N-benzylpiperidine-4-carboxamide

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Piperidinecarboxamide (10.2 g, 78.0 mmol) in DMSO (10 mL) was treated with benzyl bromide (20.0 mL, 168 mmol). The mixture was diluted with EtOAc and washed with 1N aq. HCl, 5N aq. NaOH, dried over MgSO4, and concentrated to give 5.90 g (35%) of N-benzyl-4-piperidinecarboxamide. [1H]-NMR(CDCl3) consistent with structure. washed with 1N aq. HCl, 5N aq. NaOH dried over MgSO4 concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Piperidinecarboxamide (10.2 g, 78.0 mmol) in DMSO (10 mL) was treated with benzyl bromide (20.0 mL, 168 mmol). The mixture was diluted with EtOAc and washed with 1N aq. HCl, 5N aq. NaOH, dried over MgSO4, and concentrated to give 5.90 g (35%) of N-benzyl-4-piperidinecarboxamide. [1H]-NMR(CDCl3) consistent with structure. washed with 1N aq. HCl, 5N aq. NaOH dried over MgSO4 concentrated

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of N-benzylisonipecotamide (7.34g, 34 mmol) in 60 mL of anhydrous THF, was added, LiAlH4 (1.9 g, 51 mmol) and the mixture was stirred at room temperature for 10 minutes followed by heating to reflux for 3 h. The reaction was quenched by addition of 100 mL sat'd. sodium potassium tartrate, and was extracted with EtOAc (3×50 mL). The combined extracts were washed with 20 mL water and 20 mL brine then dried over MgSO4, filtered and concentrated to give the desired product. 1H-NMR (400 MHz, CDCl3) δ7.13 (m, 5H), 3.42 (s, 2H), 2H), 2.91 (m, 2H), 2.59 (m, 2H), 1.97 (m, 2H), 1.62 (m, 2H), 2.21 (m, 5H). by heating to reflux for 3 h The reaction was quenched by addition of 100 mL sodium potassium tartrate, and was extracted with EtOAc (3×50 mL) The combined extracts were washed with 20 mL water and 20 mL brine then dried over MgSO4 filtered concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of isonipecotamide (12.3 g, 96 mmol) in 200 mL of dichloromethane, was added, benzaldehyde (10.6 g, 100 mmol) and sodium triacetoxyborohydride (29.7 gm, 140 mmol) and the mixture was stirred at room temperature for 5 days. The thick white mixture was diluted with 100 mL water and extracted with EtOAc (2×20 mL). The aqueous phase was basified with 1N NaOH to pH>12. The resulting white precipitate was collected by suction filtration. The white solid was subsequently taken up in 50 mL of EtOAc, and was washed with 20 mL of brine, then dried (MgSO4), filtered and concentrated to give 10.84 g (50%) of the desired product. 1H-NMR (400 MHz, CDCl3) δ7.85 (m, 5H), 5.45 (s, 1H), 5.34 (s, 1H), 3.5 (s, 2H), 2.93 (d, J=10.96 Hz, 2H), 2.16 (t, J=12.13 Hz, 1H), 2.01 (t, J=11.74 Hz, 2H), 1.87 (d, J=12.52 Hz, 2H), 1.76 (q, J=12.52 Hz, 2H). was added extracted with EtOAc (2×20 mL) The resulting white precipitate was collected by suction filtration was washed with 20 mL of brine dried (MgSO4) filtered concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of N-benzylisonipecotamide (7.34 g, 34 mmol) in 60 mL of anhydrous THF, was added, LiAlH4 (1.9 g, 51 mmol) and the mixture was stirred at room temperature for 10 minutes followed by heating to reflux for 3 h. The reaction was quenched by addition of 100 mL sat'd. sodium potassium tartrate, and was extracted with EtOAc (3×50 mL). The combined extracts were washed with 20 mL water and 20 mL brine then dried over MgSO4, filtered and concentrated to give the desired product. 1H-NMR (400 MHz, CDCl3) δ 7-13 (m, 5H), 3.42 (s, 2H), 2.91 (m, 2H), 2.59 (m, 2H), 1.97 (m, 2H), 1.62 (m, 2H), 2.21 (m, 5H). by heating to reflux for 3 h The reaction was quenched by addition of 100 mL sodium potassium tartrate, and was extracted with EtOAc (3×50 mL) The combined extracts were washed with 20 mL water and 20 mL brine then dried over MgSO4 filtered concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of isonipecotamide (12.3 g, 96 mmol) in 200 mL of dichloromethane, was added, benzaldehyde (10.6 g, 100 mmol) and sodium triacetoxyborohydride (29.7 gm, 140 mmol) and the mixture was stirred at room temperature for 5 days. The thick white mixture was diluted with 100 mL water and extracted with EtOAc (2×20 mL) The aqueous phase was basified with 1N NaOH to pH 22 12. The resulting white precipitate was collected by suction filtration. The white solid was subsequently taken up in 50 mL of EtOAc, and was washed with 20 mL of brine, then dried (MgSO4), filtered and concentrated to give 10.84 g (50%) of the desired product. was added extracted with EtOAc (2×20 mL) The aqueous phase The resulting white precipitate was collected by suction filtration was washed with 20 mL of brine dried (MgSO4) filtered concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The following was added to sequentially to DMF (3 mL): 1-(4-chlorobenzyl)-3-methyl-1H-indole-2-carboxylic acid (90 mg, 0.315 mmol), DIPEA (0.170 mL, 0.945 mmol), and HATU (144 mg, 0.378 mmol). This was allowed to stir for 30 min at rt, after which time the crude N-benzylpiperidine-4-carboxamide (˜70 mg, 0.315 mmol) was added. The reaction was stirred at rt for 17 h, at which time the reaction was diluted with 1:1 EtOAc:diethyl ether and washed with 10% aq. sodium carbonate (2×), dried over magnesium sulfate, and concentrated. The residue was purified via silica gel flash chromatography (20 g silica, 50% EtOAc/Hexanes) to afford the title compound as an oil. Yield: (77 mg, 0.153 mmol, 51%) 1H NMR (400 MHz, CDCl3) 7.59, 7.34-7.14, 7.03, 5.73, 5.57, 5.43-5.32, 4.76, 4.43, 3.77-3.64, 3.10, 2.80, 2.19-1.52 The reaction was stirred at rt for 17 h, at which time the reaction diethyl ether and washed with 10% aq. sodium carbonate (2×) dried over magnesium sulfate concentrated The residue was purified via silica gel flash chromatography (20 g silica, 50% EtOAc/Hexanes)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The following was added to sequentially to DMF (2 mL): 1-(4-chlorobenzyl)-7-methyl-1H-indole-2-carboxylic acid (50 mg, 0.167 mmol), DIPEA (0.10 mL, 0.584 mmol), EDC (38 mg, 0.200 mmol), and HOBT (31 mg, 0.200 mmol). This was allowed to stir for 30 min at rt, after which time the crude N-benzylpiperidine-4-carboxamide (˜36 mg, 0.20 mmol) was added. The reaction was stirred at rt for 18 h, at which time the reaction was diluted with 1:1 EtOAc:diethyl ether and washed with 10% aq. sodium carbonate (2×), dried over magnesium sulfate, and concentrated. The residue was purified via silica gel flash chromatography (20 g silica, 50% EtOAc/Hexanes) to afford the title compound as a white powder. (Yield: 39 mg, 0.078 mmol, 47%) 1H NMR (400 MHz, CDCl3) 7.50, 7.38-7.26, 7.18, 7.05-6.97, 6.81, 6.63, 5.72, 5.66-5.57, 4.70-3.89, 4.44, 2.86-2.66, 2.57, 2.32-2.23, 1.77 The reaction was stirred at rt for 18 h, at which time the reaction diethyl ether and washed with 10% aq. sodium carbonate (2×) dried over magnesium sulfate concentrated The residue was purified via silica gel flash chromatography (20 g silica, 50% EtOAc/Hexanes)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Piperidinecarboxamide (10.2 g, 78.0 mmol) in DMSO (10 mL) was treated with benzyl bromide (20.0 mL, 168 mmol). The mixture was diluted with EtOAc and washed with 1N aq. HCl, 5N aq. NaOH, dried over MgSO4, and concentrated to give 5.90 g (35%) of N-benzyl-4-piperidinecarboxamide. [1H]-NMR(CDCl3) consistent with structure. washed with 1N aq. HCl, 5N aq. NaOH dried over MgSO4 concentrated