1-benzyl-4-[(2-fluorophenyl)methyl]piperidin-4-ol

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

Conditions: temp:-4.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-Benzyl-4-piperidone (10 g, 53 mmol) in diethyl ether (80 ml) was added dropwise to a cooled (-4° C.), stirred mixture of 2-fluorobenzyl magnesium bromide (prepared from magnesium and 2-fluorobenzyl bromide (9.56 ml, 80 mmol) in diethyl ether (65 ml)) under an atmosphere of nitrogen. The reaction mixture was stirred whilst warming to room temperature (30 minutes) then at room temperature for 20 minutes. The reaction mixture was quenched with 2M hydrochloric acid (100 ml). The aqueous was separated and washed with diethyl ether (100 ml). The aqueous was basified with 2M sodium hydroxide solution then exhaustively extracted with dichloromethane. The combined organics were dried (sodium sulphate) then evaporated to give crude 1-benzyl-4-(2-fluorobenzyl)-4-hydroxypiperidine as a gum (9.0 g). This crude product in methanol (100 ml) was treated with formic acid (6 ml), ammonium formate (9.5 g, 0.15 mol) and 10% palladium on carbon (900 mg). The mixture was stirred whilst heating at reflux for 4 hours, cooled, filtered then evaporated to afford 4-(2-fluorobenzyl)-4-hydroxypiperidine as a gum (3.4 g); m/z (ES) 210 (M+ +1). This amine (3.35 g, 16 mmol) in dichloromethane (75 ml) was treated with di-t-butyldicarbonate (3.5 g, 16 mmol) and stirred at ambient temperature for 18 hours, washed with aqueous 10% citric acid, dried (potassium carbonate), evaporated to give a gum which was purified by column chromatography on silica using ethyl acetate/n-hexane (1:1) to afford the title compound as a colourless, viscous gum (3.62 g, 73%). δH (360 MHz, CDCl3) 1.46 (9H, s, (CH3)3C), 1.48 (2H, d, J=13 Hz, 2×CH), 1.63 (2H, ddd, J1 =5, J2 =13, J3 =17 Hz, 2×CH), 2.82 (2H, d, J=1 Hz, CH2Ph), 3.11 (2H, ddd, J1 =3, J2 =J3 =13 Hz, 2×CH), 3.84 (2H, d, J=13 Hz, 2×CH), 7.02-7.27 (4H, m, C6H4); m/z (ES) 310 (M+ +1). The reaction mixture was stirred whilst warming to room temperature (30 minutes) The reaction mixture was quenched with 2M hydrochloric acid (100 ml) The aqueous was separated washed with diethyl ether (100 ml) then exhaustively extracted with dichloromethane The combined organics were dried (sodium sulphate) then evaporated

Conditions: temp:-4.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-Benzyl-4-piperidone (10 g, 53 mmol) in diethyl ether (80 ml) was added dropwise to a cooled (-4° C.), stirred mixture of 2-fluorobenzyl magnesium bromide (prepared from magnesium and 2-fluorobenzyl bromide (9.56 ml, 80 mmol) in diethyl ether (65 ml)) under an atmosphere of nitrogen. The reaction mixture was stirred whilst warming to room temperature (30 minutes) then at room temperature for 20 minutes. The reaction mixture was quenched with 2M hydrochloric acid (100 ml). The aqueous was separated and washed with diethyl ether (100 ml). The aqueous was basified with 2M sodium hydroxide solution then exhaustively extracted with dichloromethane. The combined organics were dried (sodium sulphate) then evaporated to give crude 1-benzyl-4-(2-fluorobenzyl)-4-hydroxypiperidine as a gum (9.0 g). This crude product in methanol (100 ml) was treated with formic acid (6 ml), ammonium formate (9.5 g, 0.15 mol) and 10% palladium on carbon (900 mg). The mixture was stirred whilst heating at reflux for 4 hours, cooled, filtered then evaporated to afford 4-(2-fluorobenzyl)-4-hydroxypiperidine as a gum (3.4 g); m/z (ES) 210 (M+ +1). This amine (3.35 g, 16 mmol) in dichloromethane (75 ml) was treated with di-t-butyldicarbonate (3.5 g, 16 mmol) and stirred at ambient temperature for 18 hours, washed with aqueous 10% citric acid, dried (potassium carbonate), evaporated to give a gum which was purified by column chromatography on silica using ethyl acetate/n-hexane (1:1) to afford the title compound as a colourless, viscous gum (3.62 g, 73%). δH (360 MHz, CDCl3) 1.46 (9H, s, (CH3)3C), 1.48 (2H, d, J=13 Hz, 2×CH), 1.63 (2H, ddd, J1 =5, J2 =13, J3 =17 Hz, 2×CH), 2.82 (2H, d, J=1 Hz, CH2Ph), 3.11 (2H, ddd, J1 =3, J2 =J3 =13 Hz, 2×CH), 3.84 (2H, d, J=13 Hz, 2×CH), 7.02-7.27 (4H, m, C6H4); m/z (ES) 310 (M+ +1). The reaction mixture was stirred whilst warming to room temperature (30 minutes) The reaction mixture was quenched with 2M hydrochloric acid (100 ml) The aqueous was separated washed with diethyl ether (100 ml) then exhaustively extracted with dichloromethane The combined organics were dried (sodium sulphate) then evaporated

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

Procedure: A solution of EXAMPLE 1A (39.0 g, 131 mmol) in ethyl acetate (500 mL) was treated with Pd/C (3.90 g), stirred under hydrogen atmosphere (60 psi) until the reaction was complete by TLC analysis, and filtered. The filtrate was concentrated to give a residue that was used without further purification. MS (ESI) m/e 210 (M+H)+. filtered The filtrate was concentrated to give a residue that was used without further purification

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

Procedure: A suspension of Mg (3.50 g, 144 mmol) in diethyl ether (75 mL) was treated with 2-fluorobenzyl chloride (19.0 g, 131 mmol), stirred until all the Mg dissolved, treated with N-benzyl 4-piperidone (27.2 g, 144 mmol) in RATIO THF/diethyl ether (40 mL), and stirred at room temperature until the reaction was complete by TLC analysis. The mixture was partitioned between ethyl acetate and saturated NH4Cl and the aqueous layer was extracted with ethyl acetate twice. The combined organic layers were dried (MgSO4), filtered, and concentrated to give a residue which was used without further purification. MS (ESI) m/e 300 (M+H)+. dissolved The mixture was partitioned between ethyl acetate and saturated NH4Cl the aqueous layer was extracted with ethyl acetate twice The combined organic layers were dried (MgSO4) filtered concentrated to give a residue which was used without further purification

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

Procedure: A suspension of Mg (3.50 g, 144 mmol) in diethyl ether (75 mL) was treated with 2-fluorobenzyl chloride (19.0 g, 131 mmol), stirred until all the Mg dissolved, treated with N-benzyl 4-piperidone (27.2 g, 144 mmol) in RATIO THF/diethyl ether (40 mL), and stirred at room temperature until the reaction was complete by TLC analysis. The mixture was partitioned between ethyl acetate and saturated NH4Cl and the aqueous layer was extracted with ethyl acetate twice. The combined organic layers were dried (MgSO4), filtered, and concentrated to give a residue which was used without further purification. MS (ESI) m/e 300 (M+H)+. dissolved The mixture was partitioned between ethyl acetate and saturated NH4Cl the aqueous layer was extracted with ethyl acetate twice The combined organic layers were dried (MgSO4) filtered concentrated to give a residue which was used without further purification

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

Conditions: temp:-4.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-Benzyl-4-piperidone (10 g, 53 mmol) in diethyl ether (80 ml) was added dropwise to a cooled (-4° C.), stirred mixture of 2-fluorobenzyl magnesium bromide (prepared from magnesium and 2-fluorobenzyl bromide (9.56 ml, 80 mmol) in diethyl ether (65 ml)) under an atmosphere of nitrogen. The reaction mixture was stirred whilst warming to room temperature (30 minutes) then at room temperature for 20 minutes. The reaction mixture was quenched with 2M hydrochloric acid (100 ml). The aqueous was separated and washed with diethyl ether (100 ml). The aqueous was basified with 2M sodium hydroxide solution then exhaustively extracted with dichloromethane. The combined organics were dried (sodium sulphate) then evaporated to give crude 1-benzyl-4-(2-fluorobenzyl)-4-hydroxypiperidine as a gum (9.0 g). This crude product in methanol (100 ml) was treated with formic acid (6 ml), ammonium formate (9.5 g, 0.15 mol) and 10% palladium on carbon (900 mg). The mixture was stirred whilst heating at reflux for 4 hours, cooled, filtered then evaporated to afford 4-(2-fluorobenzyl)-4-hydroxypiperidine as a gum (3.4 g); m/z (ES) 210 (M+ +1). This amine (3.35 g, 16 mmol) in dichloromethane (75 ml) was treated with di-t-butyldicarbonate (3.5 g, 16 mmol) and stirred at ambient temperature for 18 hours, washed with aqueous 10% citric acid, dried (potassium carbonate), evaporated to give a gum which was purified by column chromatography on silica using ethyl acetate/n-hexane (1:1) to afford the title compound as a colourless, viscous gum (3.62 g, 73%). δH (360 MHz, CDCl3) 1.46 (9H, s, (CH3)3C), 1.48 (2H, d, J=13 Hz, 2×CH), 1.63 (2H, ddd, J1 =5, J2 =13, J3 =17 Hz, 2×CH), 2.82 (2H, d, J=1 Hz, CH2Ph), 3.11 (2H, ddd, J1 =3, J2 =J3 =13 Hz, 2×CH), 3.84 (2H, d, J=13 Hz, 2×CH), 7.02-7.27 (4H, m, C6H4); m/z (ES) 310 (M+ +1). The reaction mixture was stirred whilst warming to room temperature (30 minutes) The reaction mixture was quenched with 2M hydrochloric acid (100 ml) The aqueous was separated washed with diethyl ether (100 ml) then exhaustively extracted with dichloromethane The combined organics were dried (sodium sulphate) then evaporated

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

Procedure: A solution of EXAMPLE 1A (39.0 g, 131 mmol) in ethyl acetate (500 mL) was treated with Pd/C (3.90 g), stirred under hydrogen atmosphere (60 psi) until the reaction was complete by TLC analysis, and filtered. The filtrate was concentrated to give a residue that was used without further purification. MS (ESI) m/e 210 (M+H)+. filtered The filtrate was concentrated to give a residue that was used without further purification

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

Procedure: A suspension of Mg (3.50 g, 144 mmol) in diethyl ether (75 mL) was treated with 2-fluorobenzyl chloride (19.0 g, 131 mmol), stirred until all the Mg dissolved, treated with N-benzyl 4-piperidone (27.2 g, 144 mmol) in RATIO THF/diethyl ether (40 mL), and stirred at room temperature until the reaction was complete by TLC analysis. The mixture was partitioned between ethyl acetate and saturated NH4Cl and the aqueous layer was extracted with ethyl acetate twice. The combined organic layers were dried (MgSO4), filtered, and concentrated to give a residue which was used without further purification. MS (ESI) m/e 300 (M+H)+. dissolved The mixture was partitioned between ethyl acetate and saturated NH4Cl the aqueous layer was extracted with ethyl acetate twice The combined organic layers were dried (MgSO4) filtered concentrated to give a residue which was used without further purification