4-(4-butylpiperidin-1-yl)butanenitrile

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In a 25 mL oven-dried flask was added Mg turnings (123 mg, 5.1 mmol) which was activated by the use of a heat-gun under vacuum. Under inert atmosphere was added a solution of 1-benzyloxy-2-iodo-benzene (25) (1.18 g, 3.8 mmol) in Et2O (10 mL) and the reaction mixture was allowed to reflux for 3.5 hours. A solution of 4-(4-n-butylpiperidin-1-yl)butanenitrile 4 (0.53 g, 2.5 mmol) dissolved in CH2Cl2 (3 mL) was added and the reaction mixture and was stirred at 40° C. over-night. The reaction mixture was quenched by addition of H2SO4 (10 mL, 2 M) and left stirring for 1 hour, followed by addition of NaOH (20 mL, 2 M) until basic conditions. The reaction mixture was extrated with ethyl acetate (3×50 mL)) and the combined organic phases are washed with brine (10 mL) and NaOH (10 mL, 2 M), and the combined organic phases were dried (MgSO4) and evaporated to dryness to produce 1.28 g of crude 26. The crude product was subjected to CC [eluent: Tol:EtOAc (1:1)] to give pure 26 (0.51 g, 51%); LC-MS [M+H]+ 393 (cald. 393.7). In a 25 mL oven-dried flask a heat-gun under vacuum to reflux for 3.5 hours was added The reaction mixture was quenched by addition of H2SO4 (10 mL, 2 M) left stirring for 1 hour followed by addition of NaOH (20 mL, 2 M) until basic conditions are washed with brine (10 mL) and NaOH (10 mL, 2 M) the combined organic phases were dried (MgSO4) evaporated to dryness to produce 1.28 g of crude 26

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

実験手順: In a 10 mL oven-dried flask charged with Mg turnings (95 mg, 3.9 mmol) which was activated under vacuum by the use of a heat-gun. Under inert atmosphere was added a suspension of 1-iodo-2,4-dimethylbenzene (0.69 g, 2.9 mmol) in Et2O (4.5 mL) under spontaneously reflux, and the reaction mixture was allowed to reflux for 3 hours. Compound 4 (0.41 g, 2.0 mmol) dissolved in CH2Cl2 (2 mL) was added under inert atmosphere to the reaction mixture and left stirring at rt overnight. The reaction mixture was quenched by addition of H2SO4 (8 mL, 2 M) and stirred at rt for 4 hours, then the reaction mixture was basified by addition of NaOH (20 mL, 2 M). Addition of THF (20 mL) was followed by extraction with ethyl acetate (3×50 mL) and the combined organic phases are washed with brine (10 mL) and NaOH (10 mL, 2 M), and the organic phases were dried (MgSO4) and evaporated to dryness to produce 0.61 g of crude 20. The crude product was subjected to CC [eluent: CH2Cl2:MeOH (99:1)] to give pure 20 (0.21 g, 35%); LC-MS [M+H]+ 315 (cald. 315.5). In a 10 mL oven-dried flask Under inert atmosphere was added under spontaneously reflux to reflux for 3 hours was added under inert atmosphere to the reaction mixture left The reaction mixture was quenched by addition of H2SO4 (8 mL, 2 M) stirred at rt for 4 hours the reaction mixture was basified by addition of NaOH (20 mL, 2 M) Addition of THF (20 mL) was followed by extraction with ethyl acetate (3×50 mL) the combined organic phases are washed with brine (10 mL) and NaOH (10 mL, 2 M) the organic phases were dried (MgSO4) evaporated to dryness to produce 0.61 g of crude 20

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

実験手順: In a 10 mL oven-dried flask was added Mg turnings (94 mg, 3.8 mmol) which was activated under vacuum by the use of a heat-gun. Under inert atmosphere was added a suspension of 1-iodo-2,3-dimethylbenzene (0.69 g, 3.0 mmol) in Et2O (5 mL) under spontaneously reflux, and the reaction mixture was allowed to reflux for 4 hours. A suspension of compound 4 (0.41 g, 2.0 mmol) in CH2Cl2 (2 mL) was added to the reaction mixture and left at rt overnight. The reaction mixture was quenched by addition of H2SO4 (7 mL, 2 M) and stirred at rt for 3 hours, followed by addition of NaOH (20 mL, 2 M) until basic conditions. The reaction mixture was extracted with ethyl acetate (3×50 mL) and the combined organic phases are washed with brine (10 mL) and NaOH (10 mL, 2 M), and the organic phases were dried (MgSO4) and evaporated to dryness to produce 0.69 g of crude 19. The crude product was subjected to CC [eluent: CH2Cl2: MeOH (99:1)] to give pure 19 (0.40 g, 64%); LC-MS [M+H]+ 315 (cald. 315.5). In a 10 mL oven-dried flask Under inert atmosphere was added under spontaneously reflux to reflux for 4 hours was added to the reaction mixture The reaction mixture was quenched by addition of H2SO4 (7 mL, 2 M) followed by addition of NaOH (20 mL, 2 M) until basic conditions The reaction mixture was extracted with ethyl acetate (3×50 mL) the combined organic phases are washed with brine (10 mL) and NaOH (10 mL, 2 M) the organic phases were dried (MgSO4) evaporated to dryness to produce 0.69 g of crude 19

反応条件: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In a 10 mL oven-dried flask was added Mg turnings (94 mg, 3.8 mmol) which was activated by the use of a heat-gun under vacuum. Under inert atmosphere was added a suspension of 1-ethoxy-2-iodobenzene (0.71 g, 2.9 mmol) in Et2O (3 mL) and the reaction mixture was allowed to reflux for 3 hours. Compound 4 (0.40 g, 1.9 mmol) dissolved in CH2Cl2 (3 mL) was added and the mixture was stirred at 40° C. for additional 3 hours. The reaction mixture was quenched by addition of H2SO4 (10 mL, 2 M) and left stirring overnight at room temperature, followed by addition of NaOH (20 mL, 2 M) until basic conditions. The reaction mixture was extrated with ethyl acetate (3×50 mL) ) and the combined organic phases are washed with brine (10 mL) and NaOH (10 mL, 2 M), and the combined organic phases were dried (MgSO4) and evaporated to dryness to produce 0.60 g of crude 18. The crude product was subjected to CC [eluent:Tol:EtOAc (1:1)] to give pure 18 (0.32 g, 34%); LC-MS [M+H]+ 331 (cald. 331.5). In a 10 mL oven-dried flask a heat-gun under vacuum Under inert atmosphere was added to reflux for 3 hours was added The reaction mixture was quenched by addition of H2SO4 (10 mL, 2 M) left stirring overnight at room temperature followed by addition of NaOH (20 mL, 2 M) until basic conditions are washed with brine (10 mL) and NaOH (10 mL, 2 M) the combined organic phases were dried (MgSO4) evaporated to dryness to produce 0.60 g of crude 18

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

実験手順: In a 25 mL oven-dried flask was charged Mg turnings (125 mg, 5.2 mmol) which were activated by the use of a heat-gun. Under inert atmosphere was added a suspension of 2-iodoanisole (1.13 g, 5.2 rmmol) in Et2O (4 mL) and the reaction mixture was allowed to stand at rt for 1 hour. Compound 4 (720 mg, 3.4 mmol) dissolved in Et2O (4 mL) was added and the mixture was refluxed over-night. THF (15 mL) and sulfuric acid (4 mL, 2 M) was added and the reaction mixture was stirred for 4 h, followed by addition of NaOH (6 mL, 2 M). The reaction mixture was extracted with ethyl acetate (3×50 mL), and the combined organic phases were evaporated to dryness to produce 1.2 g of crude 5. The crude product was subjected to CC [eluent: CH2Cl2:CH3OH (99:1)] to give pure 5 (0.42 g, 26%). 1H NMR (CDCl3) δ 0.83 (t, 3H), 1.20-1.42 (m, 9H), 1.65-1.73 (d, 2H), 1.96-2.20 (m, 4H), 2.53 (t, 2H), 3.02-3.17 (m, 4H), 3.89 (s, 3H), 6.95-7.01 (m, 2H), 7.44 (t, 1H), 7.65 (d, 1H). In a 25 mL oven-dried flask Under inert atmosphere was added was added the mixture was refluxed over-night The reaction mixture was extracted with ethyl acetate (3×50 mL) the combined organic phases were evaporated to dryness to produce 1.2 g of crude 5

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

実験手順: In a 100 mL flask with a magnetic stirrer was placed 3 (2.3 g, 16.4 mmol), 4-bromobutyronitrile (2.4 g, 16.4 mmol), potassium carbonate powder (2.5 g, 18 mmol) in acetonitrile (20 mL). The reaction mixture was stirred at rt for 5 h followed by addition of H2O (15 mL). The mixture was extracted with ethyl acetate (3×30 mL) and the combined organic phases were evaporated to dryness to produce 3.9 of crude 4. The crude product was subjected to CC [eluent: heptane: EtOAc (1:1)] to give pure 4 (2.3 g, 87%). 1H NMR (CDCl3) δ 0.82 (t, 3H), 1.19-1.37 (m, 9H), 1.64-1.75 (d, 2H), 1.84-2.01 (m, 4H), 2.39-2.54 (m, 4H), 2.89-2.97 (d, 2H). In a 100 mL flask with a magnetic stirrer was placed The mixture was extracted with ethyl acetate (3×30 mL) the combined organic phases were evaporated to dryness to produce 3.9 of crude 4