(3-Bromopropyl)carbamic acid benzyl ester

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

Procedure: 1-(3-Chlorophenyl)piperazine hydrochloride (5 g, 25.4 mmol), benzyl 3-bromopropylcarbamate (8.3 g, 30.5 mmol) and potassium carbonate (10.5 g, 75.9 mmol) were heated to 80° C. in dimethylformamide (100 ml) for overnight under nitrogen condition. After the reaction complete, the reaction mixture was cooled to room temperature and water was added. The organic layer was extracted with ethyl acetate, and washed with water and brine. After drying with MgSO4, the organic layer was filtered and evaporated under reduced pressure to give the title compound (7.2 g, 73%) as light yellow oil, which was used in the deprotection reaction without further purification. The organic layer was extracted with ethyl acetate washed with water and brine After drying with MgSO4 the organic layer was filtered evaporated under reduced pressure

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

Procedure: Benzylchloroformate (8.6 ml, 60 mmol) was added to a stirred mixture of 3-bromopropylamine hydrobromide (6.6 g, 30 mmol) in methylene chloride (100 ml) and 3N sodium hydroxide solution (100 ml) at 0° C. After stirring two phase reaction mixture at room temperature for overnight, organic layer was separated and washed with water twice (30 ml×2). After drying with MgSO4, the volatile solvent was evaporated under reduced pressure. The residue was purified with silica gel column chromatography (EtOAc:Hx=1:4) to obtain desire compound (8.6 g, 98%) as colorless oil. two phase reaction mixture at room temperature for overnight organic layer was separated washed with water twice (30 ml×2) After drying with MgSO4 the volatile solvent was evaporated under reduced pressure The residue was purified with silica gel column chromatography (EtOAc:Hx=1:4)

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

Procedure: 1-(3-Chlorophenyl)piperazine hydrochloride (5 g, 25.4 mmol), benzyl 3-bromopropylcarbamate (8.3 g, 30.5 mmol) and potassium carbonate (10.5 g, 75.9 mmol) were heated to 80° C. in dimethylformamide (100 ml) for overnight under nitrogen condition. After the reaction complete, the reaction mixture was cooled to room temperature and water was added. The organic layer was extracted with ethyl acetate, and washed with water and brine. After drying with MgSO4, the organic layer was filtered and evaporated under reduced pressure to give the title compound (7.2 g, 73%) as light yellow oil, which was used in the deprotection reaction without further purification. The organic layer was extracted with ethyl acetate washed with water and brine After drying with MgSO4 the organic layer was filtered evaporated under reduced pressure

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

Procedure: 1-(3-Chlorophenyl)piperazine hydrochloride (5 g, 25.4 mmol), benzyl 3-bromopropylcarbamate (8.3 g, 30.5 mmol) and potassium carbonate (10.5 g, 75.9 mmol) were heated to 80° C. in dimethylformamide (100 ml) for overnight under nitrogen condition. After the reaction complete, the reaction mixture was cooled to room temperature and water was added. The organic layer was extracted with ethyl acetate, and washed with water and brine. After drying with MgSO4, the organic layer was filtered and evaporated under reduced pressure to give the title compound (7.2 g, 73%) as light yellow oil, which was used in the deprotection reaction without further purification. The organic layer was extracted with ethyl acetate washed with water and brine After drying with MgSO4 the organic layer was filtered evaporated under reduced pressure

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

Procedure: Benzylchloroformate (8.6 ml, 60 mmol) was added to a stirred mixture of 3-bromopropylamine hydrobromide (6.6 g, 30 mmol) in methylene chloride (100 ml) and 3N sodium hydroxide solution (100 ml) at 0° C. After stirring two phase reaction mixture at room temperature for overnight, organic layer was separated and washed with water twice (30 ml×2). After drying with MgSO4, the volatile solvent was evaporated under reduced pressure. The residue was purified with silica gel column chromatography (EtOAc:Hx=1:4) to obtain desire compound (8.6 g, 98%) as colorless oil. two phase reaction mixture at room temperature for overnight organic layer was separated washed with water twice (30 ml×2) After drying with MgSO4 the volatile solvent was evaporated under reduced pressure The residue was purified with silica gel column chromatography (EtOAc:Hx=1:4)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred suspension of 3-bromopropylamine hydrobromide (2 g, 9.14 mM) in 40 mL dry THF was added, via hypodermic syringe, benzyl chloroformate (1.64 g, 9.60 mM) at room temperature. After cooling to 0° C., diisopropylethylamine (1.6 mL, 9.20 mM) was added dropwise via syringe and the reaction mixture was allowed to stir at 0° C. for 1 hour. The crude reaction mixture was filtered over a pad of Celite and solvents were evaporated. The residue was flash chromatographed on silica gel, eluting with 10-20-30% EtOAc/hexane to afford 1.56 g desired product as a liquid, homogeneous by TLC in 80:20 hexane-EtOAc; was added, via hypodermic syringe at room temperature The crude reaction mixture was filtered over a pad of Celite and solvents were evaporated chromatographed on silica gel eluting with 10-20-30% EtOAc/hexane

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred suspension of 3-bromopropylamine hydrobromide (2 g, 9.14 mM) in 40 mL dry THF was added, via hypodermic syringe, benzyl chloroformate (1.64 g, 9.60 mM) at room temperature. After cooling to 0° C., diisopropylethylamine (1.6 mL, 9.20 mM) was added dropwise via syringe and the reaction mixture was allowed to stir at 0° C. for 1 hour. The crude reaction mixture was filtered over a pad of Celite and solvents were evaporated. The residue was flash chromatographed on silica gel, eluting with 10-20-30% EtOAc/hexane to afford 1.56 g desired product as a liquid, homogeneous by TLC in 80:20 hexane-EtOAc; was added, via hypodermic syringe at room temperature The crude reaction mixture was filtered over a pad of Celite and solvents were evaporated chromatographed on silica gel eluting with 10-20-30% EtOAc/hexane

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

Procedure: TEA (6.91 g, 68.5 mmol) was added drop wise to an ice-cooled mixture of 3-bromopropylamine.hydrobromide (10.0 g, 45.6 mmol) and N-(Benzyloxycarbonyloxy)-succinimide (11.22 g, 47.9 mmol) in DCM (200 mL). The stirred mixture was allowed to warm to Rt overnight, then washed with water, brine, dried (MgSO4), filtered and concentrated, providing 11.43 g (92%) of N-(Benzyloxycarbonyl)-3-bromopropylamine, as a pale yellow oil. 1H NMR (CDCl3): 7.35 (m, 5H), 5.10 (s, 2H), 4.89 (br s, 1H), 3.44 (t, J=6.6 Hz), 3.35 (dd, J=12.9, 6.3 Hz, 2H), m (2.06, 2H). LCMS (LC: Hydrophobic/TFA, RT=6.4 min; MS: 294, 296 ([M+NH4]+, 22%), 272, 274 ([M+H]+, 100%). cooled to warm to Rt overnight washed with water, brine dried (MgSO4) filtered concentrated

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

Procedure: TEA (6.91 g, 68.5 mmol) was added drop wise to an ice-cooled mixture of 3-bromopropylamine.hydrobromide (10.0 g, 45.6 mmol) and N-(Benzyloxycarbonyloxy)-succinimide (11.22 g, 47.9 mmol) in DCM (200 mL). The stirred mixture was allowed to warm to Rt overnight, then washed with water, brine, dried (MgSO4), filtered and concentrated, providing 11.43 g (92%) of N-(Benzyloxycarbonyl)-3-bromopropylamine, as a pale yellow oil. 1H NMR (CDCl3): 7.35 (m, 5H), 5.10 (s, 2H), 4.89 (br s, 1H), 3.44 (t, J=6.6 Hz), 3.35 (dd, J=12.9, 6.3 Hz, 2H), m (2.06, 2H). LCMS (LC: Hydrophobic/TFA, RT=6.4 min; MS: 294, 296 ([M+NH4]+, 22%), 272, 274 ([M+H]+, 100%). cooled to warm to Rt overnight washed with water, brine dried (MgSO4) filtered concentrated

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

Procedure: TEA (6.91 g, 68.5 mmol) was added dropwise to an ice-cooled mixture of 3-bromopropylamine.hydrobromide (10.0 g, 45.6 mmol) and N-(Benzyloxycarbonyloxy)-succinimide (11.22 g, 47.9 mmol) in DCM (200 mL). The stirred mixture was allowed to warm to room temperature overnight, then washed with water (3×), brine, dried (MgSO4), filtered and concentrated, providing 11.43 g (92%) of N-(Benzyloxycarbonyl)-3-bromopropylamine, as a pale yellow oil. cooled washed with water (3×), brine dried (MgSO4) filtered concentrated

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

Procedure: TEA (6.91 g, 68.5 mmol) was added dropwise to an ice-cooled mixture of 3-bromopropylamine.hydrobromide (10.0 g, 45.6 mmol) and N-(Benzyloxycarbonyloxy)-succinimide (11.22 g, 47.9 mmol) in DCM (200 mL). The stirred mixture was allowed to warm to room temperature overnight, then washed with water (3×), brine, dried (MgSO4), filtered and concentrated, providing 11.43 g (92%) of N-(Benzyloxycarbonyl)-3-bromopropylamine, as a pale yellow oil. cooled washed with water (3×), brine dried (MgSO4) filtered concentrated

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

Procedure: A mixture of benzyl (3-bromopropyl)aminoformate (495.2 g, 1.82 mol), prepared as in Example 6, 1-(2-methoxyphenyl)piperazine hydrochloride (377.9 g, 1.65 mol) and potassium carbonate (456.8 g, 3.31 mol) in 3L of DMF was stirred at 80° to 81° C. for 3.5 hours. The mixture was allowed to cool to room temperature and then poured into 20L of water. The mixture was extracted with ethyl acetate (3×4L). The combined ethyl acetate extracts were washed with water (2×1L) and saturated aqueous sodium chloride (1×1L), dried (Na2SO4) and treated with silica gel (200 g). The ethyl acetate was filtered and 11L of the filtrate was added slowly to 200 mL of 5.5N hydrochloric acid (2.75 mol) in ethanol at a rate such that the reaction temperature did not exceed 23° C. The mixture was aged at room temperature for 1 hour and filtered. The filtered residue was washed with ethyl acetate (3×500 mL), dried under a stream of air for 17 hours and then dried under reduced pressure at 60° C. to give benzyl 3-[4-(2-methoxyphenyl)piperazin-1-yl]propylaminoformate dihydrochloride (496 g, 1.09 mol), m.p. 174°-176° C. The mixture was extracted with ethyl acetate (3×4L) The combined ethyl acetate extracts were washed with water (2×1L) and saturated aqueous sodium chloride (1×1L) dried (Na2SO4) treated with silica gel (200 g) The ethyl acetate was filtered did not exceed 23° C The mixture was aged at room temperature for 1 hour filtered The filtered residue was washed with ethyl acetate (3×500 mL) dried under a stream of air for 17 hours dried under reduced pressure at 60° C.