Hydrochloric Acid → 5-bromo-1-methyl-3-(1-methylethyl)-1H-indole-7-carboxylic acid

HRID 1616800Notes

Reaction equation

HRID 1616800 reaction equation
[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]([CH3:16])[CH3:15].I[CH3:18].[H-].[Na+].[OH-].[Na+].Cl>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=1)[N:7]([CH3:18])[CH:6]=[C:5]2[CH:14]([CH3:16])[CH3:15]

Participants

7

Reactant 5

HCID 313Hydrochloric AcidHCID 6328Methyl iodideHCID 14798Sodium HydroxideHCID 24758Sodium hydrideHCID 678183425-Bromo-3-isopropyl-1H-indole-7-carboxylic acid

Product 1

HCID 678162465-bromo-1-methyl-3-(1-methylethyl)-1H-indole-7-carboxylic acidYield 69.2%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a stirred solution of 5-bromo-3-(1-methylethyl)-1H-indole-7-carboxylic acid (4.1 g, 14.53 mmol) in DMF (100 mL) at 0° C. was added iodomethane (3.6 mL, 57.6 mmol) followed by sodium hydride 60% dispersion in oil (1.4 g, 35.0 mmol) portionwise over 15 minutes. The reaction was allowed to warm to RT and stirred for 2 h. The reaction was recooled to 0° C., carefully quenched with water (5 mL), and evaporated to near dryness under vacuum. The residue was taken up in MeOH (50 mL) then treated with 6 N NaOH (10 mL, 60.0 mmol). The reaction was heated to 60° C. and stirred for 4 h. After cooling to RT the reaction was concentrated to near dryness, diluted with water, acidified with 6 N HCl (10 mL, 60 mmol), extracted with CH2Cl2, dried (Na2SO4), filtered, and evaporated to dryness to give the crude acid as a brown solid. Purification by silica gel chromatography (Analogix, SF40-120 g, 0 to 50% EtOAc in hexanes) gave material which was triturated with hexanes, filtered and dried under vacuum to give the product 5-bromo-1-methyl-3-(1-methylethyl)-1H-indole-7-carboxylic acid (2.98 g, 10.06 mmol, 69.2% yield) as a white solid. MS (ES)+ m/e 296.3 [M+H]+.

Workup

  1. customwas recooled to 0° C.
  2. customcarefully quenched with water (5 mL)
  3. customevaporated
  4. temperatureThe reaction was heated to 60° C.
  5. stirringstirred for 4 h
  6. temperatureAfter cooling to RT the reaction
  7. concentrationwas concentrated
  8. additiondiluted with water
  9. extractionextracted with CH2Cl2
  10. dry with materialdried (Na2SO4)
  11. filtrationfiltered
  12. customevaporated to dryness
  13. customto give the crude acid as a brown solid
  14. customPurification by silica gel chromatography (Analogix
  15. customSF40-120 g, 0 to 50% EtOAc in hexanes) gave material which
  16. customwas triturated with hexanes
  17. filtrationfiltered
  18. customdried under vacuum

Sources & evidence

ORD record
ord-88f83c16050f4feeb14a630b8d4e744e
Source dataset
uspto-grants-2014_07
Patent number
US08765792B2

Reaction notes

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