3-(1-PYRROLIDINYL)-1-BUTANOL

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 3-Pyrrolidin-1-yl-butan-1-ol (1.0 g, 7 mmol) was dissolved in DCM (20 ml). The reaction was cooled to 0-5° C. and thionyl chloride (1.65 g, 14 mmol) was added slowly. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was concentrated in vacuo and azeotroped with DCM (20 ml) to give the title compound (1.4 g, 100%) as a brown oil. to warm to room temperature The reaction was concentrated in vacuo azeotroped with DCM (20 ml)

反応条件: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 3-Pyrrolidin-1-yl-butan-1-ol (1.0 g, 7 mmol) was dissolved in DCM (20 ml). The reaction was cooled to 0-5° C. and thionyl chloride (1.65 g, 14 mmol) was added slowly. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was concentrated in vacuo and azeotroped with DCM (20 ml) to give the title compound (1.4 g, 100%) as a brown oil. to warm to room temperature The reaction was concentrated in vacuo azeotroped with DCM (20 ml)

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

実験手順: 4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (925 mg, 3.93 mmol), 3-pyrrolidin-1-yl-butan-1-ol (450 mg, 3.14 mmol), PPh3 (1.03 g, 3.93 mmol), THF (9 ml) and DIAD (0.77 ml, 3.93 mmol) were reacted together according to general procedure C. The crude material was subjected to chromatography on silica eluting with DCM:MeOH (99.5:0.5) to provide the title compound (268 mg, 24%) as a colourless oil. 1H NMR (400 MHz, CDCl3) δ7.21 (d, 2H), 6.88 (d, 2H), 4.11-3.97 (m, 2H), 3.75 (dt, 2H), 3.55 (td, 2H), 2.66-2.52 (m, 5H), 2.40 (s, 2H), 2.19-2.05 (m, 3H), 1.96 (s, 6H), 1.93-1.70 (m, 7H), 1.16 (d, 3H).

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

実験手順: 4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (925 mg, 3.93 mmol), 3-pyrrolidin-1-yl-butan-1-ol (450 mg, 3.14 mmol), PPh3 (1.03 g, 3.93 mmol), THF (9 ml) and DIAD (0.77 ml, 3.93 mmol) were reacted together according to general procedure C. The crude material was subjected to chromatography on silica eluting with DCM:MeOH (99.5:0.5) to provide the title compound (268 mg, 24%) as a colourless oil. 1H NMR (400 MHz, CDCl3) δ7.21 (d, 2H), 6.88 (d, 2H), 4.11-3.97 (m, 2H), 3.75 (dt, 2H), 3.55 (td, 2H), 2.66-2.52 (m, 5H), 2.40 (s, 2H), 2.19-2.05 (m, 3H), 1.96 (s, 6H), 1.93-1.70 (m, 7H), 1.16 (d, 3H).

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

実験手順: Pyrrolidine (28.159, 0.4 mol), toluene (200 ml), catalytic p-TsOH (200 mg) and ethyl acetoacetate (20 g, 0.15 mol) were refluxed together in a Dean-Stark apparatus under N2 for 3 hours. The reaction was cooled to room temperature and concentrated in vacuo. NaBH4 (3.1 g, 82 mmol) was dissolved in MeOH (50 ml) and cooled to 0-5° C. A portion of the previous crude reaction (5 g, 27 mmol) in MeOH (25 ml) was added to the reaction mixture and stirred for 72 hours. The reaction was quenched with an aqueous solution of NaOH (1% w/w, 50 ml) and concentrated in vacuo. The aqueous phase was extracted with TBME (3×50 ml). The combined organic extracts were dried over MgSO4, filtered, washed with TBME and concentrated in vacuo to give a mixture of the title compound, 3-pyrrolidin-1-yl-butanoic acid ethyl ester and residual TBME (3.5 g). The mixture (3.5 g) in THF (20 ml) was added to a solution of LiALH4 (1M in THF, 33.5 ml, 33.5 mmol) at 0-5° C. under N2. The reaction was allowed to warm to room temperature and stirred for 3 hours. The reaction was quenched with an aqueous solution of NaOH (1% w/w, 50 ml) at 0-5° C., filtered and washed with THF (3×20 ml). The combined organic layers were dried over MgSO4, filtered, washed with THF and concentrated in vacuo to give the title compound as a yellow oil (2 g, 73%). concentrated in vacuo cooled to 0-5° C was added to the reaction mixture The reaction was quenched with an aqueous solution of NaOH (1% w/w, 50 ml) concentrated in vacuo The aqueous phase was extracted with TBME (3×50 ml) The combined organic extracts were dried over MgSO4 filtered washed with TBME concentrated in vacuo to give

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

実験手順: Pyrrolidine (28.159, 0.4 mol), toluene (200 ml), catalytic p-TsOH (200 mg) and ethyl acetoacetate (20 g, 0.15 mol) were refluxed together in a Dean-Stark apparatus under N2 for 3 hours. The reaction was cooled to room temperature and concentrated in vacuo. NaBH4 (3.1 g, 82 mmol) was dissolved in MeOH (50 ml) and cooled to 0-5° C. A portion of the previous crude reaction (5 g, 27 mmol) in MeOH (25 ml) was added to the reaction mixture and stirred for 72 hours. The reaction was quenched with an aqueous solution of NaOH (1% w/w, 50 ml) and concentrated in vacuo. The aqueous phase was extracted with TBME (3×50 ml). The combined organic extracts were dried over MgSO4, filtered, washed with TBME and concentrated in vacuo to give a mixture of the title compound, 3-pyrrolidin-1-yl-butanoic acid ethyl ester and residual TBME (3.5 g). The mixture (3.5 g) in THF (20 ml) was added to a solution of LiALH4 (1M in THF, 33.5 ml, 33.5 mmol) at 0-5° C. under N2. The reaction was allowed to warm to room temperature and stirred for 3 hours. The reaction was quenched with an aqueous solution of NaOH (1% w/w, 50 ml) at 0-5° C., filtered and washed with THF (3×20 ml). The combined organic layers were dried over MgSO4, filtered, washed with THF and concentrated in vacuo to give the title compound as a yellow oil (2 g, 73%). concentrated in vacuo cooled to 0-5° C was added to the reaction mixture The reaction was quenched with an aqueous solution of NaOH (1% w/w, 50 ml) concentrated in vacuo The aqueous phase was extracted with TBME (3×50 ml) The combined organic extracts were dried over MgSO4 filtered washed with TBME concentrated in vacuo to give

反応条件: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 3-Pyrrolidin-1-yl-butan-1-ol (1.0 g, 7 mmol) was dissolved in DCM (20 ml). The reaction was cooled to 0-5° C. and thionyl chloride (1.65 g, 14 mmol) was added slowly. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was concentrated in vacuo and azeotroped with DCM (20 ml) to give the title compound (1.4 g, 100%) as a brown oil. to warm to room temperature The reaction was concentrated in vacuo azeotroped with DCM (20 ml)

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

実験手順: 4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (925 mg, 3.93 mmol), 3-pyrrolidin-1-yl-butan-1-ol (450 mg, 3.14 mmol), PPh3 (1.03 g, 3.93 mmol), THF (9 ml) and DIAD (0.77 ml, 3.93 mmol) were reacted together according to general procedure C. The crude material was subjected to chromatography on silica eluting with DCM:MeOH (99.5:0.5) to provide the title compound (268 mg, 24%) as a colourless oil. 1H NMR (400 MHz, CDCl3) δ7.21 (d, 2H), 6.88 (d, 2H), 4.11-3.97 (m, 2H), 3.75 (dt, 2H), 3.55 (td, 2H), 2.66-2.52 (m, 5H), 2.40 (s, 2H), 2.19-2.05 (m, 3H), 1.96 (s, 6H), 1.93-1.70 (m, 7H), 1.16 (d, 3H).

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

実験手順: Pyrrolidine (28.159, 0.4 mol), toluene (200 ml), catalytic p-TsOH (200 mg) and ethyl acetoacetate (20 g, 0.15 mol) were refluxed together in a Dean-Stark apparatus under N2 for 3 hours. The reaction was cooled to room temperature and concentrated in vacuo. NaBH4 (3.1 g, 82 mmol) was dissolved in MeOH (50 ml) and cooled to 0-5° C. A portion of the previous crude reaction (5 g, 27 mmol) in MeOH (25 ml) was added to the reaction mixture and stirred for 72 hours. The reaction was quenched with an aqueous solution of NaOH (1% w/w, 50 ml) and concentrated in vacuo. The aqueous phase was extracted with TBME (3×50 ml). The combined organic extracts were dried over MgSO4, filtered, washed with TBME and concentrated in vacuo to give a mixture of the title compound, 3-pyrrolidin-1-yl-butanoic acid ethyl ester and residual TBME (3.5 g). The mixture (3.5 g) in THF (20 ml) was added to a solution of LiALH4 (1M in THF, 33.5 ml, 33.5 mmol) at 0-5° C. under N2. The reaction was allowed to warm to room temperature and stirred for 3 hours. The reaction was quenched with an aqueous solution of NaOH (1% w/w, 50 ml) at 0-5° C., filtered and washed with THF (3×20 ml). The combined organic layers were dried over MgSO4, filtered, washed with THF and concentrated in vacuo to give the title compound as a yellow oil (2 g, 73%). concentrated in vacuo cooled to 0-5° C was added to the reaction mixture The reaction was quenched with an aqueous solution of NaOH (1% w/w, 50 ml) concentrated in vacuo The aqueous phase was extracted with TBME (3×50 ml) The combined organic extracts were dried over MgSO4 filtered washed with TBME concentrated in vacuo to give

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

実験手順: The target compound was obtained by the method according to Example 18, using 3-pyrrolidin-1-yl-butan -1-ol (racemic mixture) manufactured by the method described in the literature (J. Org. Chem., 1949, Vol. 14, p. 862) and 4-nitrofluorobenzene as starting materials. The target compound was obtained by the method

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

実験手順: The target compound was obtained by the method according to Example 18, using 3-pyrrolidin-1-yl-butan-1-ol (racemic mixture) manufactured by the method described in the literature (J. Org. Chem., 1949, Vol. 14, p. 862) and 4-nitrofluorobenzene as starting materials. The target compound was obtained by the method