5-bromopentoxymethylbenzene

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:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: 4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.5 g) as starting compound, potassium carbonate (2.8 g) and 5-benzyloxypentyl bromide (2.08 g) were reacted and treated in the same manner as in Example 168 to give 0.82 g of 4-amino-N-((1-(5-benzyloxypentyl)piperidin-4-yl)methyl)-5-chloro-2-methoxybenzamide. were reacted treated in the same manner as in Example 168

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

Procedure: 60% Sodium hydride (1.33 g) was suspended in dimethylformamide (40 ml), and benzyl alcohol (3 g) was added under ice-cooilng with stirring. The mixture was stirred at room temperature for 1 hr. The mixture was again ice-cooled, and 1,5-dibromopentane (6.4 g) was added, which was followed by stirring at room temperature for 3 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure to give 7.2 g of 5-benzyloxypentyl bromide. The mixture was stirred at room temperature for 1 hr cooled by stirring at room temperature for 3 hr the mixture was extracted with ethyl acetate The organic layer was washed with brine dried the solvent was evaporated under reduced pressure

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

Procedure: To a solution of (R)-4-butylpyrrolidin-2-one (0.42 g, 2.9 mmol) in dry dimethylformamide (10 mL) under argon was slowly added sodium hydride (60% in mineral oil, 0.14 g, 3.5 mmol) at 0° C. After stirring at 0° C. for 30 minutes, 5-benzyloxypentyl bromide (0.9 g, 3.5 mmol) was added dropwise. The resulting mixture was stirred at room temperature overnight and then diluted with ethyl acetate (50 mL). The organic solution was washed with water (4×30 mL) and brine (30 mL), dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography (silica gel, 1:1 EtOAc/hexanes) to afford 0.73 g (95%) of (R)-1-(5-benzyloxypentyl)-4-butylpyrrolidin-2-one as a colorless oil: 1H NMR (CDCl3) δ 7.33 (m, 5 H), 4.51 (s, 2 H), 3.45 (m, 3 H), 3.27 (t, 2 H), 2.99 (dd, 1 H), 2.52 (dd, 1 H), 2.32 (m, 1 H), 2.06 (m, 1 H), 1.24-1.71 (m, 12 H), 0.93 (t, 3 H). MS(ES) m/e 318 [M+H]+. at 0° C The resulting mixture was stirred at room temperature overnight The organic solution was washed with water (4×30 mL) and brine (30 mL) dried (Na2SO4) concentrated The residue was purified by flash column chromatography (silica gel, 1:1 EtOAc/hexanes)

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

Procedure: To a solution of (R)-4-butylpyrrolidin-2-one (0.42 g, 2.9 mmol) in dry dimethylformamide (10 mL) under argon was slowly added sodium hydride (60% in mineral oil, 0.14 g, 3.5 mmol) at 0° C. After stirring at 0° C. for 30 minutes, 5-benzyloxypentyl bromide (0.9 g, 3.5 mmol) was added dropwise. The resulting mixture was stirred at room temperature overnight and then diluted with ethyl acetate (50 mL). The organic solution was washed with water (4×30 mL) and brine (30 mL), dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography (silica gel, 1:1 EtOAc/hexanes) to afford 0.73 g (95%) of (R)-1-(5-benzyloxypentyl)-4-butylpyrrolidin-2-one as a colorless oil: 1H NMR (CDCl3) δ 7.33 (m, 5 H), 4.51 (s, 2 H), 3.45 (m, 3 H), 3.27 (t, 2 H), 2.99 (dd, 1 H), 2.52 (dd, 1 H), 2.32 (m, 1 H), 2.06 (m, 1 H), 1.24-1.71 (m, 12 H), 0.93 (t, 3 H). MS(ES) m/e 318 [M+H]+. at 0° C The resulting mixture was stirred at room temperature overnight The organic solution was washed with water (4×30 mL) and brine (30 mL) dried (Na2SO4) concentrated The residue was purified by flash column chromatography (silica gel, 1:1 EtOAc/hexanes)

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

Procedure: At -78° C., 27.8 ml of t-butyl lithium (1.7M) in hexane are added to 5.30 gm of 3-bromo-(1-hexenyl)benzene in 75 mls of tetrahydrofuran. The reaction is stirred for 10 minutes, and then 1.1 ml of Li2CuCl3 (0.20M/THF) is added followed dropwise by 5.78 grams of 1-bromo-5-benzyloxy pentane. After allowing the reaction mixture to come to ambient temperature over 5 hours and stirring for an additional 24 hours, silica gel is added; and the mixture is concentrated and then chromatographed (HPLC) to yield pure 3-(5-benzyloxypentyl)-1-(1-hexenyl)benzene. to come to ambient temperature over 5 hours stirring for an additional 24 hours silica gel is added and the mixture is concentrated chromatographed (HPLC)

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

Procedure: At a temperature of -78° C., 19.4 ml of t-butyl lithium (1.7M) is added to 4.0 gm of the above 3-bromo-phenol, n-pentyl ether in 50 mls tetrahydrofuran; and to this is added 3.3 ml of a freshly prepared solution of Li2CuCl3 (0.10M/THF). The mixture is stirred for 10 minutes, and then 4.35 grams of the 1-bromo-5-benzyloxy pentane are added. The reaction is allowed to warm slowly to ambient temperature over 12 hours and is then stirred an additional 24 hours before being quenched with silica gel. After removing the solvent, the mixture is chromatographed over silica gel (1:1 hexane:ether) to yield a crude mixture containing 3-(benzyloxypentyl)-phenol, n-pentyl ether. A solution of 6.0 gm of this crude mixture in ethanol is hydrogenated over 5% Pd on carbon for 5 hours. After filtering through celite and concentrating, pure 3-(5-hydroxypentyl)-phenol, n-pentyl ether is obtained as a clear oil by HPLC chromatography. is then stirred an additional 24 hours before being quenched with silica gel After removing the solvent the mixture is chromatographed over silica gel (1:1 hexane:ether) to yield a crude mixture After filtering through celite concentrating

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

Procedure: 4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.5 g) as starting compound, potassium carbonate (2.8 g) and 5-benzyloxypentyl bromide (2.08 g) were reacted and treated in the same manner as in Example 168 to give 0.82 g of 4-amino-N-((1-(5-benzyloxypentyl)piperidin-4-yl)methyl)-5-chloro-2-methoxybenzamide. were reacted treated in the same manner as in Example 168