4-[(4-chlorophenyl)methyl]piperidine

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A suspension of NaHCO3 (4 g) and 4-[(4-chlorophenyl)methyl]piperidine (18 mmol) in dimethylformamide (DMF) (25 mL) is stirred under a N2 atm at 0° C., and treated dropwise with 3-butynyltosylate (20 mmol) as a solution in DMF (50 mL). The reaction mixture is heated at 80° C. and stirred an additional 18 hours. After cooling the reaction mixture is stirred vigorously with the addition of water (200 mL), and then extracted with ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and evaporated. The residue is purified by silica gel column chromatography (100:1 CH2Cl2 :MeOH) to give 1-(3-butynyl)-4-(4-chlorophenyl)piperidine. The reaction mixture is heated at 80° C. stirred an additional 18 hours After cooling the reaction mixture extracted with ethyl acetate The organic layer is dried over magnesium sulfate filtered evaporated The residue is purified by silica gel column chromatography (100:1 CH2Cl2 :MeOH)

反応条件: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2[1-(4-(4-chlorobenzyl)piperidin)]ethyl methyl ketone. To a solution of 4-(4-chlorobenzyl)piperidine (1.0 g, 4.78 mmol) in methyl vinyl ketone (1.0 ml) was added H2O (1 drop) and the resulting solution stirred at 110° C. for 2 h. The crude mixture was purified by filtration on silica gel using CH2Cl2/MeOH as eluant to afford the title compound (1.20 g, 90%) as a pale yellow oil: 1H NMR (CDCl3) 1.35-1.55 (m, 5H), 1.63 (d, J=12.3, 2H), 2.055 (t, J=9.6, 2H), 2.154: (s, 2H), 2.40 (d, J=6.3, 2H), 2.748 (s, 2H), 2.972 (d, J=11.4, 2H), 7.034 (d, J=8.1, 2H), 7.218 (d, J=8.1, 2H). The crude mixture was purified by filtration on silica gel

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 2 g of 4-(4-chloro-benzyl)-piperidine-1-carboxylic acid tert-butyl ester, dioxane (1.5 mL), and 3N hydrochloric acid (1.0 mL, 4equiv.) was heated at reflux for 3.5 hours. The cooled mixture was made basic with saturated sodium carbonate solution and extracted with chloroform (3×10 mL). The combined extracts were dried over magnesium sulfate and concentrated under reduced pressure. The crude product (1.2 g) was an oil. was heated at reflux for 3.5 hours extracted with chloroform (3×10 mL) The combined extracts were dried over magnesium sulfate concentrated under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 2 g of 4-(4-chloro-benzyl)-piperidine-1-carboxylic acid tert-butyl ester, dioxane (1.5 mL), and 3N hydrochloric acid (1.0 mL, 4equiv.) was heated at reflux for 3.5 hours. The cooled mixture was made basic with saturated sodium carbonate solution and extracted with chloroform (3×10 mL). The combined extracts were dried over magnesium sulfate and concentrated under reduced pressure. The crude product (1.2 g) was an oil. was heated at reflux for 3.5 hours extracted with chloroform (3×10 mL) The combined extracts were dried over magnesium sulfate concentrated under reduced pressure

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A suspension of NaHCO3 (4 g) and 4-[(4-chlorophenyl)methyl]piperidine (18 mmol) in dimethylformamide (DMF) (25 mL) is stirred under a N2 atm at 0° C., and treated dropwise with 3-butynyltosylate (20 mmol) as a solution in DMF (50 mL). The reaction mixture is heated at 80° C. and stirred an additional 18 hours. After cooling the reaction mixture is stirred vigorously with the addition of water (200 mL), and then extracted with ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and evaporated. The residue is purified by silica gel column chromatography (100:1 CH2Cl2 :MeOH) to give 1-(3-butynyl)-4-(4-chlorophenyl)piperidine. The reaction mixture is heated at 80° C. stirred an additional 18 hours After cooling the reaction mixture extracted with ethyl acetate The organic layer is dried over magnesium sulfate filtered evaporated The residue is purified by silica gel column chromatography (100:1 CH2Cl2 :MeOH)

反応条件: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2[1-(4-(4-chlorobenzyl)piperidin)]ethyl methyl ketone. To a solution of 4-(4-chlorobenzyl)piperidine (1.0 g, 4.78 mmol) in methyl vinyl ketone (1.0 ml) was added H2O (1 drop) and the resulting solution stirred at 110° C. for 2 h. The crude mixture was purified by filtration on silica gel using CH2Cl2/MeOH as eluant to afford the title compound (1.20 g, 90%) as a pale yellow oil: 1H NMR (CDCl3) 1.35-1.55 (m, 5H), 1.63 (d, J=12.3, 2H), 2.055 (t, J=9.6, 2H), 2.154: (s, 2H), 2.40 (d, J=6.3, 2H), 2.748 (s, 2H), 2.972 (d, J=11.4, 2H), 7.034 (d, J=8.1, 2H), 7.218 (d, J=8.1, 2H). The crude mixture was purified by filtration on silica gel

反応条件: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2[1-(4-(4-chlorobenzyl)piperidin)]ethyl methyl ketone. To a solution of 4-(4-chlorobenzyl)piperidine (1.0 g, 4.78 mmol) in methyl vinyl ketone (1.0 ml) was added H2O (1 drop) and the resulting solution stirred at 110° C. for 2 h. The crude mixture was purified by filtration on silica gel using CH2Cl2/MeOH as eluant to afford the title compound (1.20 g, 90%) as a pale yellow oil: 1H NMR (CDCl3) 1.35-1.55 (m, 5H), 1.63 (d, J=12.3, 2H), 2.055 (t, J=9.6, 2H), 2.154: (s, 2H), 2.40 (d, J=6.3, 2H), 2.748 (s, 2H), 2.972 (d, J=11.4, 2H), 7.034 (d, J=8.1, 2H), 7.218 (d, J=8.1, 2H). The crude mixture was purified by filtration on silica gel

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The title compound is prepared from N-(2-oxo-2,3-dihydro-benzothiazol-6-yl)-oxalamic acid (Example 61b) and 4-(4-chloro-benzyl)-piperidine according to the method described in Example 1c. Melting Point: 245-247° C. (diethylether)

反応条件: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 4-(4-chlorobenzyl)piperidine (1.0 g, 4.78 mmol) in methyl vinyl ketone (1.0 ml) was added H2O (1 drop) and the resulting solution stirred at 110° C. for 2 h. The crude mixture was purified by filtration on silica gel using CH2Cl2/MeOH as eluant to afford the title compound (1.20 g, 90%) as a pale yellow oil: 1H NMR (CDCl3) 1.35-1.55 (m, 5H), 1.63 (d, J =12.3, 2H), 2.055 (t, J=9.6, 2H), 2.154 (s, 2H), 2.40 (d, J=6.3, 2H), 2.748 (s, 2H), 2.972 (d, J=11.4, 2H), 7.034 (d, J=8.1, 2H), 7.218 (d, J=8.1, 2H). The crude mixture was purified by filtration on silica gel

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A murky solution of (±)-trans-4-nitro-benzenesulfonic acid 2-azido-cyclohexyl ester (1.77 g, 5.41 mmol), 4-(4-chlorobenzyl)-piperidine (1.14 g, 5.43 mmol), and Et3N (0.75 mL, 5.4 mmol) in CH3CN (11.2 mL) was stirred at room temperature for 17 hours, 65° C. for 31 hours, and 80° C. for 5 d, allowed to cool to room temperature, and concentrated. The residue was partitioned between CH2Cl2 and 1 N NaOH, the aqueous phase was extracted with CH2Cl2 and the extracts were dried and concentrated. Chromatography of the residue with 98:1.9:0.1–95:4.75:0.25 CH2Cl2:MeOH:NH4OH to 100% MeOH and subsequent chromatography with 10:1 hexanes:EtOAc to 100% EtOAc followed by 95:5 EtOAc:MeOH gave, in order of elution, starting (±)-trans-4-nitro-benzenesulfonic acid 2-azidocyclohexyl ester (1.2 g, 68%), desired product (155 mg, 9%), and starting 4-(4-chlorobenzyl)-piperidine (810 mg, 71%). Product: 1H NMR δ 1.19–1.81 (m, 12H), 1.92–2.08 (m, 3H), 2.22 (m, 1H), 2.48 (d, J=7.0 Hz, 2H), 3.02 (m, 2H), 4.05 (m, 1H), 7.06 (m, 2H), 7.23 (m, 2H); MS m/z 333.2 (M+H)+. concentrated The residue was partitioned between CH2Cl2 and 1 N NaOH the aqueous phase was extracted with CH2Cl2 the extracts were dried concentrated MeOH gave, in order of elution