1-(4-bromophenyl)-3-chloropropan-1-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: A solution of 1-(4-Bromo-phenyl)-3-chloro-propan-1-ol* (1.5 g, 6.01 mmol) and imidazole (1.23 g, 18.03 mmol) in dimethylformamide (18 ml) was heated at 100° C. for 18 hrs then partitioned between water and ethyl acetate. The organic extracts were combined, dried (MgSO4), filtered, concentrated and purified by column chromatography (SiO2), eluting with methanol:dichloromethane (2:98) to methanol:dichloromethane (6:94) to afford the title compound (0.75 g, 44% yield). LC/MS: (PS-B3) Rt 2.48 [M+H]+ 281.14, 283.11. *This starting material can be made by the method described in Example 43A. then partitioned between water and ethyl acetate dried (MgSO4) filtered concentrated purified by column chromatography (SiO2) eluting with methanol:dichloromethane (2:98) to methanol:dichloromethane (6:94)

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

Procedure: 3-Chlorophenol was reacted with 1-(4-Bromo-phenyl)-3-chloro-propan-1-ol following the procedure set out in Example 48B to give the title compound, which was used in the next step without further purification.

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

Procedure: To a solution of 1-(4-Bromo-phenyl)-3-chloro-propan-1-one (1 g, 4.04 mmol) in tetrahydrofuran (9 ml) and water (0.58 ml) was added sodium borohydride (0.16 g, 4.28 mmol). The reaction mixture was stirred at room temperature for 2 hours, quenched with careful addition of water and extracted with ethyl acetate. The organic layers were separated, dried (MgSO4), filtered and concentrated to afford the title compound, which was used in the next step without further purification. LC/MS. (PS-A2) Rt 3.07 [M+H]+ No Ionization. quenched with careful addition of water extracted with ethyl acetate The organic layers were separated dried (MgSO4) filtered concentrated

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

Procedure: To a solution of 1-(4-Bromo-phenyl)-3-chloro-propan-1-one (1 g, 4.04 mmol) in tetrahydrofuran (9 ml) and water (0.58 ml) was added sodium borohydride (0.16 g, 4.28 mmol). The reaction mixture was stirred at room temperature for 2 hours, quenched with careful addition of water and extracted with ethyl acetate. The organic layers were separated, dried (MgSO4), filtered and concentrated to afford the title compound, which was used in the next step without further purification. LC/MS. (PS-A2) Rt 3.07 [M+H]+ No Ionization. quenched with careful addition of water extracted with ethyl acetate The organic layers were separated dried (MgSO4) filtered concentrated

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

Procedure: A solution of 1-(4-Bromo-phenyl)-3-chloro-propan-1-ol* (1.5 g, 6.01 mmol) and imidazole (1.23 g, 18.03 mmol) in dimethylformamide (18 ml) was heated at 100° C. for 18 hrs then partitioned between water and ethyl acetate. The organic extracts were combined, dried (MgSO4), filtered, concentrated and purified by column chromatography (SiO2), eluting with methanol:dichloromethane (2:98) to methanol:dichloromethane (6:94) to afford the title compound (0.75 g, 44% yield). LC/MS: (PS-B3)Rt 2.48 [M+H]+ 281.14, 283.11. then partitioned between water and ethyl acetate dried (MgSO4) filtered concentrated purified by column chromatography (SiO2) eluting with methanol:dichloromethane (2:98) to methanol:dichloromethane (6:94)

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

Procedure: 3-Chlorophenol was reacted with 1-(4-Bromo-phenyl)-3-chloro-propan-1-ol following the procedure set out in Example 48B to give the title compound, which was used in the next step without further purification.

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

Procedure: 3-Chlorophenol was reacted with 1-(4-Bromo-phenyl)-3-chloro-propan-1-ol following the procedure set out in Example 48B to give the title compound, which was used in the next step without further purification.

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1-(4-bromo-phenyl)-3-chloro-propan-1-ol (25 g, 100 mmol), (R)-1-phenylethylamine (25 mL, 200 mmol), potassium iodide (33 g, 200 mmol) and potassium carbonate (27.6 g, 200 mmol) in acetonitrile (600 mL) was prepared at room temperature and warmed to 75° C. After stirring for 40 hours, solvent was evaporated. And then distillable removal of excess (R)-1-phenylethylamine was performed at 120° C. under reduced pressure. The obtained residue was dissolved in dichloromethane (200 mL) and to the resulting solution was added triethylamine (16.7 mL, 120 mmol) and chloroacetylchloride (10 mL, 120 mmol) at 0° C. After stirring for one hour, the reaction solution was poured into 1N hydrochloric acid aqueous solution and extracted with chloroform. The extracts were dried over anhydrous sodium sulfate and concentrated. The resulting residue was diluted with 2-propanol (100 mL) and to the mixture was added potassium hydroxide (9.9 g, 150 mmol) at room temperature. After stirring for 5 hours, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium hydroxide and concentrated. Purification of the residue and separation of each diastereomer were performed by flash column chromatography on silica gel (hexane/ethyl acetate=2/1 to 1/1 as eluants) to yield 7-(4-bromo-phenyl)-4-((R)-1-phenyl-ethyl)-[1,4]oxazepan-3-one (diastereomer A; 13.1 g, 35 mmol, 35% in 3 steps) as brown oil and 7-(4-bromo-phenyl)-4-((R)-1-phenyl-ethyl)-[1,4]oxazepan-3-one (diastereomer B; 11.0 g, 29.4 mmol, 29% in 3 steps) as white solid. 7-(4-Bromo-phenyl)-4-((R)-1-phenyl-ethyl)-[1,4]oxazepan-3-one (diastereomer A): was prepared at room temperature solvent was evaporated And then distillable removal of excess (R)-1-phenylethylamine was performed at 120° C. under reduced pressure The obtained residue was dissolved in dichloromethane (200 mL) and to the resulting solution After stirring for one hour extracted with chloroform The extracts were dried over anhydrous sodium sulfate concentrated The resulting residue was diluted with 2-propanol (100 mL) and to the mixture After stirring for 5 hours extracted with ethyl acetate The organic phase was dried over anhydrous sodium hydroxide concentrated Purification of the residue and separation of each diastereomer

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1-(4-bromo-phenyl)-3-chloro-propan-1-ol (25 g, 100 mmol), (R)-1-phenylethylamine (25 mL, 200 mmol), potassium iodide (33 g, 200 mmol) and potassium carbonate (27.6 g, 200 mmol) in acetonitrile (600 mL) was prepared at room temperature and warmed to 75° C. After stirring for 40 hours, solvent was evaporated. And then distillable removal of excess (R)-1-phenylethylamine was performed at 120° C. under reduced pressure. The obtained residue was dissolved in dichloromethane (200 mL) and to the resulting solution was added triethylamine (16.7 mL, 120 mmol) and chloroacetylchloride (10 mL, 120 mmol) at 0° C. After stirring for one hour, the reaction solution was poured into 1N hydrochloric acid aqueous solution and extracted with chloroform. The extracts were dried over anhydrous sodium sulfate and concentrated. The resulting residue was diluted with 2-propanol (100 mL) and to the mixture was added potassium hydroxide (9.9 g, 150 mmol) at room temperature. After stirring for 5 hours, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium hydroxide and concentrated. Purification of the residue and separation of each diastereomer were performed by flash column chromatography on silica gel (hexane/ethyl acetate=2/1 to 1/1 as eluants) to yield 7-(4-bromo-phenyl)-4-((R)-1-phenyl-ethyl)-[1,4]oxazepan-3-one (diastereomer A; 13.1 g, 35 mmol, 35% in 3 steps) as brown oil and 7-(4-bromo-phenyl)-4-((R)-1-phenyl-ethyl)-[1,4]oxazepan-3-one (diastereomer B; 11.0 g, 29.4 mmol, 29% in 3 steps) as white solid. 7-(4-Bromo-phenyl)-4-((R)-1-phenyl-ethyl)-[1,4]oxazepan-3-one (diastereomer A): was prepared at room temperature solvent was evaporated And then distillable removal of excess (R)-1-phenylethylamine was performed at 120° C. under reduced pressure The obtained residue was dissolved in dichloromethane (200 mL) and to the resulting solution After stirring for one hour extracted with chloroform The extracts were dried over anhydrous sodium sulfate concentrated The resulting residue was diluted with 2-propanol (100 mL) and to the mixture After stirring for 5 hours extracted with ethyl acetate The organic phase was dried over anhydrous sodium hydroxide concentrated Purification of the residue and separation of each diastereomer