Potassium Carbonate → 6-(4-Hydroxy-piperidin-1-yl)-1-methyl-1H-indole-3-carboxylic acid methyl ester

HRID 1689770Notes

Reaction equation

HRID 1689770 reaction equation
[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[N:7]([CH3:15])[CH:6]=1)=[O:4].[OH:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.N1CCC[C@H]1C(O)=O.C(=O)([O-])[O-].[K+].[K+]>[Cu]I>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([N:20]3[CH2:21][CH2:22][CH:17]([OH:16])[CH2:18][CH2:19]3)=[CH:11][CH:12]=2)[N:7]([CH3:15])[CH:6]=1)=[O:4]

Participants

6

Reactant 4

HCID 11430Potassium CarbonateHCID 79341Piperidin-4-olHCID 145742L-ProlineHCID 57443279Methyl 6-bromo-1-methyl-1H-indole-3-carboxylate

Product 1

HCID 669061336-(4-Hydroxy-piperidin-1-yl)-1-methyl-1H-indole-3-carboxylic acid methyl esterYield 59.1%

Reagents, catalysts & solvents 1

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)Catalyst

Conditions

Temperature
110 °C

Procedure

A re-sealable tube is charged with 6-bromo-1-methyl-1H-indole-3-carboxylic acid methyl ester (850 mg, 1.00 equiv, 3.17 mmol), 4-hydroxypiperidine (491 mg, 1.5 equiv, 4.76 mmol), copper(I) iodide (60.379 mg, 0.1 equiv, 0.32 mmole), proline (73 mg, 0.2 equiv, 0.64 mmol) and potassium carbonate (885 mg, 2 equiv, 6.34 mmol) and purged with nitrogen. Anhydrous dimethyl sulfoxide (2 mL) is added. The tube is closed and the mixture is stirred at 110° C. for 22 h. The mixture is allowed to reach room temperature and aqueous saturated NH4Cl is added. The mixture is extracted with EtOAc (2×). The organic layers are combined, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified via chromatography (40 g silica) eluting with a gradient of 20% to 100% ethyl acetate/hexane to provide the title compound (540 mg, 59%) as a white solid. ES/MS m/z 289.0 (M+1)

Workup

  1. custompurged with nitrogen
  2. additionAnhydrous dimethyl sulfoxide (2 mL) is added
  3. customThe tube is closed
  4. customto reach room temperature
  5. additionaqueous saturated NH4Cl is added
  6. extractionThe mixture is extracted with EtOAc (2×)
  7. washwashed with water
  8. dry with materialdried over anhydrous sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated under reduced pressure
  11. customThe residue is purified via chromatography (40 g silica)
  12. washeluting with a gradient of 20% to 100% ethyl acetate/hexane

Sources & evidence

ORD record
ord-618796f5887541bea9eb024c987328d4
Source dataset
uspto-grants-2012_04
Patent number
US08153624B2

Reaction notes

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