3-chloropropoxymethylbenzene

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: 1-(3-Benzyloxypropyl)-4-piperidone is prepared from 4-piperidone and 1-chloro-3-benzyloxypropane essentially as described above in Example 38, Scheme C, step a.

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

Procedure: To a 3-L reaction vessel was charged and stirred potassium carbonate (152 g), 3-hydroxybenzaldehyde (67.6 g), dimethylformamide (DMF, 250 mL) and 3-chloropropyl phenylmethyl ether (96.4 g) at 90° C. for ˜18 h. Water (567 mL) was added followed by tert-butyl methyl ether (907 mL). The bottom aqueous layer was separated and the organic layer washed with 1N sodium hydroxide (2×567 mL) and water (1×567 mL). The organic solution was concentrated to a minimum after which ethanol (200 proof, 907 mL) was added and the solution concentrated to a minimum and filtered though a 1-μm filter. was charged The bottom aqueous layer was separated the organic layer washed with 1N sodium hydroxide (2×567 mL) and water (1×567 mL) The organic solution was concentrated to a minimum after which ethanol (200 proof, 907 mL) was added the solution concentrated to a minimum filtered though a 1-μm filter

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

Procedure: To a 3-L reaction vessel was charged and stirred potassium carbonate (152 g), 3-hydroxybenzaldehyde (67.6 g), dimethylformamide (DMF, 250 mL) and 3-chloropropyl phenylmethyl ether (96.4 g) at 90° C. for ˜18 h. Water (567 mL) was added followed by tert-butyl methyl ether (907 mL). The bottom aqueous layer was separated and the organic layer washed with 1N sodium hydroxide (2×567 mL) and water (1×567 mL). The organic solution was concentrated to a minimum after which ethanol (200 proof, 907 mL) was added and the solution concentrated to a minimum and filtered though a 1-μm filter. was charged The bottom aqueous layer was separated the organic layer washed with 1N sodium hydroxide (2×567 mL) and water (1×567 mL) The organic solution was concentrated to a minimum after which ethanol (200 proof, 907 mL) was added the solution concentrated to a minimum filtered though a 1-μm filter

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

Conditions: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under an atmosphere of nitrogen, 3-benzyloxypropyl-magnesium chloride is prepared from 1-chloro-3-benzyloxypropane (2.42 g, 13 mmol) in dry ether (13 ml) and magnesium turnings (660 mg, 26 mmol). The Grignard solution is separated from the excess of magnesium, cooled to -40° C., and a 10% solution of difluoroacetonitrile in dry THF (10 ml, 13 mmol) is added dropwise, maintaining the temperature at -40° C. After stirring at this temperature, for 30 minutes, the mixture is poured into a cold (0° C.) solution of sodium cyanide (1.27 g) and ammonium chloride (2.10 g) in water (40 ml). The mixture is stirred vigorously for 1 hour; during that time the reaction is allowed to warm up to room temperature. The organic phase is separated and extracted with 2 N HCl. Basification with concentrated ammonia (pH ~9-10), extraction with ether, drying, and evaporation gives the title compound as an oil (1.5 g). The Grignard solution is separated from the excess of magnesium maintaining the temperature at -40° C The mixture is stirred vigorously for 1 hour to warm up to room temperature The organic phase is separated extracted with 2 N HCl Basification with concentrated ammonia (pH ~9-10), extraction with ether drying evaporation

Conditions: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To magnesium turnings (30.6 g, 1.26 mol), suspended in dry ether (150 ml) is added methyl iodide (≃0.5 ml) and then a solution of 1-chloro-3-benzyloxypropane (116 g, 0.63 mol) in ether (1.1 l) at such a rate that gentle reflux is maintained. (This procedure is performed under nitrogen). After the mixture is heated for 1 more hour under reflux, titration indicates Grignard formation to be complete. The solution is separated from the excess of magnesium (glass wool), transfered to a 6 l flask and, again under nitrogen, cooled to -40° C. Fluoroacetonitrile (33.48 g, 0.57 mol) in ether (300 ml) is added slowly. The mixture is then kept at -40° C. for another 1/2 hour and is poured into a mixture of sodium cyanide (123 g), ammonium chloride (186 g), ice (600 g), and water (650 ml). The mixture is stirred vigorously and allowed to warm up to room temperature during 1 hour. Ether is added, the aqueous phase is saturated with sodium chloride, and the organic layer is separated. The aminonitrile is extracted with 1 N HCl (2×750 ml) and re-extracted with ether (2×750 ml) after basification with concentrated ammonia. Drying (Na2SO4) and evaporation gives the title compound as a brown oil (74.8 g). is maintained After the mixture is heated for 1 more hour under reflux The solution is separated from the excess of magnesium (glass wool) transfered to a 6 l flask and, again under nitrogen to warm up to room temperature during 1 hour the organic layer is separated The aminonitrile is extracted with 1 N HCl (2×750 ml) re-extracted with ether (2×750 ml) after basification with concentrated ammonia Drying (Na2SO4) and evaporation

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

Procedure: In a 2 l flask, a mixture of 3-chloropropanol (56.7 g), benzyl bromide (102.6 g) and dry THF (600 ml) is stirred and cooled with ice/salt mixture. Potassium tert-butoxide (70 g) is added in portions (5-10 g), maintaining the internal temperature at about 0° C. After the mixture is stirred for 3 more hours at room temperature, the solvent is evaporated. Addition of 1 N HCl (1 l), extraction with ether (1 l), and evaporation of solvent gives crude material (113.6 g), which is distilled under vacuum to give the title compound, (108.4 g), bp0.01 60°-80° C. cooled with ice/salt mixture After the mixture is stirred for 3 more hours at room temperature the solvent is evaporated Addition of 1 N HCl (1 l), extraction with ether (1 l), and evaporation of solvent gives crude material (113.6 g), which is distilled under vacuum

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

Procedure: A THF solution (20 ml) of N-(tert-butoxycarbonyl)-L-prolinal (4.50 g) was dropwise added to a THF solution (30 ml) of 3-(phenylmethyloxy)propyl magnesium chloride prepared from 1-chloro- 3-(phenylmethyloxy)propane (5.00 g), at -78° C. After stirring for 15 minutes, saturated ammonium chloride (10 ml) was added, and the reaction mixture was allowed to reach room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with 10% citric acid, saturated sodium hydrogencarbonate and saturated brine in order, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (eluent: n-hexane-ethyl acetate) to give two stereoisomers (1.89 g of low polar isomer and 3.05 g of high polar isomer). to reach room temperature extracted with ethyl acetate The organic layer was washed with 10% citric acid, saturated sodium hydrogencarbonate and saturated brine in order dried over anhydrous magnesium sulfate concentrated to give two stereoisomers (1.89 g of low polar isomer and 3.05 g of high polar isomer)

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

Procedure: Prepared from 2-[2-(piperid-2-yl)-ethyl]-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline and 1-chloro-3-benzyloxy-propane analogously to Example 1.