Ethyl Acetate → 1-Methyl-3-(1-methylethyl)-5-(4-morpholinyl)-1H-indole-7-carboxylic acid

HRID 1616812Notes

Reaction equation

HRID 1616812 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13]C)=[O:12])[CH:10]=1)[N:7]([CH3:15])[CH:6]=[C:5]2[CH:16]([CH3:18])[CH3:17].CS(O)=O.[Na].[CH3:24][CH2:25][O:26][C:27]([CH3:29])=O.C[N:31]1CCCC1=O>[Cu]I>[CH3:15][N:7]1[C:8]2[C:4](=[CH:3][C:2]([N:31]3[CH2:29][CH2:27][O:26][CH2:25][CH2:24]3)=[CH:10][C:9]=2[C:11]([OH:13])=[O:12])[C:5]([CH:16]([CH3:18])[CH3:17])=[CH:6]1

Participants

7

Reactant 5

HCID 8857Ethyl AcetateHCID 13387N-methyl-2-pyrrolidoneHCID 87251Methanesulfinic acidHCID 5360545SodiumHCID 67816097Methyl 5-bromo-3-isopropyl-1-methyl-1H-indole-7-carboxylate

Product 1

HCID 678144821-Methyl-3-(1-methylethyl)-5-(4-morpholinyl)-1H-indole-7-carboxylic acidYield 62.2%

Reagents, catalysts & solvents 1

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

Conditions

Temperature
150 °C

Procedure

Methyl 5-bromo-3-isopropyl-1-methyl-1H-indole-7-carboxylate (502 mg, 1.62 mmol), methanesulfinic acid, Sodium salt (811 mg, 7.9 mmol) and copper(I) iodide 1.51 g, 7.9 mmol) were suspended in N-Methyl-2-pyrrolidone (5 mL) in a sealed vial and the mixture was stirred at 150° C. for 10 hours. The suspension was cooled down, EtOAc was added and insoluble materials were removed by filtration. The filtrate was extracted with EtOAc and DCM and the combined organics were washed with brine, dried over MgSO4, filtered and the solvent evaporated. The residue was purified using normal phase chromatography Hexanes/EtOAc (gradient 0 to 100% EtOAc). Solids that crashed out were filtered, air-dried for 15 min and dried in vacuum-oven overnight to give 1-methyl-3-(1-methylethyl)-5-(4-morpholinyl)-1H-indole-7-carboxylic acid (125 mg, 62.2% yield). EtOAc was added along with some hexanes, it was sonicated, the solids that crashed out were filtered, air-dried for 15 min and dried in vacuum-oven overnight to give methyl 3-isopropyl-1-methyl-5-(methylsulfonyl)-1H-indole-7-carboxylate (198 mg, 39%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.31 (s, 3H) 1.33 (s, 3H) 3.22-3.28 (m, 4H) 3.82 (s, 3H) 3.96 (s, 3H) 7.43 (s, 1H) 7.99 (d, J=1.77 Hz, 1H) 8.32 (d, J=1.77 Hz, 1H). MS (ES) [M+H]+ 310.1.

Workup

  1. temperatureThe suspension was cooled down
  2. custominsoluble materials were removed by filtration
  3. extractionThe filtrate was extracted with EtOAc and DCM
  4. washthe combined organics were washed with brine
  5. dry with materialdried over MgSO4
  6. filtrationfiltered
  7. customthe solvent evaporated
  8. customThe residue was purified
  9. filtrationSolids that crashed out were filtered
  10. customair-dried for 15 min
  11. customdried in vacuum-oven overnight

Sources & evidence

ORD record
ord-0486672d983b4297ac0b008f108fb61a
Source dataset
uspto-grants-2014_07
Patent number
US08765792B2

Reaction notes

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