[(3S,4R)-1-benzyl-4-(4-fluorophenyl)piperidin-3-yl]methanol

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

Procedure: A solution of trans (4R)-1-benzyl-3-carboxymethyl-4-(4′-fluorophenyl)-piperidine-2-one (1.97 g) in tetrahydrofuran (20 ml) was treated with borane-tetrahydrofuran complex (19.6 ml, 1 molar) and heated at reflux for 6 hours. After cooling, the reaction was quenched with 1 molar hydrochloric acid, then stirred and heated at reflux for a further 1 hour. The mixture was cooled to ambient temperature, the pH adjusted to 9 with 1 molar sodium hydroxide, and extracted with ethyl acetate (3×20 ml). The combined organic extracts were washed with saturated sodium chloride and evaporated to give trans-(4R)-1-benzyl-4-(4′-fluorophenyl)-3-hydroxymethylpiperidine (1.59 g, 92%). heated at reflux for 6 hours After cooling the reaction was quenched with 1 molar hydrochloric acid heated at reflux for a further 1 hour extracted with ethyl acetate (3×20 ml) The combined organic extracts were washed with saturated sodium chloride evaporated

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

Procedure: A solution of trans (4R)-1-benzyl-3-carboxymethyl-4-(4′-fluorophenyl)-piperidine-2-one (1.97 g) in tetrahydrofuran (20 ml) was treated with borane-tetrahydrofuran complex (19.6 ml, 1 molar) and heated at reflux for 6 hours. After cooling, the reaction was quenched with 1 molar hydrochloric acid, then stirred and heated at reflux for a further 1 hour. The mixture was cooled to ambient temperature, the pH adjusted to 9 with 1 molar sodium hydroxide, and extracted with ethyl acetate (3×20 ml). The combined organic extracts were washed with saturated sodium chloride and evaporated to give trans-(4R)-1-benzyl-4-(4′-fluorophenyl)-3-hydroxymethylpiperidine (1.59 g, 92%). heated at reflux for 6 hours After cooling the reaction was quenched with 1 molar hydrochloric acid heated at reflux for a further 1 hour extracted with ethyl acetate (3×20 ml) The combined organic extracts were washed with saturated sodium chloride evaporated

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Lithium aluminium hydride in THF (7.24 ml of a 1M solution) was carefully added to substantially anhydrous magnesium chloride (0.698 g), in THF (32 ml) with stirring under nitrogen keeping the temperature below 20° C. The mixture was stirred and heated to 50° C. and then a solution of (+)-1-benzyl-3-hydroxymethyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine (2.15 g, preparable as described in WO96/36636) in THF (3.92 ml) and toluene (2.32 ml) was added dropwise over approximately 30 minutes. The reaction mixture was stirred and boiled under reflux for 4.0 hours. The mixture was cooled to 0-5° C. in an ice/water bath whilst sodium hydroxide solution (2.48 g, 5%w/w) was added. The suspension was filtered. The residue was washed with THF (8 ml) and the combined filtrate and washings were evaporated under reduced pressure to give a yellow oil. This oil was analysed by GLC, Chiral HPLC and 1H nmr. The title compound contained 0.24% of the desfluoro compound. The mixture was stirred The reaction mixture was stirred under reflux for 4.0 hours was added The suspension was filtered The residue was washed with THF (8 ml) the combined filtrate and washings were evaporated under reduced pressure to give a yellow oil

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium aluminium hydride in THF (2.0 ml of a 1M solution) was carefully added to substantially anhydrous magnesium chloride (0.19 g, 1.5% H2O) under nitrogen. The mixture was stirred and heated to 50° C. and then a solution of (+)-1-benzyl-3-hydroxymethyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine (0.60 g) in THF (1.7 ml) was added dropwise over approximately 2 minutes. The reaction mixture was stirred and boiled under reflux for 4 hours. The mixture was cooled to ambient temperature and then stirred in an ice/water bath whilst water (0.1 ml) then 5M sodium hydroxide solution (0.1 ml) and water (0.1 ml) were added. The suspension was diluted with THF (5 ml) and the mixture filtered. The residue was washed with THF (3×5 ml) and the combined filtrate and washings were evaporated under reduced pressure to give a yellow oil (0.49 g). This oil was analysed by GLC, Chiral HPLC and 1H nmr using the conditions described above. Starting material 13.2% was still present in the product as analysed by GLC. The amount of desfluoro compound as determined by HPLC was less than 0.1%. The reaction mixture was stirred under reflux for 4 hours The mixture was cooled to ambient temperature the mixture filtered The residue was washed with THF (3×5 ml) the combined filtrate and washings were evaporated under reduced pressure

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Lithium aluminium hydride in THF (2.0 ml of a 1M solution) was carefully added to substantially anhydrous magnesium chloride (0.19 g, 1.5% H2O) under nitrogen. The mixture was stirred and heated to 50° C. and then a solution of (+)-1-benzyl-3-hydroxymethyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine (0.60 g, preparation given in WO96136636) in THF (1.7 ml) was added dropwise over approximately 2 minutes. The reaction mixture was stirred and boiled under reflux for 4.2 hours. The mixture was cooled to ambient temperature and then stirred in an ice/water bath whilst water (0.1 ml) then 5M sodium hydroxide solution (0.1 ml) and water (0.1 ml) were added. The suspension was diluted with THF (5 ml) and the mixture filtered. The residue was washed with THF (3×5 ml) and the combined filtrate and washings were evaporated under reduced pressure to give a yellow oil (0.49 g). This oil was analysed by GLC, Chiral HPLC and 1H nmr. The reaction mixture was stirred under reflux for 4.2 hours The mixture was cooled to ambient temperature the mixture filtered The residue was washed with THF (3×5 ml) the combined filtrate and washings were evaporated under reduced pressure

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Lithium aluminium hydride in THF (2.0 ml of a 1M solution) was carefully added to substantially anhydrous magnesium chloride (0.19 g, 1.5% H2O) under nitrogen. The mixture was stirred and heated to 50° C. and then a solution of (+)-1-benzyl-3-hydroxymethyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine (0.60 g, preparation given in WO96136636) in THF (1.7 ml) was added dropwise over approximately 2 minutes. The reaction mixture was stirred and boiled under reflux for 4.2 hours. The mixture was cooled to ambient temperature and then stirred in an ice/water bath whilst water (0.1 ml) then 5M sodium hydroxide solution (0.1 ml) and water (0.1 ml) were added. The suspension was diluted with THF (5 ml) and the mixture filtered. The residue was washed with THF (3×5 ml) and the combined filtrate and washings were evaporated under reduced pressure to give a yellow oil (0.49 g). This oil was analysed by GLC, Chiral HPLC and 1H nmr. The reaction mixture was stirred under reflux for 4.2 hours The mixture was cooled to ambient temperature the mixture filtered The residue was washed with THF (3×5 ml) the combined filtrate and washings were evaporated under reduced pressure

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

Procedure: A solution of trans (4R)-1-benzyl-3-carboxymethyl-4-(4′-fluorophenyl)-piperidine-2-one (1.97 g) in tetrahydrofuran (20 ml) was treated with borane-tetrahydrofuran complex (19.6 ml, 1 molar) and heated at reflux for 6 hours. After cooling, the reaction was quenched with 1 molar hydrochloric acid, then stirred and heated at reflux for a further 1 hour. The mixture was cooled to ambient temperature, the pH adjusted to 9 with 1 molar sodium hydroxide, and extracted with ethyl acetate (3×20 ml). The combined organic extracts were washed with saturated sodium chloride and evaporated to give trans-(4R)-1-benzyl-4-(4′-fluorophenyl)-3-hydroxymethylpiperidine (1.59 g, 92%). heated at reflux for 6 hours After cooling the reaction was quenched with 1 molar hydrochloric acid heated at reflux for a further 1 hour extracted with ethyl acetate (3×20 ml) The combined organic extracts were washed with saturated sodium chloride evaporated