Acetic Acid → methyl 1-(4-methoxybenzyl)-3-(2-(quinuclidin-4-ylmethylamino)ethyl)-1H-indole-4-carboxylate

HRID 2369925Notes

Reaction equation

HRID 2369925 reaction equation
Cl.Cl.[N:3]12[CH2:10][CH2:9][C:6]([CH2:11][NH2:12])([CH2:7][CH2:8]1)[CH2:5][CH2:4]2.C[O-].[Na+].C(O)(=O)C.C([BH3-])#N.[Na+].[CH3:24][O:25][C:26]1[CH:49]=[CH:48][C:29]([CH2:30][N:31]2[C:39]3[CH:38]=[CH:37][CH:36]=[C:35]([C:40]([O:42][CH3:43])=[O:41])[C:34]=3[C:33]([CH2:44][CH2:45]C=O)=[CH:32]2)=[CH:28][CH:27]=1>CO>[CH3:24][O:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:30][N:31]2[C:39]3[CH:38]=[CH:37][CH:36]=[C:35]([C:40]([O:42][CH3:43])=[O:41])[C:34]=3[C:33]([CH2:44][CH2:45][NH:12][CH2:11][C:6]34[CH2:9][CH2:10][N:3]([CH2:8][CH2:7]3)[CH2:4][CH2:5]4)=[CH:32]2)=[CH:48][CH:49]=1

Participants

7

Reactant 5

HCID 176Acetic AcidHCID 5003444Sodium cyanoborohydrideHCID 10942334Sodium MethoxideHCID 66891790Quinuclidin-4-ylmethanamine dihydrochlorideHCID 86672720methyl 1-(4-methoxybenzyl)-3-(3-oxopropyl)-1H-indole-4-carboxylate

Product 1

HCID 66899061methyl 1-(4-methoxybenzyl)-3-(2-(quinuclidin-4-ylmethylamino)ethyl)-1H-indole-4-carboxylateYield 53%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent2×

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).

Workup

  1. stirringThe mixture was stirred at room temperature until the reaction
  2. customwas complete by TLC (1-2 h)
  3. concentrationThe reaction mixture was concentrated
  4. customabsorbed onto silica gel
  5. custompurified by column chromatography (80:18:2 methylene chloride/methanol/concentrated ammonium hydroxide)

Sources & evidence

ORD record
ord-eafb4293f0834870aef7757e9ecaf415
Source dataset
uspto-grants-2014_04
Patent number
US08710046B2

Reaction notes

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