TETRAHYDRO-THIOPYRAN-4-YLAMINE HYDROCHLORIDE

Conditions: temp:13.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of tetrahydro-2H-thiopyran-4-amine hydrochloride (80.0 g) in THF (800 mL) were added triethylamine (239 mL) and 2-nitrobenzenesulfonyl chloride (126.9 g) under ice-cooling at an inside temperature of 2-24° C., and the mixture was stirred at room temperature for 23 hr. The reaction solution was partitioned and extracted with ethyl acetate and water, and the organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to the extent crystals do not precipitate and purified by silica gel column chromatography [eluent; hexane:ethyl acetate=50:50 (volume ratio)]. The obtained solid was washed with ethanol-diisopropyl ether (1:4), and dried under reduced pressure to give the title compound (145.6 g, yield 92%) as a pale-green solid. The reaction solution was partitioned extracted with ethyl acetate and water the organic layer was washed with water and saturated brine dried over magnesium sulfate concentrated under reduced pressure to the extent crystals do not precipitate purified by silica gel column chromatography [eluent; hexane:ethyl acetate=50:50 (volume ratio)] The obtained solid was washed with ethanol-diisopropyl ether (1:4) dried under reduced pressure

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

Procedure: A mixture of 2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxoacetic acid (Example 44, 0.60 g, 2.07 mmol), tetrahydro-2H-thiopyran-4-amine hydrochloride (0.23 g, 2.48 mmol), triethylamine (433 μL, 3.11 mmol), EDCI (0.39 g, 2.48 mmol) and HOBt (0.38 g, 2.48 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 days. The reaction mixture was poured into saturated NaHCO3 solution and extracted with ethyl acetate. The extract was washed with saturated NaHCO3 solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate 90:10 to 50:50) to give the title compound (0.23 g, 82%) as a white amorphous. extracted with ethyl acetate The extract was washed with saturated NaHCO3 solution and brine dried over anhydrous magnesium sulfate filtered concentrated under reduced pressure The residue was purified by silica gel column chromatography (hexane/ethyl acetate 90:10 to 50:50)

Conditions: temp:13.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of tetrahydro-2H-thiopyran-4-amine hydrochloride (80.0 g) in THF (800 mL) were added triethylamine (239 mL) and 2-nitrobenzenesulfonyl chloride (126.9 g) under ice-cooling at an inside temperature of 2-24° C., and the mixture was stirred at room temperature for 23 hr. The reaction solution was partitioned and extracted with ethyl acetate and water, and the organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to the extent crystals do not precipitate and purified by silica gel column chromatography [eluent; hexane:ethyl acetate=50:50 (volume ratio)]. The obtained solid was washed with ethanol-diisopropyl ether (1:4), and dried under reduced pressure to give the title compound (145.6 g, yield 92%) as a pale-green solid. The reaction solution was partitioned extracted with ethyl acetate and water the organic layer was washed with water and saturated brine dried over magnesium sulfate concentrated under reduced pressure to the extent crystals do not precipitate purified by silica gel column chromatography [eluent; hexane:ethyl acetate=50:50 (volume ratio)] The obtained solid was washed with ethanol-diisopropyl ether (1:4) dried under reduced pressure

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

Procedure: A mixture of 2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxoacetic acid (Example 44, 0.60 g, 2.07 mmol), tetrahydro-2H-thiopyran-4-amine hydrochloride (0.23 g, 2.48 mmol), triethylamine (433 μL, 3.11 mmol), EDCI (0.39 g, 2.48 mmol) and HOBt (0.38 g, 2.48 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 days. The reaction mixture was poured into saturated NaHCO3 solution and extracted with ethyl acetate. The extract was washed with saturated NaHCO3 solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate 90:10 to 50:50) to give the title compound (0.23 g, 82%) as a white amorphous. extracted with ethyl acetate The extract was washed with saturated NaHCO3 solution and brine dried over anhydrous magnesium sulfate filtered concentrated under reduced pressure The residue was purified by silica gel column chromatography (hexane/ethyl acetate 90:10 to 50:50)

Conditions: temp:13.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of tetrahydro-2H-thiopyran-4-amine hydrochloride (80.0 g) in THF (800 mL) were added triethylamine (239 mL) and 2-nitrobenzenesulfonyl chloride (126.9 g) under ice-cooling at an inside temperature of 2-24° C., and the mixture was stirred at room temperature for 23 hr. The reaction solution was partitioned and extracted with ethyl acetate and water, and the organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to the extent crystals do not precipitate and purified by silica gel column chromatography [eluent; hexane:ethyl acetate=50:50 (volume ratio)]. The obtained solid was washed with ethanol-diisopropyl ether (1:4), and dried under reduced pressure to give the title compound (145.6 g, yield 92%) as a pale-green solid. The reaction solution was partitioned extracted with ethyl acetate and water the organic layer was washed with water and saturated brine dried over magnesium sulfate concentrated under reduced pressure to the extent crystals do not precipitate purified by silica gel column chromatography [eluent; hexane:ethyl acetate=50:50 (volume ratio)] The obtained solid was washed with ethanol-diisopropyl ether (1:4) dried under reduced pressure