azepane-1-carbonyl chloride

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

Procedure: To a solution of (S)-1-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazin-1-ylmethyl}-3-methyl-butylamine monohydrochloride (189 mg, 0.46 mmol) in benzene (2 mL) were added sequentially N,N-diisopropylethylamine (0.26 mL, 1.5 mmol), 4-dimethylaminopyridine (20 mg), and azepane-1-carbonyl chloride (0.13 mL, 0.78 mmol) under nitrogen atmosphere. The resulting reaction mixture was refluxed for 16 hours, then cooled to ambient temperature. The reaction mixture was filtered to remove the white solid formed during the reaction; the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc (25 mL) and washed successively with saturated aqueous NaHCO3 solution (25 mL), brine (2×25 mL), and dried over Na2SO4. The solution was concentrated in vacuo affording a slightly amber colored oil. The crude product was purified first by flash chromatography (50% EtOAc in hexanes), then by preparative plate (50% EtOAc in hexanes) affording 46.6 mg (20%) of the pure titled compound as a clear oil. APCI-MS m/z 513.3 (MH+). The resulting reaction mixture was refluxed for 16 hours The reaction mixture was filtered to remove the white solid formed during the reaction the filtrate was concentrated in vacuo The residue was dissolved in EtOAc (25 mL) washed successively with saturated aqueous NaHCO3 solution (25 mL), brine (2×25 mL) dried over Na2SO4 The solution was concentrated in vacuo affording a slightly amber colored oil The crude product was purified first by flash chromatography (50% EtOAc in hexanes)

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

Procedure: To a solution of (S)-1-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazin-1-ylmethyl}-3-methyl-butylamine monohydrochloride (189 mg, 0.46 mmol) in benzene (2 mL) were added sequentially N,N-diisopropylethylamine (0.26 mL, 1.5 mmol), 4-dimethylaminopyridine (20 mg), and azepane-1-carbonyl chloride (0.13 mL, 0.78 mmol) under nitrogen atmosphere. The resulting reaction mixture was refluxed for 16 hours, then cooled to ambient temperature. The reaction mixture was filtered to remove the white solid formed during the reaction; the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc (25 mL) and washed successively with saturated aqueous NaHCO3 solution (25 mL), brine (2×25 mL), and dried over Na2SO4. The solution was concentrated in vacuo affording a slightly amber colored oil. The crude product was purified first by flash chromatography (50% EtOAc in hexanes), then by preparative plate (50% EtOAc in hexanes) affording 46.6 mg (20%) of the pure titled compound as a clear oil. APCI-MS m/z 513.3 (MH+). The resulting reaction mixture was refluxed for 16 hours The reaction mixture was filtered to remove the white solid formed during the reaction the filtrate was concentrated in vacuo The residue was dissolved in EtOAc (25 mL) washed successively with saturated aqueous NaHCO3 solution (25 mL), brine (2×25 mL) dried over Na2SO4 The solution was concentrated in vacuo affording a slightly amber colored oil The crude product was purified first by flash chromatography (50% EtOAc in hexanes)

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of azepane (2 g, 20.2 mmol) in 30 mL of anhydrous toluene was added DIEA (3.5 mL, 20.0 mmol) and pyridine (1.63 mL, 20.2 mmol). The mixture was cooled to −10° C. under nitrogen. Once at the prescribed temperature, carbon dioxide gas was bubbled through the solution for 30 min, and then a solution of thionyl chloride (1.74 mL, 24.0 mmol) in 10 mL of toluene was added at −10° C. Upon completion of addition, the reaction mixture was stirred for 1 hr while the temperature was kept under 10° C. The reaction mixture was then diluted with ethyl acetate, washed with cold 0.5 N HCl solution and brine, dried over Na2SO4, and concentrated to give the title compound (2.76 g, 85%) as a pale yellow oil. Once at the prescribed temperature, carbon dioxide gas was bubbled through the solution for 30 min Upon completion of addition was kept under 10° C washed with cold 0.5 N HCl solution and brine dried over Na2SO4 concentrated

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of azepane (2 g, 20.2 mmol) in 30 mL of anhydrous toluene was added DIEA (3.5 mL, 20.0 mmol) and pyridine (1.63 mL, 20.2 mmol). The mixture was cooled to −10° C. under nitrogen. Once at the prescribed temperature, carbon dioxide gas was bubbled through the solution for 30 min, and then a solution of thionyl chloride (1.74 mL, 24.0 mmol) in 10 mL of toluene was added at −10° C. Upon completion of addition, the reaction mixture was stirred for 1 hr while the temperature was kept under 10° C. The reaction mixture was then diluted with ethyl acetate, washed with cold 0.5 N HCl solution and brine, dried over Na2SO4, and concentrated to give the title compound (2.76 g, 85%) as a pale yellow oil. Once at the prescribed temperature, carbon dioxide gas was bubbled through the solution for 30 min Upon completion of addition was kept under 10° C washed with cold 0.5 N HCl solution and brine dried over Na2SO4 concentrated

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

Procedure: To a solution of (S)-1-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazin-1-ylmethyl}-3-methyl-butylamine monohydrochloride (189 mg, 0.46 mmol) in benzene (2 mL) were added sequentially N,N-diisopropylethylamine (0.26 mL, 1.5 mmol), 4-dimethylaminopyridine (20 mg), and azepane-1-carbonyl chloride (0.13 mL, 0.78 mmol) under nitrogen atmosphere. The resulting reaction mixture was refluxed for 16 hours, then cooled to ambient temperature. The reaction mixture was filtered to remove the white solid formed during the reaction; the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc (25 mL) and washed successively with saturated aqueous NaHCO3 solution (25 mL), brine (2×25 mL), and dried over Na2SO4. The solution was concentrated in vacuo affording a slightly amber colored oil. The crude product was purified first by flash chromatography (50% EtOAc in hexanes), then by preparative plate (50% EtOAc in hexanes) affording 46.6 mg (20%) of the pure titled compound as a clear oil. APCI-MS m/z 513.3 (MH+). The resulting reaction mixture was refluxed for 16 hours The reaction mixture was filtered to remove the white solid formed during the reaction the filtrate was concentrated in vacuo The residue was dissolved in EtOAc (25 mL) washed successively with saturated aqueous NaHCO3 solution (25 mL), brine (2×25 mL) dried over Na2SO4 The solution was concentrated in vacuo affording a slightly amber colored oil The crude product was purified first by flash chromatography (50% EtOAc in hexanes)