1'-苄基-3氢-螺[异苯并呋喃-1,4'-哌啶]-3-酮

反应条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 1′-benzyl-3H-spiro[isobenzofuran-1,4′-piperidin]-3-one 1b (6 g, 20.4 mmol) in dichloromethane (30 mL) was added dropwise 1-chloroethyl chloroformate (2.9 g, 20.4 mmol). The mixture was stirred at 25° C. for 5 hr and then was concentrated to dryness under reduced pressure. The residue was dissolved in methanol and the mixture was heated to reflux for 30 min. The mixture was concentrated to dryness and ether was added. The precipitated solid was collected by filtration and washed with ether, dried in air to obtain 3H-spiro[isobenzofuran-1,4′-piperidin]-3-one 1c as its HCl salt (3.6 g). 1H-NMR (400 MHz, DMSO-d6) δ 9.16 (br, 2H), 7.86-7.81 (m, 2H), 7.63 (t, J=7.6 Hz, 1H), 7.56 (d, J=7.2 Hz, 1H), 3.39-3.42 (m, 2H), 3.11-3.14 (m, 2H), 2.47-2.48 (m, 2H), 1.85 (d, J=14.4 Hz, 2H). MS (ESI) m/z (M+H+): 203.24. was concentrated to dryness under reduced pressure The residue was dissolved in methanol the mixture was heated to reflux for 30 min The mixture was concentrated to dryness and ether was added The precipitated solid was collected by filtration washed with ether dried in air

反应条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 1′-benzyl-3H-spiro[isobenzofuran-1,4′-piperidin]-3-one 1b (6 g, 20.4 mmol) in dichloromethane (30 mL) was added dropwise 1-chloroethyl chloroformate (2.9 g, 20.4 mmol). The mixture was stirred at 25° C. for 5 hr and then was concentrated to dryness under reduced pressure. The residue was dissolved in methanol and the mixture was heated to reflux for 30 min. The mixture was concentrated to dryness and ether was added. The precipitated solid was collected by filtration and washed with ether, dried in air to obtain 3H-spiro[isobenzofuran-1,4′-piperidin]-3-one 1c as its HCl salt (3.6 g). 1H-NMR (400 MHz, DMSO-d6) δ 9.16 (br, 2H), 7.86-7.81 (m, 2H), 7.63 (t, J=7.6 Hz, 1H), 7.56 (d, J=7.2 Hz, 1H), 3.39-3.42 (m, 2H), 3.11-3.14 (m, 2H), 2.47-2.48 (m, 2H), 1.85 (d, J=14.4 Hz, 2H). MS (ESI) m/z (M+H+): 203.24. was concentrated to dryness under reduced pressure The residue was dissolved in methanol the mixture was heated to reflux for 30 min The mixture was concentrated to dryness and ether was added The precipitated solid was collected by filtration washed with ether dried in air

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of 2-bromobenzoic acid (20.12 g, 0.1 mol) in THF (200 mL) was treated dropwise with n-BuLi (2.5 M, 80 mL) at −78° C. The mixture was stirred at this temperature for 30 min, followed by dropwise addition of a solution of N-benzylpiperdine-4-one (26 g, 137 mmol) in THF (100 mL). The resulting mixture was stirred at −78° C. for 30 min, and was then allowed to warm to room temperature and stirred overnight. The reaction was quenched with water (100 mL) and the resulting mixture was washed with ether (100 mL). The aqueous layer was refluxed for 1 hr and then acidified to pH 2.5. The mixture was extracted with CHCl3 (3×50 mL), the combined organic layers were washed with brine, dried over Na2SO4 and concentrated to dryness to obtain 1′-benzyl-3H-spiro[isobenzofuran-1,4′-piperidin]-3-one 1b (6 g). The resulting mixture was stirred at −78° C. for 30 min stirred overnight The reaction was quenched with water (100 mL) the resulting mixture was washed with ether (100 mL) The aqueous layer was refluxed for 1 hr The mixture was extracted with CHCl3 (3×50 mL) the combined organic layers were washed with brine dried over Na2SO4 concentrated to dryness

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of 2-bromobenzoic acid (20.12 g, 0.1 mol) in THF (200 mL) was treated dropwise with n-BuLi (2.5 M, 80 mL) at −78° C. The mixture was stirred at this temperature for 30 min, followed by dropwise addition of a solution of N-benzylpiperdine-4-one (26 g, 137 mmol) in THF (100 mL). The resulting mixture was stirred at −78° C. for 30 min, and was then allowed to warm to room temperature and stirred overnight. The reaction was quenched with water (100 mL) and the resulting mixture was washed with ether (100 mL). The aqueous layer was refluxed for 1 hr and then acidified to pH 2.5. The mixture was extracted with CHCl3 (3×50 mL), the combined organic layers were washed with brine, dried over Na2SO4 and concentrated to dryness to obtain 1′-benzyl-3H-spiro[isobenzofuran-1,4′-piperidin]-3-one 1b (6 g). The resulting mixture was stirred at −78° C. for 30 min stirred overnight The reaction was quenched with water (100 mL) the resulting mixture was washed with ether (100 mL) The aqueous layer was refluxed for 1 hr The mixture was extracted with CHCl3 (3×50 mL) the combined organic layers were washed with brine dried over Na2SO4 concentrated to dryness

反应条件: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a mixture of 1′-(phenylmethyl)-spiro[isobenzofuran-1(3H),4′-piperidin]-3-one (25 g, 85.2 mmol) [C.A.S. 37663-42-6] in toluene (600 ml), was added 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide (Lawesson's reagent) (34.47 g, 85.2 mmol was added. The reaction mixture was heated at 140° C. for 2 h. After cooling, the mixture was poured into NH4Cl (aqueous sat. solution) and extracted with DCM. The organic phase was separated, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (silica gel; DCM/MeOH 3% as eluent). The desired fractions were collected and concentrated in vacuo to a residue that was purified by HPLC to yield intermediate D72 (8 g, 30.3%). was added After cooling extracted with DCM The organic phase was separated dried (MgSO4) concentrated in vacuo The residue was purified by column chromatography (silica gel; DCM/MeOH 3% as eluent) The desired fractions were collected concentrated in vacuo to a residue that was purified by HPLC to yield intermediate D72 (8 g, 30.3%)

反应条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 1′-benzyl-3H-spiro[isobenzofuran-1,4′-piperidin]-3-one 1b (6 g, 20.4 mmol) in dichloromethane (30 mL) was added dropwise 1-chloroethyl chloroformate (2.9 g, 20.4 mmol). The mixture was stirred at 25° C. for 5 hr and then was concentrated to dryness under reduced pressure. The residue was dissolved in methanol and the mixture was heated to reflux for 30 min. The mixture was concentrated to dryness and ether was added. The precipitated solid was collected by filtration and washed with ether, dried in air to obtain 3H-spiro[isobenzofuran-1,4′-piperidin]-3-one 1c as its HCl salt (3.6 g). 1H-NMR (400 MHz, DMSO-d6) δ 9.16 (br, 2H), 7.86-7.81 (m, 2H), 7.63 (t, J=7.6 Hz, 1H), 7.56 (d, J=7.2 Hz, 1H), 3.39-3.42 (m, 2H), 3.11-3.14 (m, 2H), 2.47-2.48 (m, 2H), 1.85 (d, J=14.4 Hz, 2H). MS (ESI) m/z (M+H+): 203.24. was concentrated to dryness under reduced pressure The residue was dissolved in methanol the mixture was heated to reflux for 30 min The mixture was concentrated to dryness and ether was added The precipitated solid was collected by filtration washed with ether dried in air

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of 2-bromobenzoic acid (20.12 g, 0.1 mol) in THF (200 mL) was treated dropwise with n-BuLi (2.5 M, 80 mL) at −78° C. The mixture was stirred at this temperature for 30 min, followed by dropwise addition of a solution of N-benzylpiperdine-4-one (26 g, 137 mmol) in THF (100 mL). The resulting mixture was stirred at −78° C. for 30 min, and was then allowed to warm to room temperature and stirred overnight. The reaction was quenched with water (100 mL) and the resulting mixture was washed with ether (100 mL). The aqueous layer was refluxed for 1 hr and then acidified to pH 2.5. The mixture was extracted with CHCl3 (3×50 mL), the combined organic layers were washed with brine, dried over Na2SO4 and concentrated to dryness to obtain 1′-benzyl-3H-spiro[isobenzofuran-1,4′-piperidin]-3-one 1b (6 g). The resulting mixture was stirred at −78° C. for 30 min stirred overnight The reaction was quenched with water (100 mL) the resulting mixture was washed with ether (100 mL) The aqueous layer was refluxed for 1 hr The mixture was extracted with CHCl3 (3×50 mL) the combined organic layers were washed with brine dried over Na2SO4 concentrated to dryness

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of 5.8 g. of 1'-benzyl-1,3-dihydrospiro[isobenzofuran-1,4'-piperidine]-3-one, 40 ml. of benzene, and 2.5 ml. of ethyl chloroformate is heated under reflux for 18 hours and concentrated to a solid. Recrystallization from benzene-cyclohexane provides colorless crystals, m.p. 150°-151°, of 1,3-dihydro-1'-ethoxycarbonylspiro[isobenzofuran-1,4'-piperidine]-3-one. Reduction with lithium aluminum hydride by the method described in Example 16b provides 4-hydroxy-4-(α-hydroxy-2-tolyl)-1-methylpiperidine, m.p. 118°-119°. under reflux for 18 hours concentrated to a solid Recrystallization from benzene-cyclohexane provides colorless crystals, m.p. 150°-151°

反应条件: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a mixture of 1′-(phenylmethyl)-spiro[isobenzofuran-1(3H),4′-piperidin]-3-one (25 g, 85.2 mmol) [C.A.S. 37663-42-6] in toluene (600 ml), was added 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide (Lawesson's reagent) (34.47 g, 85.2 mmol was added. The reaction mixture was heated at 140° C. for 2 h. After cooling, the mixture was poured into NH4Cl (aqueous sat. solution) and extracted with DCM. The organic phase was separated, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (silica gel; DCM/MeOH 3% as eluent). The desired fractions were collected and concentrated in vacuo to a residue that was purified by HPLC to yield intermediate D72 (8 g, 30.3%). was added After cooling extracted with DCM The organic phase was separated dried (MgSO4) concentrated in vacuo The residue was purified by column chromatography (silica gel; DCM/MeOH 3% as eluent) The desired fractions were collected concentrated in vacuo to a residue that was purified by HPLC to yield intermediate D72 (8 g, 30.3%)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of 5.8 g. of 1'-benzyl-1,3-dihydrospiro[isobenzofuran-1,4'-piperidine]-3-one, 40 ml. of benzene, and 2.5 ml. of ethyl chloroformate is heated under reflux for 18 hours and concentrated to a solid. Recrystallization from benzene-cyclohexane provides colorless crystals, m.p. 150°-151°, of 1,3-dihydro-1'-ethoxycarbonylspiro[isobenzofuran-1,4'-piperidine]-3-one. Reduction with lithium aluminum hydride by the method described in Example 16b provides 4-hydroxy-4-(α-hydroxy2-tolyl)-1-methylpiperidine, m.p. 118°-119°. under reflux for 18 hours concentrated to a solid Recrystallization from benzene-cyclohexane provides colorless crystals, m.p. 150°-151°

反应条件: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a mixture of 1′-(phenylmethyl)-spiro[isobenzofuran-1(3H),4′-piperidin]-3-one (25 g, 85.2 mmol) [C.A.S. 37663-42-6] in toluene (600 ml), was added 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide (Lawesson's reagent) (34.47 g, 85.2 mmol was added. The reaction mixture was heated at 140° C. for 2 h. After cooling, the mixture was poured into NH4Cl (aqueous sat. solution) and extracted with DCM. The organic phase was separated, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (silica gel; DCM/MeOH 3% as eluent). The desired fractions were collected and concentrated in vacuo to a residue that was purified by HPLC to yield intermediate D72 (8 g, 30.3%). was added After cooling extracted with DCM The organic phase was separated dried (MgSO4) concentrated in vacuo The residue was purified by column chromatography (silica gel; DCM/MeOH 3% as eluent) The desired fractions were collected concentrated in vacuo to a residue that was purified by HPLC to yield intermediate D72 (8 g, 30.3%)

反应条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 1′-benzyl-3H-spiro[isobenzofuran-1,4′-piperidin]-3-one 1b (6 g, 20.4 mmol) in dichloromethane (30 mL) was added dropwise 1-chloroethyl chloroformate (2.9 g, 20.4 mmol). The mixture was stirred at 25° C. for 5 hr and then was concentrated to dryness under reduced pressure. The residue was dissolved in methanol and the mixture was heated to reflux for 30 min. The mixture was concentrated to dryness and ether was added. The precipitated solid was collected by filtration and washed with ether, dried in air to obtain 3H-spiro[isobenzofuran-1,4′-piperidin]-3-one 1c as its HCl salt (3.6 g). 1H-NMR (400 MHz, DMSO-d6) δ 9.16 (br, 2H), 7.86-7.81 (m, 2H), 7.63 (t, J=7.6 Hz, 1H), 7.56 (d, J=7.2 Hz, 1H), 3.39-3.42 (m, 2H), 3.11-3.14 (m, 2H), 2.47-2.48 (m, 2H), 1.85 (d, J=14.4 Hz, 2H). MS (ESI) m/z (M+H+): 203.24. was concentrated to dryness under reduced pressure The residue was dissolved in methanol the mixture was heated to reflux for 30 min The mixture was concentrated to dryness and ether was added The precipitated solid was collected by filtration washed with ether dried in air