Carbon Dioxide → 5-chloro-6-fluoro-1H-indole-7-carboxylic acid

HRID 855209Notes

Reaction equation

HRID 855209 reaction equation
[Li]CCCC.CCCCCC.[Cl:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[F:22])[NH:18][CH:17]=[CH:16]2.CC([O-])(C)C.[K+].[C:29](=[O:31])=[O:30]>C1COCC1.O>[Cl:12][C:13]1[CH:14]=[C:15]2[C:19](=[C:20]([C:29]([OH:31])=[O:30])[C:21]=1[F:22])[NH:18][CH:17]=[CH:16]2

Participants

8

Reactant 5

HCID 280Carbon DioxideHCID 8058HexaneHCID 27736475-chloro-6-fluoro-1H-indoleHCID 23665647Potassium tert-butoxideHCID 178418339Butyllithium

Product 1

HCID 251136475-chloro-6-fluoro-1H-indole-7-carboxylic acid

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
10 °C

Procedure

35 ml THF was cooled down to −75° C. under argon and 19.05 ml of a 1.6M solution of n-BuLi in hexane (30.5 mmol) were added. Then a solution of 2.35 g of 5-chloro-6-fluoro-1H-indole (13.7 mmol) in 9 ml THF was added dropwise (temperature kept between −70 and −75° C.) over 15 min. After 5 additional min stirring at this temperature a solution of 3.7 g potassium tert-butylate in 15 ml THF was added over 10 min (temperature kept between −70 and −75° C.). The brown solution was stirred 2 h at the same temperature and then treated with a large excess of solid CO2. The temperature was then raised to 10° C. over a period of 75 min, and treated with 30 ml water. After separation of the organic phase, the aqueous phase was extracted with 2×20 ml diethylether, treated with concentrated HCl until pH 1. The suspension was then filtered, the solid washed with water and dried in high vacuo. The residue was stirred with 10 ml hexane/diethylether 9:1 for 15 min and filtered, washed with 5 ml of the same mixture and the collected solid dried in high vacuo, leading to 2.2 g of 5-chloro-6-fluoro-1H-indole-7-carboxylic acid as a light brown solid (75%). MS: 212.2 (M−H)−.

Workup

  1. additionwas added over 10 min (temperature kept between −70 and −75° C.)
  2. customAfter separation of the organic phase
  3. extractionthe aqueous phase was extracted with 2×20 ml diethylether
  4. additiontreated with concentrated HCl until pH 1
  5. filtrationThe suspension was then filtered
  6. washthe solid washed with water
  7. customdried in high vacuo
  8. stirringThe residue was stirred with 10 ml hexane/diethylether 9:1 for 15 min
  9. filtrationfiltered
  10. washwashed with 5 ml of the same mixture
  11. customthe collected solid dried in high vacuo

Sources & evidence

ORD record
ord-388fcf3a043b4d23884f259d1bb7d1f4
Source dataset
uspto-grants-2007_08
Patent number
US07259183B2

Reaction notes

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