) and extracted with dichloromethane (2×40 ml). The combined organic layers were washed with brine (20 ml), dried (MgSO4) and evaporated. The crude material (130 mg) was further purified by flash chromatography on silica gel (dichloromethane/MeOH/NH4OH 150:10:1) to yield the title compound as white solid (95 mg, 89%), MS (ISP) m/z=427.3 [(M+H)+], mp 142° C. to stir for 3 h at room temperature extracted with dichloromethane (2×40 ml) The combined organic layers were washed with brine (20 ml) dried (MgSO4) evaporated The crude material (130 mg) was further purified by flash chromatography on silica gel (dichloromethane/MeOH/NH4OH 150:10:1)

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

Procedure: Into a 200-ml autoclave (made of Hastelloy) were introduced 50 g of methyl 3-oxopentanoate (manufactured by Wacker Chemicals Co., Ltd.) and 75 ml of methanol. The atmosphere in the autoclave was replaced with nitrogen gas. Thereto was added a solution prepared by dissolving 325 mg of Ru2Cl4 ((+)-(T)BINAP)2Et3N as a ruthenium-optically active phosphine complex in 3.8 ml of methylene chloride. Asymmetric hydrogenation was conducted at a reaction temperature of 30° C. and a hydrogen pressure of 30 atm. After the reaction mixture was thus reacted for 50 hours, it was taken out of the autoclave. The methanol was distilled off, and the residue was subjected to vacuum distillation to obtain 49.8 g of methyl (R)-3-hydroxypentanoate. Yield, 98%. Thereto was added a solution prepared was conducted at a reaction temperature of 30° C. After the reaction mixture was thus reacted for 50 hours The methanol was distilled off the residue was subjected to vacuum distillation

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

Procedure: To a stirred solution of (R)-methyl 3-hydroxypentanoate (49.4 mg, 48 μl, 0.374 mmol) in dioxane (3 ml) was added at room temperature potassium trimethylsilanolate (63.9 mg, 0.5 mmol) and the mixture was allowed to stir for additional 23 h. Afterwards N,N-diisopropylethyl-amine (177 mg, 1.37 mmol), trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and TBTU (120 mg, 0.374 mmol) were added, and the mixture was allowed to stir for 3 h at room temperature. The reaction mixture was poured into saturated NaHCO3 solution (20 ml) and extracted with dichloromethane (2×40 ml). The combined organic layers were washed with brine (20 ml), dried (MgSO4) and evaporated. The crude material (140 mg) was further purified by flash chromatography on silica gel (dichloromethane/MeOH 9:1) to yield the title compound as white solid (58 mg, 54%), MS (ISP) m/z=429.4 [(M+H)+], mp 201° C. to stir for 3 h at room temperature extracted with dichloromethane (2×40 ml) The combined organic layers were washed with brine (20 ml) dried (MgSO4) evaporated The crude material (140 mg) was further purified by flash chromatography on silica gel (dichloromethane/MeOH 9:1)