[1-benzyl-4-(hydroxymethyl)pyrrolidin-3-yl]methanol

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: To a solution of (1-benzylpyrrolidine-3,4-diyl)dimethanol (1.44 g) in toluene (60 mL) was added Et3N (1.72 mL), TsCl (1.75 g) and DMAP (40 mg). The reaction mixture was stirred at room temperature for 12 h under N2, washed with water once, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was used for next step. To a solution of the above product in toluene (20 mL) was added Et3N (0.85 mL). The reaction mixture was heated to reflux for 4 h and cooled to room temperature. The reaction mixture was washed with water followed by brine, dried over anhydrous Na2SO4 and filtrated. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) CH2Cl2/CH3OH) to afford the title compound (0.51 g, 62.30%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 204.3 (M+1); 1H NMR (400 MHz, CDCl3) δ: 2.31-2.35 (m, 2H), 2.71 (m, 2H), 2.79-2.81 (m, 2H), 3.57-3.60 (m, 4H), 3.76-3.80 (m, 2H), 7.24-7.34 (m, 5H) ppm. washed with water once dried over anhydrous Na2SO4 filtered The filtrate was concentrated in vacuo To a solution of the above product in toluene (20 mL) was added Et3N (0.85 mL) The reaction mixture was heated to reflux for 4 h cooled to room temperature The reaction mixture was washed with water dried over anhydrous Na2SO4 filtrated The filtrate was concentrated in vacuo the residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) CH2Cl2/CH3OH)

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

実験手順: To a solution of (1-benzylpyrrolidine-3,4-diyl)dimethanol (1.44 g) in toluene (60 mL) was added Et3N (1.72 mL), TsCl (1.75 g) and DMAP (40 mg). The reaction mixture was stirred at room temperature for 12 h under N2, washed with water once, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was used for next step. To a solution of the above product in toluene (20 mL) was added Et3N (0.85 mL). The reaction mixture was heated to reflux for 4 h and cooled to room temperature. The reaction mixture was washed with water followed by brine, dried over anhydrous Na2SO4 and filtrated. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) CH2Cl2/CH3OH) to afford the title compound (0.51 g, 62.30%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 204.3 (M+1); 1H NMR (400 MHz, CDCl3) δ: 2.31-2.35 (m, 2H), 2.71 (m, 2H), 2.79-2.81 (m, 2H), 3.57-3.60 (m, 4H), 3.76-3.80 (m, 2H), 7.24-7.34 (m, 5H) ppm. washed with water once dried over anhydrous Na2SO4 filtered The filtrate was concentrated in vacuo To a solution of the above product in toluene (20 mL) was added Et3N (0.85 mL) The reaction mixture was heated to reflux for 4 h cooled to room temperature The reaction mixture was washed with water dried over anhydrous Na2SO4 filtrated The filtrate was concentrated in vacuo the residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) CH2Cl2/CH3OH)

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

実験手順: To a solution of dimethyl 1-benzylpyrrolidine-3,4-dicarboxylate (0.50 g) in THF (20 mL) was added LiAlH4 (3.0 eq) at 0° C. under N2. The reaction mixture was heated to the room temperature and stirred for 24 h. The reaction was quenched with water, 10% NaOH and water in turn. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was chromatographed with a silica gel column (eluting agent: 10:1 (v/v) CH2Cl2/CH3OH) to give the title compound (0.31 g, 63.79%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 222.3 (M+1). The reaction was quenched with water, 10% NaOH and water in turn The mixture was filtered the filtrate was concentrated in vacuo The residue was chromatographed with a silica gel column (eluting agent: 10:1 (v/v) CH2Cl2/CH3OH)

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 solution of (1-benzyl-4-hydroxymethyl-pyrrolidin-3-yl)-methanol (7.89 g, 31.2 mmol) and p-toluenesulfonic acid monohydrate (7.12 g, 37.4 mmol) in toluene (150 mL) was heated under a Dean Stark trap (120° C., 20 h). The reaction mixture was cooled (rt) and treated with 1 N NaOH (50 mL). The aqueous phase was extracted with methyl tert-butyl ether (3×50 mL). The combined organic layers were dried, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography using MeOH (0.2 M NH3):DCM (0-5%) to afford the title compound as a yellow oil (5.08 g, 80%). 1H NMR (500 MHz, CDCl3): 7.37-7.29 (m, 4H), 7.29-7.24 (m, 1H), 3.87-3.79 (m, 2H), 3.65-3.56 (m, 4H), 2.86-2.75 (m, 2H), 2.75-2.66 (m, 2H), 2.34 (dt, J=12.2, 6.1, 2H). The aqueous phase was extracted with methyl tert-butyl ether (3×50 mL) The combined organic layers were dried filtered concentrated in vacuo The resulting residue was purified by silica gel column chromatography

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

実験手順: To a cooled (0° C.) solution of 1-benzyl-pyrrolidine-3,4-dicarboxylic acid dimethyl ester (8.66 g, 31.2 mmol) in THF (40 mL) was added LAH (2 M in THF, 62 mL, 62 mmol) over a ten minute period. The reaction mixture was stirred while warming (rt, 17 h). The reaction mixture was then cooled (0° C.), and stirred (15 min), and slowly treated sequentially with an addition of H2O (2.8 mL), 2 M NaOH (4.3 mL), and H2O (8.5 mL). The reaction mixture was then heated to reflux (64° C., 1 h). The reaction mixture was cooled and filtered through Celite® and the solid was washed with EtOAc. The filtrate was concentrated in vacuo to afford the title compound as a yellow oil (7.89 g, 100%). 1H NMR (500 MHz, CDCl3): 7.38-7.21 (m, 5H), 3.84-3.70 (m, 4H), 3.65-3.59 (m, 2H), 2.70-2.58 (m, 4H), 2.58-2.47 (m, 2H). The reaction mixture was then cooled (0° C.) stirred (15 min) The reaction mixture was then heated to reflux (64° C., 1 h) The reaction mixture was cooled filtered through Celite® the solid was washed with EtOAc The filtrate was concentrated in vacuo

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

実験手順: To a solution of (1-benzylpyrrolidine-3,4-diyl)dimethanol (1.44 g) in toluene (60 mL) was added Et3N (1.72 mL), TsCl (1.75 g) and DMAP (40 mg). The reaction mixture was stirred at room temperature for 12 h under N2, washed with water once, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was used for next step. To a solution of the above product in toluene (20 mL) was added Et3N (0.85 mL). The reaction mixture was heated to reflux for 4 h and cooled to room temperature. The reaction mixture was washed with water followed by brine, dried over anhydrous Na2SO4 and filtrated. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) CH2Cl2/CH3OH) to afford the title compound (0.51 g, 62.30%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 204.3 (M+1); 1H NMR (400 MHz, CDCl3) δ: 2.31-2.35 (m, 2H), 2.71 (m, 2H), 2.79-2.81 (m, 2H), 3.57-3.60 (m, 4H), 3.76-3.80 (m, 2H), 7.24-7.34 (m, 5H) ppm. washed with water once dried over anhydrous Na2SO4 filtered The filtrate was concentrated in vacuo To a solution of the above product in toluene (20 mL) was added Et3N (0.85 mL) The reaction mixture was heated to reflux for 4 h cooled to room temperature The reaction mixture was washed with water dried over anhydrous Na2SO4 filtrated The filtrate was concentrated in vacuo the residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) CH2Cl2/CH3OH)

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

実験手順: To a solution of dimethyl 1-benzylpyrrolidine-3,4-dicarboxylate (0.50 g) in THF (20 mL) was added LiAlH4 (3.0 eq) at 0° C. under N2. The reaction mixture was heated to the room temperature and stirred for 24 h. The reaction was quenched with water, 10% NaOH and water in turn. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was chromatographed with a silica gel column (eluting agent: 10:1 (v/v) CH2Cl2/CH3OH) to give the title compound (0.31 g, 63.79%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 222.3 (M+1). The reaction was quenched with water, 10% NaOH and water in turn The mixture was filtered the filtrate was concentrated in vacuo The residue was chromatographed with a silica gel column (eluting agent: 10:1 (v/v) CH2Cl2/CH3OH)