1-azabicyclo[2.2.2]octan-4-ylmethanamine;dihydrochloride

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

Procedure: To a stirred solution of quinuclidin-4-ylmethanamine dihydrochloride (894 mg, 4.2 mmol) in methanol (12 mL) at room temperature was added sodium methoxide (25 wt % in MeOH, 1.8 mL, 8.4 mmol) dropwise. The reaction was stirred at room temperature for 1 h and then glacial acetic acid (0.6 mL, 9.7 mmol) was added to neutralize the basicity of the mixture. Sodium cyanoborohydride (528 mg, 8.4 mmol) was added, followed by a solution of methyl 1-(2-oxoethyl)-1H-indazole-7-carboxylate (920 mg, 4.2 mmol) from Step E above in methanol (10 mL). The mixture was stirred at room temperature until the reaction was complete by TLC (1-2 h). The reaction mixture was concentrated, absorbed onto silica gel, and purified by column chromatography (80:18:2 methylene chloride/methanol/concentrated ammonium hydroxide) to afford methyl 1-(2-(quinuclidin-4-ylmethylamino)ethyl)-1H-indazole-7-carboxylate as a yellow oil (563 mg, 39%): 1H NMR (300 MHz, CD3OD) δ 8.26 (s, 1H), 8.09-8.03 (m, 2H), 7.27 (t, J=7.2 Hz, 1H), 4.95 (t, J=5.7 Hz, 2H), 4.01 (s, 3H), 3.50-3.44 (m, 2H), 3.39 (t, J=7.8 Hz, 6H), 2.93 (s, 2H), 1.85 (t, J=8.1 Hz, 6H). The mixture was stirred at room temperature until the reaction was complete by TLC (1-2 h) The reaction mixture was concentrated absorbed onto silica gel purified by column chromatography (80:18:2 methylene chloride/methanol/concentrated ammonium hydroxide)

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

Procedure: To a solution of quinuclidin-4-ylmethanamine dihydrochloride (433 mg, 2.0 mmol) in MeOH (20 mL) at room temperature was added sodium methoxide (25 wt % in MeOH, 0.9 mL, 4.1 mmol) dropwise. The reaction mixture was stirred at room temperature for 1 h and then glacial acetic acid (0.3 mL, 4.7 mmol) was added to neutralize the basicity of the mixture. Sodium cyanoborohydride (255 mg, 4.1 mmol) was added, followed by methyl 1-(4-methoxybenzyl)-3-(2-oxoethyl)-1H-indole-4-carboxylate (691 mg, 2.4 mmol) from Step C above in MeOH (25 mL). The mixture was stirred at room temperature until the reaction was complete by TLC (1-2 h). The reaction mixture was concentrated, absorbed onto silica gel, and purified by column chromatography (80:18:2 methylene chloride/methanol/concentrated ammonium hydroxide) to afford methyl 1-(4-methoxybenzyl)-3-(2-(quinuclidin-4-ylmethylamino)ethyl)-1H-indole-4-carboxylate as colourless oil (53%): 1H NMR (300 MHz, CD3OD) δ 7.62 (d, J=8.1 Hz, 1H), 7.58 (d, J=7.5 Hz, 1H), 7.29 (s, 1H), 7.20-7.07 (m, 3H), 6.84 (d, J=6.0 Hz, 2H), 5.31 (s, 2H), 3.93 (s, 3H), 3.74 (s, 3H), 3.13 (t, J=7.2 Hz, 2H), 2.95 (t, J=7.8 Hz, 6H), 2.84 (t, J=7.2 Hz, 2H), 2.44 (s, 2H), 1.46 (t, J=7.8 Hz, 6H); MS (ESI+) m/z 462 (M+H). The mixture was stirred at room temperature until the reaction was complete by TLC (1-2 h) The reaction mixture was concentrated absorbed onto silica gel purified by column chromatography (80:18:2 methylene chloride/methanol/concentrated ammonium hydroxide)

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

Procedure: To a solution of quinuclidin-4-ylmethanamine dihydrochloride (433 mg, 2.0 mmol) in MeOH (20 mL) at room temperature was added sodium methoxide (25 wt % in MeOH, 0.9 mL, 4.1 mmol) dropwise. The reaction mixture was stirred at room temperature for 1 h and then glacial acetic acid (0.3 mL, 4.7 mmol) was added to neutralize the basicity of the mixture. Sodium cyanoborohydride (255 mg, 4.1 mmol) was added, followed by methyl 1-(4-methoxybenzyl)-3-(2-oxoethyl)-1H-indole-4-carboxylate (691 mg, 2.4 mmol) from Step C above in MeOH (25 mL). The mixture was stirred at room temperature until the reaction was complete by TLC (1-2 h). The reaction mixture was concentrated, absorbed onto silica gel, and purified by column chromatography (80:18:2 methylene chloride/methanol/concentrated ammonium hydroxide) to afford methyl 1-(4-methoxybenzyl)-3-(2-(quinuclidin-4-ylmethylamino)ethyl)-1H-indole-4-carboxylate as colourless oil (53%): 1H NMR (300 MHz, CD3OD) δ 7.62 (d, J=8.1 Hz, 1H), 7.58 (d, J=7.5 Hz, 1H), 7.29 (s, 1H), 7.20-7.07 (m, 3H), 6.84 (d, J=6.0 Hz, 2H), 5.31 (s, 2H), 3.93 (s, 3H), 3.74 (s, 3H), 3.13 (t, J=7.2 Hz, 2H), 2.95 (t, J=7.8 Hz, 6H), 2.84 (t, J=7.2 Hz, 2H), 2.44 (s, 2H), 1.46 (t, J=7.8 Hz, 6H); MS (ESI+) m/z 462 (M+H). The mixture was stirred at room temperature until the reaction was complete by TLC (1-2 h) The reaction mixture was concentrated absorbed onto silica gel purified by column chromatography (80:18:2 methylene chloride/methanol/concentrated ammonium hydroxide)

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

Procedure: To a solution of quinuclidin-4-ylmethanamine dihydrochloride (433 mg, 2.0 mmol) in MeOH (20 mL) at room temperature was added sodium methoxide (25 wt % in MeOH, 0.9 mL, 4.1 mmol) dropwise. The reaction mixture was stirred at room temperature for 1 h and then glacial acetic acid (0.3 mL, 4.7 mmol) was added to neutralize the basicity of the mixture. Sodium cyanoborohydride (255 mg, 4.1 mmol) was added, followed by methyl 1-(4-methoxybenzyl)-3-(2-oxoethyl)-1H-indole-4-carboxylate (691 mg, 2.4 mmol) from Step C above in MeOH (25 mL). The mixture was stirred at room temperature until the reaction was complete by TLC (1-2 h). The reaction mixture was concentrated, absorbed onto silica gel, and purified by column chromatography (80:18:2 methylene chloride/methanol/concentrated ammonium hydroxide) to afford methyl 1-(4-methoxybenzyl)-3-(2-(quinuclidin-4-ylmethylamino)ethyl)-1H-indole-4-carboxylate as colourless oil (53%): 1H NMR (300 MHz, CD3OD) δ 7.62 (d, J=8.1 Hz, 1H), 7.58 (d, J=7.5 Hz, 1H), 7.29 (s, 1H), 7.20-7.07 (m, 3H), 6.84 (d, J=6.0 Hz, 2H), 5.31 (s, 2H), 3.93 (s, 3H), 3.74 (s, 3H), 3.13 (t, J=7.2 Hz, 2H), 2.95 (t, J=7.8 Hz, 6H), 2.84 (t, J=7.2 Hz, 2H), 2.44 (s, 2H), 1.46 (t, J=7.8 Hz, 6H); MS (ESI+) m/z 462 (M+H). The mixture was stirred at room temperature until the reaction was complete by TLC (1-2 h) The reaction mixture was concentrated absorbed onto silica gel purified by column chromatography (80:18:2 methylene chloride/methanol/concentrated ammonium hydroxide)

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

Procedure: To a stirred solution of quinuclidin-4-ylmethanamine dihydrochloride (894 mg, 4.2 mmol) in methanol (12 mL) at room temperature was added sodium methoxide (25 wt % in MeOH, 1.8 mL, 8.4 mmol) dropwise. The reaction was stirred at room temperature for 1 h and then glacial acetic acid (0.6 mL, 9.7 mmol) was added to neutralize the basicity of the mixture. Sodium cyanoborohydride (528 mg, 8.4 mmol) was added, followed by a solution of methyl 1-(2-oxoethyl)-1H-indazole-7-carboxylate (920 mg, 4.2 mmol) from Step E above in methanol (10 mL). The mixture was stirred at room temperature until the reaction was complete by TLC (1-2 h). The reaction mixture was concentrated, absorbed onto silica gel, and purified by column chromatography (80:18:2 methylene chloride/methanol/concentrated ammonium hydroxide) to afford methyl 1-(2-(quinuclidin-4-ylmethylamino)ethyl)-1H-indazole-7-carboxylate as a yellow oil (563 mg, 39%): 1H NMR (300 MHz, CD3OD) δ 8.26 (s, 1H), 8.09-8.03 (m, 2H), 7.27 (t, J=7.2 Hz, 1H), 4.95 (t, J=5.7 Hz, 2H), 4.01 (s, 3H), 3.50-3.44 (m, 2H), 3.39 (t, J=7.8 Hz, 6H), 2.93 (s, 2H), 1.85 (t, J=8.1 Hz, 6H). The mixture was stirred at room temperature until the reaction was complete by TLC (1-2 h) The reaction mixture was concentrated absorbed onto silica gel purified by column chromatography (80:18:2 methylene chloride/methanol/concentrated ammonium hydroxide)

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

Procedure: To a solution of quinuclidin-4-ylmethanamine dihydrochloride (433 mg, 2.0 mmol) in MeOH (20 mL) at room temperature was added sodium methoxide (25 wt % in MeOH, 0.9 mL, 4.1 mmol) dropwise. The reaction mixture was stirred at room temperature for 1 h and then glacial acetic acid (0.3 mL, 4.7 mmol) was added to neutralize the basicity of the mixture. Sodium cyanoborohydride (255 mg, 4.1 mmol) was added, followed by methyl 1-(4-methoxybenzyl)-3-(2-oxoethyl)-1H-indole-4-carboxylate (691 mg, 2.4 mmol) from Step C above in MeOH (25 mL). The mixture was stirred at room temperature until the reaction was complete by TLC (1-2 h). The reaction mixture was concentrated, absorbed onto silica gel, and purified by column chromatography (80:18:2 methylene chloride/methanol/concentrated ammonium hydroxide) to afford methyl 1-(4-methoxybenzyl)-3-(2-(quinuclidin-4-ylmethylamino)ethyl)-1H-indole-4-carboxylate as colourless oil (53%): 1H NMR (300 MHz, CD3OD) δ 7.62 (d, J=8.1 Hz, 1H), 7.58 (d, J=7.5 Hz, 1H), 7.29 (s, 1H), 7.20-7.07 (m, 3H), 6.84 (d, J=6.0 Hz, 2H), 5.31 (s, 2H), 3.93 (s, 3H), 3.74 (s, 3H), 3.13 (t, J=7.2 Hz, 2H), 2.95 (t, J=7.8 Hz, 6H), 2.84 (t, J=7.2 Hz, 2H), 2.44 (s, 2H), 1.46 (t, J=7.8 Hz, 6H); MS (ESI+) m/z 462 (M+H). The mixture was stirred at room temperature until the reaction was complete by TLC (1-2 h) The reaction mixture was concentrated absorbed onto silica gel purified by column chromatography (80:18:2 methylene chloride/methanol/concentrated ammonium hydroxide)