Hydrochloric Acid → 3-methyl-1-(1-methylethyl)-6-(methyloxy)-1H-indole-4-carboxylic acid

HRID 873472Notes

Reaction equation

HRID 873472 reaction equation
Br[C:2]1[CH:3]=[C:4]([C:15]([O:17]C)=[O:16])[C:5]2[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:19][O-:20].[Na+].CO.Cl>O.CCOC(C)=O.[Cu]I.CN1C(=O)CCC1>[CH3:14][C:6]1[C:5]2[C:4]([C:15]([OH:17])=[O:16])=[CH:3][C:2]([O:20][CH3:19])=[CH:10][C:9]=2[N:8]([CH:11]([CH3:12])[CH3:13])[CH:7]=1

Participants

9

Reactant 4

HCID 313Hydrochloric AcidHCID 887MethanolHCID 10942334Sodium MethoxideHCID 67464634methyl 6-bromo-1-isopropyl-3-methyl-1H-indole-4-carboxylate

Product 1

HCID 674653313-methyl-1-(1-methylethyl)-6-(methyloxy)-1H-indole-4-carboxylic acidYield 80%

Reagents, catalysts & solvents 4

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 962WaterSolvent2×HCID 8857Ethyl AcetateSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
120 °C

Procedure

To methyl 6-bromo-3-methyl-1-(1-methylethyl)-1H-indole-4-carboxylate (1.3 g, 4.19 mmol) and copper(I) iodide (1.0 g, 5.25 mmol) was added NMP (8 mL). To the mixture was added dropwise a solution of sodium methoxide 25 wt % in methanol (4.0 mL, 17.49 mmol) with stirring. The reaction was heated to 120° C. and stirred for 1.5 hr. The reaction was allowed to cool and when the temperature reached 80° C., water (200 uL) was added. The reaction was allowed to continue to cool to RT and stirred overnight. The reaction was acidified with 1 N HCl (17 mL) and diluted with water and EtOAc. The mixture was filtered through Celite and washed with EtOAc. The filtrate was poured into a reparatory funnel and the organic phase was separated, washed with brine, dried (MgSO4), filtered, and concentrated under vacuum. Purification by silica gel chromatography (Analogix, SF25-60 g, 20 to 50% EtOAc in hexanes) gave after concentration, trituration with hexanes, filtration and drying under vacuum 3-methyl-1-(1-methylethyl)-6-(methyloxy)-1H-indole-4-carboxylic acid (825 mg, 3.34 mmol, 80% yield) as an light yellow solid. MS(ES)+m/e 248.3 [M+H]+.

Workup

  1. stirringstirred for 1.5 hr
  2. temperatureto cool
  3. customreached 80° C.
  4. temperatureto cool to RT
  5. stirringstirred overnight
  6. filtrationThe mixture was filtered through Celite
  7. washwashed with EtOAc
  8. additionThe filtrate was poured into a reparatory funnel
  9. customthe organic phase was separated
  10. washwashed with brine
  11. dry with materialdried (MgSO4)
  12. filtrationfiltered
  13. concentrationconcentrated under vacuum
  14. customPurification by silica gel chromatography (Analogix
  15. customSF25-60 g, 20 to 50% EtOAc in hexanes) gave
  16. concentrationafter concentration, trituration
  17. filtrationwith hexanes, filtration

Sources & evidence

ORD record
ord-c6e6dce8649b4d2f8e12ebadbb1047c0
Source dataset
uspto-grants-2015_03
Patent number
US08975291B2

Reaction notes

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