Water → 6-bromo-3-fluoro-1-isopropyl-1H-indole-4-carboxylic acid

HRID 62431Notes

Reaction equation

HRID 62431 reaction equation
[Br:1][C:2]1[CH:3]=[C:4]([C:15]([O:17]C)=[O:16])[C:5]2[C:6]([F:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[OH-].[Li+].O.[Al]>O1CCCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]([C:15]([OH:17])=[O:16])[C:5]2[C:6]([F:14])=[CH:7][N:8]([CH:11]([CH3:12])[CH3:13])[C:9]=2[CH:10]=1

Participants

7

Reactant 4

HCID 962WaterHCID 3939Lithium HydroxideHCID 5359268AluminumHCID 67466589methyl 6-bromo-3-fluoro-1-isopropyl-1H-indole-4-carboxylate

Product 1

HCID 674645826-bromo-3-fluoro-1-isopropyl-1H-indole-4-carboxylic acidYield 76.2%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a 100 ml round bottom flask was added methyl 6-bromo-3-fluoro-1-isopropyl-1H-indole-4-carboxylate (33.0 mg, 0.105 mmol), Methanol (700 μl), Tetrahydrofuran (THF) (1401 μl) and a magnetic stir bar. To the same was added lithium hydroxide, H2O (13.22 mg, 0.315 mmol) and the mixture was stirred at room temperature. Reaction progress was monitored by LCMS. LCMS(18 h) showed 60% conversion. The reaction was heated to 50° C. in an aluminum heating block with stirring. After complete conversion the solvent was removed in-vacuo and the remaining residue was dissolved with water (1 ml) and 1N HCl was added dropwise (9 drops) until precipitation stopped. The fine pale-yellow solid was collected by vacuum filtration. LCMS and HPLC showed 100% purity and NMR supports the desired structure. The product, 6-bromo-3-fluoro-1-isopropyl-1H-indole-4-carboxylic acid (24 mg, 0.080 mmol, 76% yield), was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 13.07 (br. s., 1H), 8.12 (t, J=1.89 Hz, 1H), 7.77 (d, J=2.27 Hz, 1H), 7.66 (d, J=1.77 Hz, 1H), 4.88 (qd, J=5.31, 6.65 Hz, 1H), 1.40 (d, 6H). MS(ES) [M+H]+ 300.1.

Workup

  1. customReaction progress
  2. customLCMS(18 h)
  3. stirringwith stirring
  4. customAfter complete conversion the solvent was removed in-vacuo
  5. dissolutionthe remaining residue was dissolved with water (1 ml) and 1N HCl
  6. additionwas added dropwise (9 drops)
  7. customuntil precipitation
  8. filtrationThe fine pale-yellow solid was collected by vacuum filtration

Sources & evidence

ORD record
ord-eb70ecf00a3048d39786300359b10b9b
Source dataset
uspto-grants-2016_09
Patent number
US09446041B2

Reaction notes

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