Acetic Acid → methyl 1-(2-(quinuclidin-4-ylmethylamino)ethyl)-1H-indazole-7-carboxylate

HRID 2168558Notes

Reaction equation

HRID 2168558 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+].O=[CH:25][CH2:26][N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2[C:36]([O:38][CH3:39])=[O:37])[CH:29]=[N:28]1>CO>[N:3]12[CH2:10][CH2:9][C:6]([CH2:11][NH:12][CH2:25][CH2:26][N:27]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][C:34]=4[C:36]([O:38][CH3:39])=[O:37])[CH:29]=[N:28]3)([CH2:7][CH2:8]1)[CH2:5][CH2:4]2

Participants

7

Reactant 5

HCID 176Acetic AcidHCID 5003444Sodium cyanoborohydrideHCID 10942334Sodium MethoxideHCID 66891790Quinuclidin-4-ylmethanamine dihydrochlorideHCID 86672700methyl 1-(2-oxoethyl)-1H-indazole-7-carboxylate

Product 1

HCID 66899335methyl 1-(2-(quinuclidin-4-ylmethylamino)ethyl)-1H-indazole-7-carboxylateYield 39.1%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent2×

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).

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-5d67922e6f89487e836603b20d927832
Source dataset
uspto-grants-2015_06
Patent number
US09045501B2

Reaction notes

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