4-bromobutoxymethylbenzene

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:

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

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

Procedure: Part 1: (±)-7-Benzyloxy-1-(fluorophenoxy)-heptane-2-ol (Scheme VIII; 42) Magnesium (2.4 g, 98 mmol) was added to a 250 ml flask and flame dried. Dry THF, 25 ml, and 1 ml of dibromoethane were then added. 1-Bromo-4-benzyloxy-butane 41 (12 g, 49.4 mmol) dissolved in 50 ml of dry THF was added dropwise and the reaction mixture was stirred at room temperature. After 1 hour, the reaction mixture is cooled in an ice-water bath and 90 mg of copper cyanide is added. After 10 minutes in an ice-bath, 4-fluorophenyl-glycidyl ether (5 g, 29.6 mmol) dissolved in 30 ml of dry THF is added slowly. The reaction is monitored by TLC (ethyl acetate:hexane 3:7). After 15 minutes, the reaction is quenched with saturated aqueous ammonium chloride, concentrated and partitioned between water-ethyl acetate. The ethyl acetate layer is then washed with brine, dried over Na2SO4 and concentrated to give the desired benzyloxy-heptane 42. The structure was confirmed by 1H-NMR. flame dried Dry THF, 25 ml, and 1 ml of dibromoethane were then added was added dropwise the reaction mixture is cooled in an ice-water bath After 10 minutes in an ice-bath is added slowly After 15 minutes the reaction is quenched with saturated aqueous ammonium chloride concentrated partitioned between water-ethyl acetate The ethyl acetate layer is then washed with brine dried over Na2SO4 concentrated

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Fluorophenol (500 mg) and benzyl 4-bromobutyl ether (1.1 g) were dissolved in DMF (20 mL), and potassium carbonate (1.0 g) was added thereto at room temperature, followed by stirring at 100° C. for 18 hours. The reaction mixture was allowed to cool to room temperature, and water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed sequentially with water and saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=90/10) to obtain 1-[4-(benzyloxy)butoxy]-4-fluorobenzene (851 mg). at room temperature to cool to room temperature followed by extraction with ethyl acetate The organic layer was washed sequentially with water and saturated brine dried over anhydrous sodium sulfate the solvent was evaporated The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=90/10)

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 (1.1 g) as starting compound, potassium carbonate (1.5 g) and 4-benzyloxybutyl bromide (1.0 g) were reacted and treated in the same manner as in Example 168 to give 0.32 g of 4-amino-5-chloro-2-methoxy-N-((1-(4-benzyloxybutyl)piperidin-4-yl)methyl)benzamide. 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 (1.2 g) was suspended in tetrahydrofuran (30 ml), and benzyl alcohol (3.0 g) was added under ice-cooling with stirring. The mixture was stirred at room temperature for 30 min, and again ice-cooled. 1,4-Dibromobutane (6.0 g) was added and the mixture was stirred 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 3.8 g of 4-benzyloxybutyl bromide. cooling The mixture was stirred at room temperature for 30 min again ice-cooled the mixture was stirred 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:0.00; pressure:0.00; stir: