tert-butyl 2-benzyl-4-oxopiperidine-1-carboxylate

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 (±)-1,1-dimethylethyl 4-oxo-2-(phenylmethyl)-1-piperidine carboxylate (0.1 mol) and N-(4-phenyl-4-piperidinyl)acetamide (0.1 mol) in 2-propanol (500 ml) was hydrogenated at 50° C. with platinum (4 g) as a catalyst in the presence of titanium (IV)isopropoxide (28.5 g) and thiophene (4%; 1 ml). After uptake of hydrogen the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 97/3). The pure fractions were collected and the solvent was evaporated, yielding 40 g (74.1% ) of (±)-1,1-dimethylethyl 4-[4-(acetylamino)-4-phenyl-1-piperidinyl]-2-(phenylmethyl)-1-piperidinecarboxylate (intermediate 19). After uptake of hydrogen the catalyst was filtered off the filtrate was evaporated The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 97/3) The pure fractions were collected the solvent was evaporated

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

実験手順: Potassium tert-butoxide (4.49 mL, 1M in THF) was added over about 5 minutes to (methoxymethyl)triphenylphosphonium chloride (1.42 g, 4.15 mmol) suspended in anhydrous THF (25 mL) at 0° C. The resulting suspension was stirred at about this temperature for about 45 minutes at which time, tert-butyl 2-benzyl-4-oxopiperidine-1-carboxylate (1.0 g, 3.46 mmol) dissolved in THF (5 mL) was added. The reaction mixture was allowed to warm to ambient and stir for another 6 h. The reaction was quenched by the addition of ammonium chloride solution and then taken up in EtOAc. After washing twice with water and once with brine, the organic portion was dried over magnesium sulfate, filtered and concentrated. The resulting semi-solid residue was purified via silica gel chromatography to give (Z)-tert-butyl 2-benzyl-4-(methoxymethylene)piperidine-1-carboxylate (375 mg, 34%). LCMS (APCI+) m/z 218.1 [M+H]+; Rt=4.51 min. was added to warm The reaction was quenched by the addition of ammonium chloride solution After washing twice with water and once with brine the organic portion was dried over magnesium sulfate filtered concentrated The resulting semi-solid residue was purified via silica gel chromatography

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: Potassium tert-butoxide (4.49 mL, 1M in THF) was added over about 5 minutes to (methoxymethyl) triphenylphosphonium chloride (1.42 g, 4.15 mmol) suspended in anhydrous THF (25 mL) at 0° C. The resulting suspension was stirred at about this temperature for about 45 minutes at which time, tert-butyl 2-benzyl-4-oxopiperidine-1-carboxylate (1.0 g, 3.46 mmol) dissolved in THF (5 mL) was added. The reaction mixture was allowed to warm to ambient and stir for another 6 h. The reaction was quenched by the addition of ammonium chloride solution and then taken up in EtOAc. After washing twice with water and once with brine, the organic portion was dried over magnesium sulfate, filtered and concentrated. The resulting semi-solid residue was purified via silica gel chromatography to give (Z)-tert-butyl 2-benzyl-4-(methoxymethylene)piperidine-1-carboxylate (375 mg, 34%). LCMS (APCI+) m/z 218.1 [M+H]+; Rt=4.51 min. was added to warm The reaction was quenched by the addition of ammonium chloride solution After washing twice with water and once with brine the organic portion was dried over magnesium sulfate filtered concentrated The resulting semi-solid residue was purified via silica gel chromatography

反応条件: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2-benzyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (15 g, 51.8 mmol) (from SYNTECH) in DME (250 mL) under nitrogen atmosphere was simultaneously added toluene-4-sulfonylmethyl isocyanide (15.2 g, 77.7 mmol, in 250 mL DME) and potassium tert-butoxide (156 mL, 1 M in tert-butanol) over 1 h so that the temperature was kept below −10° C. The solution was stirred at −10° C. for 2 h and then allowed to reach room temperature over 16 h. To the reaction mixture was added H2O (400 mL) and the solution was stirred for 20 min and then extracted with DEE (×3) and EtOAc (×3). The combined organic phases were dried over Na2SO4 and evaporated. The residue was purified by column chromatography using EtOAc/heptane (10-60% gradient EtOAc) to yield tert-butyl 2-benzyl-4-cyanopiperidine-1-carboxylate (11.85 g, 76%). 1H NMR (600 MHz, cdcl3) δ 1.38-1.46 (m, 9H), 1.63-2.14 (m, 4H), 2.62-3.33 (m, 4H), 4.17 (m, 1H), 4.48 (m, 1H), 7.11-7.41 (m, 5H); MS m/z 301 (M+H)+. over 1 h was kept below −10° C to reach room temperature over 16 h the solution was stirred for 20 min extracted with DEE (×3) and EtOAc (×3) The combined organic phases were dried over Na2SO4 evaporated The residue was purified by column chromatography

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

実験手順: A mixture of (±)-1,1-dimethylethyl 4-oxo-2-(phenylmethyl)-1-piperidine carboxylate (0.1 mol) and N-(4-phenyl-4-piperidinyl)acetamide (0.1 mol) in 2-propanol (500 ml) was hydrogenated at 50° C. with platinum (4 g) as a catalyst in the presence of titanium(IV)isopropoxide (28.5 g) and thiophene (4%; 1 ml). After uptake of hydrogen, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 97/3). The pure fractions were collected and the solvent was evaporated, yielding 40 g (74.1%) of (±)-1,1-dimethylethyl 4-[4-(acetylamino)-4-phenyl-1-piperidinyl]-2-(phenylmethyl)-1-piperidinecarboxylate (intermediate 19). After uptake of hydrogen, the catalyst was filtered off the filtrate was evaporated The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 97/3) The pure fractions were collected the solvent was evaporated

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

実験手順: A mixture of (±)-1,1-dimethylethyl 4-oxo-2-(phenylmethyl)-1-piperidine carboxylate (0.1 mol) and N-(4-phenyl-4-piperidinyl)acetamide (0.1 mol) in 2-propanol (500 ml) was hydrogenated at 50° C. with platinum (4 g) as a catalyst in the presence of titanium (IV)isopropoxide (28.5 g) and thiophene (4%; 1 ml). After uptake of hydrogen the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 97/3). The pure fractions were collected and the solvent was evaporated, yielding 40 g (74.1% ) of (±)-1,1-dimethylethyl 4-[4-(acetylamino)-4-phenyl-1-piperidinyl]-2-(phenylmethyl)-1-piperidinecarboxylate (intermediate 19). After uptake of hydrogen the catalyst was filtered off the filtrate was evaporated The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 97/3) The pure fractions were collected the solvent was evaporated

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

実験手順: Potassium tert-butoxide (4.49 mL, 1M in THF) was added over about 5 minutes to (methoxymethyl)triphenylphosphonium chloride (1.42 g, 4.15 mmol) suspended in anhydrous THF (25 mL) at 0° C. The resulting suspension was stirred at about this temperature for about 45 minutes at which time, tert-butyl 2-benzyl-4-oxopiperidine-1-carboxylate (1.0 g, 3.46 mmol) dissolved in THF (5 mL) was added. The reaction mixture was allowed to warm to ambient and stir for another 6 h. The reaction was quenched by the addition of ammonium chloride solution and then taken up in EtOAc. After washing twice with water and once with brine, the organic portion was dried over magnesium sulfate, filtered and concentrated. The resulting semi-solid residue was purified via silica gel chromatography to give (Z)-tert-butyl 2-benzyl-4-(methoxymethylene)piperidine-1-carboxylate (375 mg, 34%). LCMS (APCI+) m/z 218.1 [M+H]+; Rt=4.51 min. was added to warm The reaction was quenched by the addition of ammonium chloride solution After washing twice with water and once with brine the organic portion was dried over magnesium sulfate filtered concentrated The resulting semi-solid residue was purified via silica gel chromatography