(3S,4R)-(-)-4-(4'-FLUOROPHENYL)3-HYDROXYMETHYL)-PIPERIDINE

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

Procedure: A 200-ml four-necked glass flask equipped with a thermometer and a reflux condenser was charged with 63 ml of toluene and 10.54 g (50.37 mmol) of (−)-(3S,4R)-4-(4-fluorophenyl)-3-hydroxymethylpiperidine, and the mixture was warmed and dissolved. 1.13 g (62.71 mmol) Of water was added to the above mixture at 50° C. to allow to crystallize. Thereafter, the mixture was kept for one hour at a temperature of from 20° to 30° C., and then the crystals were collected by filtration. The obtained crystals were thoroughly washed with 20 ml of toluene, to give white crystals of (−)-(3S,4R)-4-(4-fluorophenyl)-3-hydroxymethylpiperidine monohydrate. Thereafter, the crystals were dried under a reduced pressure at a temperature of 30° C. or lower, and weighed 10.24 g. The yield was 89.45% based on (−)-(3S,4R)-4-(4-fluorophenyl)-3-hydroxymethylpiperidine. A 200-ml four-necked glass flask equipped with a thermometer and a reflux condenser the mixture was warmed dissolved to crystallize the crystals were collected by filtration The obtained crystals were thoroughly washed with 20 ml of toluene

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

Procedure: A 200-ml four-necked glass flask equipped with a thermometer and a reflux condenser was charged with 63 ml of toluene and 10.54 g (50.37 mmol) of (−)-(3S,4R)-4-(4-fluorophenyl)-3-hydroxymethylpiperidine, and the mixture was warmed and dissolved. 1.13 g (62.71 mmol) of water was added to the above mixture at 50° C. to allow to crystallize. Thereafter, the mixture was kept for one hour at a temperature of from 20° to 30° C., and then the crystals were collected by filtration. The obtained crystals were thoroughly washed with 20 ml of toluene, to give white crystals of (−)-(3S,4R)-4-(4-fluorophenyl)-3-hydroxymethylpiperidine monohydrate. Thereafter, the crystals were dried under a reduced pressure at a temperature of 30° C. or lower, and weighed 10.24 g. The yield was 89.45% based on (−)-(3S,4R)-4-(4-fluorophenyl)-3-hydroxymethylpiperidine. A 200-ml four-necked glass flask equipped with a thermometer and a reflux condenser the mixture was warmed dissolved to crystallize the crystals were collected by filtration The obtained crystals were thoroughly washed with 20 ml of toluene

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

Procedure: A 200-ml four-necked glass flask equipped with a thermometer and a reflux condenser was charged with 63 ml of toluene and 10.54 g (50.37 mmol) of (−)-(3S,4R)-4-(4-fluorophenyl)-3-hydroxymethylpiperidine, and the mixture was warmed and dissolved. 1.13 g (62.71 mmol) of water was added to the above mixture at 50° C. to allow to crystallize. Thereafter, the mixture was kept for one hour at a temperature of from 20° to 30° C., and then the crystals were collected by filtration. The obtained crystals were thoroughly washed with 20 ml of toluene, to give white crystals of (−)-(3S,4R)-4-(4-fluorophenyl)-3-hydroxymethylpiperidine monohydrate. Thereafter, the crystals were dried under a reduced pressure at a temperature of 30° C. or lower, and weighed 10.24 g. The yield was 89.45% based on (−)-(3S,4R)-4-(4-fluorophenyl)-3-hydroxymethylpiperidine. A 200-ml four-necked glass flask equipped with a thermometer and a reflux condenser the mixture was warmed dissolved to crystallize the crystals were collected by filtration The obtained crystals were thoroughly washed with 20 ml of toluene

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

Procedure: A 200-ml four-necked glass flask equipped with a thermometer and a reflux condenser was charged with 63 ml of toluene and 10.54 g (50.37 mmol) of (-)-(3S,4R)-4-(4-fluorophenyl)-3-hydroxymethylpiperidine, and the mixture was warmed and dissolved. 1.13 g (62.71 mmol) of water was added to the above mixture at 50° C. to allow to crystallize. Thereafter, the mixture was kept for one hour at a temperature of from 20° to 30° C., and then the crystals were collected by filtration. The obtained crystals were thoroughly washed with 20 ml of toluene, to give white crystals of (-)-(3S,4R)-4-(4-fluorophenyl)-3-hydroxymethylpiperidine monohydrate. Thereafter, the crystals were dried under a reduced pressure at a temperature of 30° C. or lower, and weighed 10.24 g. The yield was 89.45% based on (-)-(3S,4R)-4-(4-fluorophenyl)-3-hydroxymethylpiperidine. A 200-ml four-necked glass flask equipped with a thermometer and a reflux condenser the mixture was warmed dissolved to crystallize the crystals were collected by filtration The obtained crystals were thoroughly washed with 20 ml of toluene

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

Procedure: Subsequently, 10.00 g (44.0 mmol) of the trans-(−)-4-(4-fluorophenyl)-3-hydroxymethylpiperidine monohydrate, 6.60 g (44.0 mmol) of L-tartaric acid, and 50 ml of methanol were mixed together, and 50 ml of isopropanol was added to the resulting mixture under ice-cooling. The mixture was allowed to stand to precipitate crystals, and the resulting crystals were filtered. The crystals were washed with a 10 ml mixed solvent of 5 ml of methanol and 5 ml of isopropanol and dried, to give 5.60 g (15.6 mmol) of L-tartrate of trans-(−)-4-(4-fluorophenyl)-3-hydroxymethylpiperidine (yield: 35.5%). cooling to precipitate crystals the resulting crystals were filtered The crystals were washed with a 10 ml mixed solvent of 5 ml of methanol and 5 ml of isopropanol dried

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

Procedure: A 200-ml four-necked glass flask equipped with a thermometer and a reflux condenser was charged with 63 ml of toluene and 10.54 g (50.37 mmol) of (−)-(3S,4R)-4-(4-fluorophenyl)-3-hydroxymethylpiperidine, and the mixture was warmed and dissolved. 1.13 g (62.71 mmol) Of water was added to the above mixture at 50° C. to allow to crystallize. Thereafter, the mixture was kept for one hour at a temperature of from 20° to 30° C., and then the crystals were collected by filtration. The obtained crystals were thoroughly washed with 20 ml of toluene, to give white crystals of (−)-(3S,4R)-4-(4-fluorophenyl)-3-hydroxymethylpiperidine monohydrate. Thereafter, the crystals were dried under a reduced pressure at a temperature of 30° C. or lower, and weighed 10.24 g. The yield was 89.45% based on (−)-(3S,4R)-4-(4-fluorophenyl)-3-hydroxymethylpiperidine. A 200-ml four-necked glass flask equipped with a thermometer and a reflux condenser the mixture was warmed dissolved to crystallize the crystals were collected by filtration The obtained crystals were thoroughly washed with 20 ml of toluene

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

Procedure: A 200-ml four-necked glass flask equipped with a thermometer and a reflux condenser was charged with 63 ml of toluene and 10.54 g (50.37 mmol) of (−)-(3S,4R)-4-(4-fluorophenyl)-3-hydroxymethylpiperidine, and the mixture was warmed and dissolved. 1.13 g (62.71 mmol) Of water was added to the above mixture at 50° C. to allow to crystallize. Thereafter, the mixture was kept for one hour at a temperature of from 20° to 30° C., and then the crystals were collected by filtration. The obtained crystals were thoroughly washed with 20 ml of toluene, to give white crystals of (−)-(3S,4R)-4-(4-fluorophenyl)-3-hydroxymethylpiperidine monohydrate. Thereafter, the crystals were dried under a reduced pressure at a temperature of 30° C. or lower, and weighed 10.24 g. The yield was 89.45% based on (−)-(3S,4R)-4-(4-fluorophenyl)-3-hydroxymethylpiperidine. A 200-ml four-necked glass flask equipped with a thermometer and a reflux condenser the mixture was warmed dissolved to crystallize the crystals were collected by filtration The obtained crystals were thoroughly washed with 20 ml of toluene

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

Procedure: To a mixture of [(3S,4R)-4-(4-fluorophenyl)piperidine-3-yl]methanol (3.0 g, 14 mmol), sodium carbonate (6.1 g, 57 mmol), dichloromethane (40 mL) and water (40 mL) was added di-tert-butyl Bicarbonate (3.8 g, 17 mmol) under ice cooling, followed by stirring at the same temperature for 30 minutes. The reaction mixture was added to a mixed solution of dichloromethane and water, and the organic layer was separated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:1) to give the title compound (4.0 g, 90% yield). the organic layer was separated The organic layer was washed with brine dried over anhydrous magnesium sulfate the solvent was distilled away under reduced pressure The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:1)

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

Procedure: Compound E1 (±)-trans-3-ethoxycarbonyl-4(4'-fluorophenyl)piperidin-2,6-dione (2.0 g) was reduced with lithium aluminium hydride (0.58 g) in refluxing tetrahydrofuran (50 ml) for 4 hours. Work up as described in Example 5 gave the title compound as a solid (0.28 g, 22%).

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

Procedure: A 200-ml four-necked glass flask equipped with a thermometer and a reflux condenser was charged with 63 ml of toluene and 10.54 g (50.37 mmol) of (−)-(3S,4R)-4-(4-fluorophenyl)-3-hydroxymethylpiperidine, and the mixture was warmed and dissolved. 1.13 g (62.71 mmol) of water was added to the above mixture at 50° C. to allow to crystallize. Thereafter, the mixture was kept for one hour at a temperature of from 20° to 30° C., and then the crystals were collected by filtration. The obtained crystals were thoroughly washed with 20 ml of toluene, to give white crystals of (−)-(3S,4R)-4-(4-fluorophenyl)-3-hydroxymethylpiperidine monohydrate. Thereafter, the crystals were dried under a reduced pressure at a temperature of 30° C. or lower, and weighed 10.24 g. The yield was 89.45% based on (−)-(3S,4R)-4-(4-fluorophenyl)-3-hydroxymethylpiperidine. A 200-ml four-necked glass flask equipped with a thermometer and a reflux condenser the mixture was warmed dissolved to crystallize the crystals were collected by filtration The obtained crystals were thoroughly washed with 20 ml of toluene

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

Procedure: A 200-ml four-necked glass flask equipped with a thermometer and a reflux condenser was charged with 63 ml of toluene and 10.54 g (50.37 mmol) of (-)-(3S,4R)-4-(4-fluorophenyl)-3-hydroxymethylpiperidine, and the mixture was warmed and dissolved. 1.13 g (62.71 mmol) of water was added to the above mixture at 50° C. to allow to crystallize. Thereafter, the mixture was kept for one hour at a temperature of from 20° to 30° C., and then the crystals were collected by filtration. The obtained crystals were thoroughly washed with 20 ml of toluene, to give white crystals of (-)-(3S,4R)-4-(4-fluorophenyl)-3-hydroxymethylpiperidine monohydrate. Thereafter, the crystals were dried under a reduced pressure at a temperature of 30° C. or lower, and weighed 10.24 g. The yield was 89.45% based on (-)-(3S,4R)-4-(4-fluorophenyl)-3-hydroxymethylpiperidine. A 200-ml four-necked glass flask equipped with a thermometer and a reflux condenser the mixture was warmed dissolved to crystallize the crystals were collected by filtration The obtained crystals were thoroughly washed with 20 ml of toluene

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

Procedure: Subsequently, 10.00 g (44.0 mmol) of the trans-(−)-4-(4-fluorophenyl)-3-hydroxymethylpiperidine monohydrate, 6.60 g (44.0 mmol) of L-tartaric acid, and 50 ml of methanol were mixed together, and 50 ml of isopropanol was added to the resulting mixture under ice-cooling. The mixture was allowed to stand to precipitate crystals, and the resulting crystals were filtered. The crystals were washed with a 10 ml mixed solvent of 5 ml of methanol and 5 ml of isopropanol and dried, to give 5.60 g (15.6 mmol) of L-tartrate of trans-(−)-4-(4-fluorophenyl)-3-hydroxymethylpiperidine (yield: 35.5%). cooling to precipitate crystals the resulting crystals were filtered The crystals were washed with a 10 ml mixed solvent of 5 ml of methanol and 5 ml of isopropanol dried