(1-benzylpiperidin-2-yl)methanol

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

Procedure: The product from Step 2 (600 mg) was coupled with (1-benzyl-piperidin-2-yl)-methanol (379 mg) as is Example 10, Step 3 to yield the title compound (320 mg) after silica gel chromatography with 10% ethyl acetate/hexanes to 20% ethyl acetate/hexanes as the gradient eluant.

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

Procedure: To an ice-cooled THF solution of tetrabutylammonium fluoride (1M, 3.2 ml) was dropwise added a THF (2 ml) solution of 1-benzyl-2-(tert-butyldimethylsilyloxymethyl)-piperidine (1.00 g, 3.2 mmol). After stirring at room temperature for 2 hours, a reaction solution was poured onto water followed by extraction with ethyl acetate (30 ml). The extract was washed successively with water and saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The crude product thus obtained was purified by a column chromatography on silica gel (SiO2 : 20 g, CHCl3) to afford 0.41 g of the title compound. a reaction solution was poured onto water followed by extraction with ethyl acetate (30 ml) The extract was washed successively with water and saturated aqueous sodium chloride dried over anhydrous magnesium sulfate The solvent was removed under reduced pressure The crude product thus obtained was purified by a column chromatography on silica gel (SiO2 : 20 g, CHCl3)

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

Procedure: To an ice-cooled THF solution of tetrabutylammonium fluoride (1M, 3.2 ml) was dropwise added a THF (2 ml) solution of 1-benzyl-2-(tert-butyldimethylsilyloxymethyl)-piperidine (1.00 g, 3.2 mmol). After stirring at room temperature for 2 hours, a reaction solution was poured onto water followed by extraction with ethyl acetate (30 ml). The extract was washed successively with water and saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The crude product thus obtained was purified by a column chromatography on silica gel (SiO2 : 20 g, CHCl3) to afford 0.41 g of the title compound. a reaction solution was poured onto water followed by extraction with ethyl acetate (30 ml) The extract was washed successively with water and saturated aqueous sodium chloride dried over anhydrous magnesium sulfate The solvent was removed under reduced pressure The crude product thus obtained was purified by a column chromatography on silica gel (SiO2 : 20 g, CHCl3)

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

Procedure: (RS)-(1-Benzyl-piperidin-2-yl)-methanol (R. Sreekumar et al, Tetrahedron Lett., 1998, 39 5151) (10.0 g) was converted to the title compound (5.2 g) by treatment with triphenylphosphine (13.0 g) and N-bromosuccinimide (9.4 g) in dichloromethane using literature procedures, (Tetrahedron Lett, 1999, 40, 7477-8).

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

Procedure: Then, 10.0 g of the 1-benzyl-2-piperidine methanol and 4.30 g of diketene were reacted similarly as in Reference Example 1, and the reaction product was purified by silica gel column chromatography (eluent:chloroform:methanol=9:1 v/v), to obtain 9.86 g of acetoacetic acid-N-benzyl-2-piperidinylmethyl ester (yield: 69.9%). This was used in the reaction of Example 5 without distillation. the reaction product was purified by silica gel column chromatography (eluent:chloroform:methanol=9:1 v/v)

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

Procedure: A mixture of 12.9 g of 2-piperidine methanol, 13.2 g of benzyl chloride, 10.5 g of triethylamine and 50 ml of toluene was stirred at reflux for 4 hours. The reaction mixture was filtered, the filtrate was concentrated, and the concentrate was distilled under reduced pressure to obtain 11.3 g of 1-benzyl-2-piperidine methanol (yield: 52.9%). b.p.: 107° C./2 mmHg at reflux for 4 hours The reaction mixture was filtered the filtrate was concentrated the concentrate was distilled under reduced pressure

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

Procedure: A mixture of 12.9 g of 2-piperidine methanol, 13.2 g of benzyl chloride, 10.5 g of triethylamine and 50 ml of toluene was stirred at reflux for 4 hours. The reaction mixture was filtered, the filtrate was concentrated, and the concentrate was distilled under reduced pressure to obtain 11.3 g of 1-benzyl-2-piperidine methanol (yield: 52.9%). b.p.: 107° C./2 mmHg at reflux for 4 hours The reaction mixture was filtered the filtrate was concentrated the concentrate was distilled under reduced pressure

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

Procedure: To a stirred solution of compound 13 (3.6 g, 15.00 mmol) in chloroform (50 mL) was added thionyl chloride (1.34 mL) at 0° C. The reaction mixture was heated at reflux for 2 hours and then concentrated. The residue was dissolved in EtOAc and washed with saturated sodium bicarbonate solution, water and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by chromatography on 230-400 mesh silica gel eluting with 10% EtOAc-hexane to provide compound 14 as an oil. The reaction mixture was heated at reflux for 2 hours concentrated The residue was dissolved in EtOAc washed with saturated sodium bicarbonate solution, water and brine The organic layer was dried over Na2SO4 filtered concentrated The crude material was purified by chromatography on 230-400 mesh silica gel eluting with 10% EtOAc-hexane

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

Procedure: To a stirred solution of piperidine-2-methanol (12; 6 g, 52.09 mmol) in dimethylformamide (DMF, 50 mL) were added successively K2CO3 (10.78 g, 78.14 mmol) and benzyl bromide (6.85 mL, 57.30 mmol) at 0° C. and the mixture stirred at rt for 16 hours. The reaction mixture was then filtered and the filtrate was concentrated. The residue was dissolved in EtOAc and the organic layer was washed with water and brine solution. The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by chromatography on 230-400 mesh silica gel eluting with 30% EtOAc-hexane to provide compound 13. The reaction mixture was then filtered the filtrate was concentrated The residue was dissolved in EtOAc the organic layer was washed with water and brine solution The organic layer was dried over Na2SO4 filtered concentrated The crude material was purified by chromatography on 230-400 mesh silica gel eluting with 30% EtOAc-hexane

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

Procedure: To a stirred solution of piperidine-2-methanol (12; 6 g, 52.09 mmol) in dimethylformamide (DMF, 50 mL) were added successively K2CO3 (10.78 g, 78.14 mmol) and benzyl bromide (6.85 mL, 57.30 mmol) at 0° C. and the mixture stirred at rt for 16 hours. The reaction mixture was then filtered and the filtrate was concentrated. The residue was dissolved in EtOAc and the organic layer was washed with water and brine solution. The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by chromatography on 230-400 mesh silica gel eluting with 30% EtOAc-hexane to provide compound 13. The reaction mixture was then filtered the filtrate was concentrated The residue was dissolved in EtOAc the organic layer was washed with water and brine solution The organic layer was dried over Na2SO4 filtered concentrated The crude material was purified by chromatography on 230-400 mesh silica gel eluting with 30% EtOAc-hexane

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

Procedure: The product from Step 2 (600 mg) was coupled with (1-benzyl-piperidin-2-yl)-methanol (379 mg) as is Example 10, Step 3 to yield the title compound (320 mg) after silica gel chromatography with 10% ethyl acetate/hexanes to 20% ethyl acetate/hexanes as the gradient eluant.

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

Procedure: To a stirred solution of compound 13 (3.6 g, 15.00 mmol) in chloroform (50 mL) was added thionyl chloride (1.34 mL) at 0° C. The reaction mixture was heated at reflux for 2 hours and then concentrated. The residue was dissolved in EtOAc and washed with saturated sodium bicarbonate solution, water and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by chromatography on 230-400 mesh silica gel eluting with 10% EtOAc-hexane to provide compound 14 as an oil. The reaction mixture was heated at reflux for 2 hours concentrated The residue was dissolved in EtOAc washed with saturated sodium bicarbonate solution, water and brine The organic layer was dried over Na2SO4 filtered concentrated The crude material was purified by chromatography on 230-400 mesh silica gel eluting with 10% EtOAc-hexane