Sodium hydride → HCID 66898649, compound

HRID 2369867Notes

Reaction equation

HRID 2369867 reaction equation
Cl.Cl.[NH2:3][C@@H:4]1[CH:9]2[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]2)[CH2:5]1.[H-].[Na+].O=[CH:15][CH2:16][CH2:17][N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[C:27]([O:29][CH3:30])=[O:28])[CH:20]=[CH:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCOCC1.C(O)(=O)C>[N:6]12[CH2:11][CH2:10][CH:9]([CH2:8][CH2:7]1)[C@@H:4]([NH:3][CH2:15][CH2:16][CH2:17][N:18]1[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[C:27]([O:29][CH3:30])=[O:28])[CH:20]=[CH:19]1)[CH2:5]2

Participants

7

Reactant 4

HCID 24758Sodium hydrideHCID 5049666Sodium triacetoxyborohydrideHCID 12494972(R)-(+)-3-Aminoquinuclidine DihydrochlorideHCID 86672697HCID 86672697, compound

Product 1

HCID 66898649HCID 66898649, compoundYield 77.4%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 312751,4-DioxaneSolvent2×

Conditions

Temperature
60 °C

Procedure

To a stirred solution of (R)-(+)-3-aminoquinuclidine dihydrochloride (287 mg, 1.4 mmol) in 1,4-dioxane (10 mL) was added 60% sodium hydride (86 mg, 3.6 mmol) in portions. The mixture was heated at 60° C. for 1 h and then a solution of methyl 1-(3-oxopropyl)-1H-indole-7-carboxylate (278 mg, 1.2 mmol) from Step B above in 1,4-dioxane (20 mL) was added, followed by glacial acetic acid (1% of total solvent used). The reaction mixture was stirred at 60° C. for 2 h and cooled to room temperature. Sodium triacetoxyborohydride (763 mg, 3.6 mmol) was then added in portions and the reaction mixture was stirred at room temperature for 4 h. The solvent was removed under reduced pressure and the crude material was purified by column chromatography (silica gel, 80:18:2 methylene chloride/methanol/concentrated ammonium hydroxide) to give (R)-methyl 1-(3-(quinuclidin-3-ylamino)propyl)-1H-indole-7-carboxylate (317 mg, 77%) as a yellow oil: 1H NMR (300 MHz, CD3OD) δ 7.78 (d, J=13.0 Hz, 1H), 7.62 (d, J=12.5 Hz, 1H), 7.30 (d, J=5.0 Hz, 1H), 7.10 (t, J=13.0 Hz, 1H), 6.56 (d, J=5.5 Hz, 1H), 4.49 (t, J=11.5 Hz, 2H), 3.96 (s, 3H), 3.07-2.99 (m, 1H), 2.82-2.65 (m, 5H), 2.44-2.27 (m, 3H), 1.89-1.64 (m, 5H), 1.53-1.32 (m, 2H).

Workup

  1. temperaturecooled to room temperature
  2. stirringthe reaction mixture was stirred at room temperature for 4 h
  3. customThe solvent was removed under reduced pressure
  4. customthe crude material was purified by column chromatography (silica gel, 80:18:2 methylene chloride/methanol/concentrated ammonium hydroxide)

Sources & evidence

ORD record
ord-a2b4f38ad0ba4963a835fa100337179f
Source dataset
uspto-grants-2014_04
Patent number
US08710046B2

Reaction notes

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