1-but-3-ynylpiperidine

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:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To the mixture of Pd(PPh3)Cl2 (24 mg, 0.034 mmol, 0.02 equiv.), CuI (13 mg, 0.068 mmol, 0.04 equiv.) and 3-bromobenzaldehyde (0.316 g, 1.7 mmol, 1 equiv.), pyrrolidine (10 mL) were added under N2. The use of pyrrolidine is preferred in the context of this synthesis. A stream of N2 was bubbled into to the solution for 5 min, and then 1-but-3-ynyl-piperidine (0.46 g, 3.3 mmol, 2 equiv.) was added. The reaction mixture was stirred at 50° C. for 40 h. This temperature is preferred in the context of this synthesis. On TLC and HPLC, the reaction was complete. The white precipitate (Et3N.HBr) was filtered and washed with EtOAc. The solvent was evaporated and the residue was re-dissolved in EtOAc. The organic layer was washed with aqueous NaOH (1N) twice, and dried over MgSO4. After filtration, the EtOAc solution was poured directly onto a short pad of silica gel (neutralized with 5% Et3N in hexanes) and washed with EtOAc. The solvent was evaporated to afford the product as a brown oil (0.35 g, 1.45 mmol, 86%); purity >95% on HPLC; MS M+H+242. This product does not need further purification in its use for subsequent steps in the context of this invention. A yield of 86% is in marked contrast with conventional methodologies, which produce the title compound with typical yields that do not exceed 30%. were added under N2 A stream of N2 was bubbled into to the solution for 5 min This temperature is preferred in the context of this synthesis The white precipitate (Et3N.HBr) was filtered washed with EtOAc The solvent was evaporated the residue was re-dissolved in EtOAc The organic layer was washed with aqueous NaOH (1N) twice dried over MgSO4 After filtration the EtOAc solution was poured directly onto a short pad of silica gel (neutralized with 5% Et3N in hexanes) washed with EtOAc The solvent was evaporated

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To the mixture of Pd(PPh3)Cl2 (24 mg, 0.034 mmol, 0.02 equiv.), CuI (13 mg, 0.068 mmol, 0.04 equiv.) and 3-bromobenzaldehyde (0.316 g, 1.7 mmol, 1 equiv.), pyrrolidine (10 mL) were added under N2. The use of pyrrolidine is preferred in the context of this synthesis. A stream of N2 was bubbled into to the solution for 5 min, and then 1-but-3-ynyl-piperidine (0.46 g, 3.3 mmol, 2 equiv.) was added. The reaction mixture was stirred at 50° C. for 40 h. This temperature is preferred in the context of this synthesis. On TLC and HPLC, the reaction was complete. The white precipitate (Et3N.HBr) was filtered and washed with EtOAc. The solvent was evaporated and the residue was re-dissolved in EtOAc. The organic layer was washed with aqueous NaOH (1N) twice, and dried over MgSO4. After filtration, the EtOAc solution was poured directly onto a short pad of silica gel (neutralized with 5% Et3N in hexanes) and washed with EtOAc. The solvent was evaporated to afford the product as a brown oil (0.35 g, 1.45 mmol, 86%); purity >95% on HPLC; MS M+H+242. This product does not need further purification in its use for subsequent steps in the context of this invention. A yield of 86% is in marked contrast with conventional methodologies, which produce the title compound with typical yields that do not exceed 30%. were added under N2 A stream of N2 was bubbled into to the solution for 5 min This temperature is preferred in the context of this synthesis The white precipitate (Et3N.HBr) was filtered washed with EtOAc The solvent was evaporated the residue was re-dissolved in EtOAc The organic layer was washed with aqueous NaOH (1N) twice dried over MgSO4 After filtration the EtOAc solution was poured directly onto a short pad of silica gel (neutralized with 5% Et3N in hexanes) washed with EtOAc The solvent was evaporated

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of toluene-4-sulfonic acid but-3-ynyl ester (45.0 g) and piperidine (40 mL) in ethanol (70 mL) was treated with a solution of potassium carbonate (27.8 g) in water (70 mL). The mixture was heated to 80° C. for 2 h, cooled to RT, and extracted with DCM (3×100 mL). The combined organic phases were dried (magnesium sulfate), and evaporated. Distillation of the residue (110° C., 30 mm Hg) gave the title compound as a colorless oil (17.3 g). cooled to RT extracted with DCM (3×100 mL) The combined organic phases were dried (magnesium sulfate) evaporated Distillation of the residue (110° C., 30 mm Hg)

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of toluene-4-sulfonic acid but-3-ynyl ester (45.0 g) and piperidine (40 mL) in ethanol (70 mL) was treated with a solution of potassium carbonate (27.8 g) in water (70 mL). The mixture was heated to 80° C. for 2 h, cooled to RT, and extracted with DCM (3×100 mL). The combined organic phases were dried (magnesium sulfate), and evaporated. Distillation of the residue (110° C., 30 mm Hg) gave the title compound as a colorless oil (17.3 g). cooled to RT extracted with DCM (3×100 mL) The combined organic phases were dried (magnesium sulfate) evaporated Distillation of the residue (110° C., 30 mm Hg)

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-(4-Piperidin-1-yl-but-1-ynyl)-5-piperidin-1-ylmethyl-pyridine. To a solution of trifluoro-methanesulfonic acid 5-piperidin-1-ylmethyl-pyridin-2-yl ester (0.10 g, 0.31 mmol), 1-but-3-ynyl-piperidine (0.051 g, 0.37 mmol), and TEA (2 mL) in dry DMF (1 mL) was added dichlorobis(triphenylphosphine)-palladium(II) (0.004 g, 0.006 mmol) and copper(I) iodide (0.004 g, 0.016 mmol). The reaction mixture was heated at 80° C. for 4 h, cooled to rt, diluted with DCM (25 mL), and filtered through a pad of diatomaceous earth. The mixture was diluted with 1 N NaOH (25 mL) and extracted with DCM (3×25 mL). The organic layers were combined, dried (Na2SO4), and concentrated, and chromatography of the resulting residue (SiO2: 3-6% 2 M NH3 in MeOH/DCM) gave the title compound (0.01 g, 10%). MS (ESI): exact mass calcd. for C20H29N3, 311.2; m/z found, 312.5 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.45 (d, J=2.0, 1H), 7.62 (d, J=8.3, 1H), 7.25 (d, J=8.1, 1H), 3.47 (s, 2H), 2.74-2.70 (m, 4H), 2.62-2.59 (m, 4H), 2.37 (br s, 4H), 1.65-1.55 (m, 8H), 1.46-1.44 (m, 4H). cooled to rt filtered through a pad of diatomaceous earth The mixture was diluted with 1 N NaOH (25 mL) extracted with DCM (3×25 mL) dried (Na2SO4) concentrated

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To the mixture of Pd(PPh3)Cl2 (24 mg, 0.034 mmol, 0.02 equiv.), CuI (13 mg, 0.068 mmol, 0.04 equiv.) and 3-bromobenzaldehyde (0.316 g, 1.7 mmol, 1 equiv.), pyrrolidine (10 mL) were added under N2. The use of pyrrolidine is preferred in the context of this synthesis. A stream of N2 was bubbled into to the solution for 5 min, and then 1-but-3-ynyl-piperidine (0.46 g, 3.3 mmol, 2 equiv.) was added. The reaction mixture was stirred at 50° C. for 40 h. This temperature is preferred in the context of this synthesis. On TLC and HPLC, the reaction was complete. The white precipitate (Et3N.HBr) was filtered and washed with EtOAc. The solvent was evaporated and the residue was re-dissolved in EtOAc. The organic layer was washed with aqueous NaOH (1N) twice, and dried over MgSO4. After filtration, the EtOAc solution was poured directly onto a short pad of silica gel (neutralized with 5% Et3N in hexanes) and washed with EtOAc. The solvent was evaporated to afford the product as a brown oil (0.35 g, 1.45 mmol, 86%); purity >95% on HPLC; MS M+H+242. This product does not need further purification in its use for subsequent steps in the context of this invention. A yield of 86% is in marked contrast with conventional methodologies, which produce the title compound with typical yields that do not exceed 30%. were added under N2 A stream of N2 was bubbled into to the solution for 5 min This temperature is preferred in the context of this synthesis The white precipitate (Et3N.HBr) was filtered washed with EtOAc The solvent was evaporated the residue was re-dissolved in EtOAc The organic layer was washed with aqueous NaOH (1N) twice dried over MgSO4 After filtration the EtOAc solution was poured directly onto a short pad of silica gel (neutralized with 5% Et3N in hexanes) washed with EtOAc The solvent was evaporated

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of toluene-4-sulfonic acid but-3-ynyl ester (45.0 g) and piperidine (40 mL) in ethanol (70 mL) was treated with a solution of potassium carbonate (27.8 g) in water (70 mL). The mixture was heated to 80° C. for 2 h, cooled to RT, and extracted with DCM (3×100 mL). The combined organic phases were dried (magnesium sulfate), and evaporated. Distillation of the residue (110° C., 30 mm Hg) gave the title compound as a colorless oil (17.3 g). cooled to RT extracted with DCM (3×100 mL) The combined organic phases were dried (magnesium sulfate) evaporated Distillation of the residue (110° C., 30 mm Hg)

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

実験手順: The title compound (13%) was prepared in a manner similar to that described in Example 18, Step D, using (6-bromo-pyridin-2-ylmethyl)-(2-methoxy-ethyl)-amine (0.300 g, 1.23 mmol) and 1-but-3-ynyl-piperidine (0.336 g, 2.45 mmol). MS (ESI): exact mass calcd. for C18H27N3O, 301.44; m/z found, 302.4 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.56 (t, 7.7, 1H), 7.26 (d, J=7.1, 1H), 7.23 (d, J=7.7, 1H), 3.90 (s, 2H), 3.52-3.45 (m, 2H), 3.34 (s, 3H), 2.80 J=5.2, 2H), 2.70-2.59 (m, 4H), 2.48-2.40 (m, 4H), 1.67-1.54 (m, 5H), 1.46-1.38 (m, 2H).