2-Methoxyethylamine → 2-(2-Methoxy-ethylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-benzamide

HRID 1875390Notes

Reaction equation

HRID 1875390 reaction equation
Br[C:2]1[CH:9]=[C:8]([N:10]2[C:18]3[CH2:17][C:16]([CH3:20])([CH3:19])[CH2:15][C:14](=[O:21])[C:13]=3[C:12]([CH3:22])=[CH:11]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:23][O:24][CH2:25][CH2:26][NH2:27].CC(C)([O-:31])C.[Na+]>C1(C)C=CC=CC=1.CS(C)=O.C(O)C.[OH-].[Na+].OO.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:23][O:24][CH2:25][CH2:26][NH:27][C:2]1[CH:9]=[C:8]([N:10]2[C:18]3[CH2:17][C:16]([CH3:20])([CH3:19])[CH2:15][C:14](=[O:21])[C:13]=3[C:12]([CH3:22])=[CH:11]2)[CH:7]=[CH:6][C:3]=1[C:4]([NH2:5])=[O:31]

Participants

11

Reactant 3

HCID 80182-MethoxyethylamineHCID 118539082-Bromo-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-benzonitrileHCID 23676156Sodium t-butoxide

Product 1

HCID 118539112-(2-Methoxy-ethylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-benzamideYield 85.2%

Reagents, catalysts & solvents 7

HCID 784Hydrogen PeroxideCatalystHCID 14798Sodium HydroxideCatalystHCID 167845palladium(II) acetateCatalystHCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)CatalystHCID 962WaterSolventHCID 1140TolueneSolventHCID 22338741Dimethylsulfoxide ethanolSolvent2×

Conditions

Temperature
115 °C

Procedure

A “Personal Chemistry” microwave vial was charged with the title compound of Example 2 (107.1 mg, 0.3 mmol), 2-methoxyethylamine (91.3 mg, 1.2 mmol), palladium (II) acetate (3.4 mg, 5 mol %), 1,1′-bis(diphenylphosphino)ferrocene (16.6 mg, 10 mol %), and sodium tert-butoxide (57.7 mg, 0.6 mmol). The reagents were suspended in toluene (2 mL) and were heated with microwave radiation to a temperature of 115° C. for fifteen minutes. After allowing the reaction vessel to cool, the suspension was filtered and the filtrate evaporated. After purifying the crude intermediate nitrile by flash chromatography, hydrolysis was performed by dissolving the residue in 25% dimethylsulfoxide/ethanol, adding 5 drops of 1 N sodium hydroxide and 5 drops of 30% aqueous hydrogen peroxide, followed by stirring at room temperature for 3 hours. The DMSO/ethanol mixture was then diluted with water and extracted with CH2Cl2 (3×). The combined organics were washed with brine (2×), dried over Na2SO4, and concentrated. The compound was purified by column chromatography (hexane/EtOAc) to yield the title compound (94.4 mg, 85% yield) of an off-white powder. LCMS m/z: (M+H) 370.2.

Workup

  1. temperatureto cool
  2. filtrationthe suspension was filtered
  3. customthe filtrate evaporated
  4. customAfter purifying the crude intermediate nitrile
  5. customby flash chromatography, hydrolysis
  6. extractionextracted with CH2Cl2 (3×)
  7. washThe combined organics were washed with brine (2×)
  8. dry with materialdried over Na2SO4
  9. concentrationconcentrated
  10. customThe compound was purified by column chromatography (hexane/EtOAc)

Sources & evidence

ORD record
ord-72bd7f72b75c4bceb3f130f1b1b43cb2
Source dataset
uspto-grants-2012_11
Patent number
US08309548B2

Reaction notes

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