2-Methylindole → HCID 11258293, compound

HRID 1713337Notes

Reaction equation

HRID 1713337 reaction equation
[CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Li]CCCC.CC(C)([O-])C.[K+].[F:22][C:23]([F:40])([F:39])[C:24](=[O:38])[CH2:25][C:26]1([CH3:37])[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([F:36])[CH:34]=2)[O:29][CH2:28][CH2:27]1>C(OCC)C.C1COCC1>[F:40][C:23]([F:22])([F:39])[C:24]([CH2:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2)([OH:38])[CH2:25][C:26]1([CH3:37])[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([F:36])[CH:34]=2)[O:29][CH2:28][CH2:27]1

Participants

7

Reactant 4

HCID 72242-MethylindoleHCID 23665647Potassium tert-butoxideHCID 57809915HCID 57809915, compoundHCID 178418339Butyllithium

Product 1

HCID 11258293HCID 11258293, compound

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolvent2×HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

To a chilled (−78° C.) solution of 95.0 mg (0.72 mmol) of 2-methylindole in 10 mL of diethyl ether was added 710 μL (1.77 mmol) of a 2.5 M solution of n-BuLi in hexanes. After 5 minutes, 1.16 mL (1.16 mmol) of a 1 M solution of potassium tert-butoxide in THF was added and the mixture was warmed until a yellow precipitate formed. After 20 minutes, the reaction was cooled to −78° C. and 200 mg (0.72 mmol) of 1,1,1-trifluoro-3-(6-fluoro-4-methylchroman-4-yl)propan-2-one (Example 1) in 2 mL of diethyl ether was added. The reaction stirred at −78° C. for 30 minutes and was then warmed to room temperature, quenched with saturated aqueous ammonium chloride and extracted with diethyl ether. The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified on a PLC plate with hexanes-EtOAc (8:2) to afford a mixture of two diastereomers. The diastereomers were separated on a PLC plate (hexanes-CH2Cl2 (1:1)) to give two diastereomer. One was purified again by PLC plate (hexanes-CH2Cl2 (1:1)) to afford 20 mg of the first diastereomer (M+1=408) and the second was triturated with hexanes and the solid collected by filtration to afford 15 mg of the other diastereomer (M+1=408) of the title compound.

Workup

  1. temperaturethe mixture was warmed until a yellow precipitate
  2. customformed
  3. waitAfter 20 minutes
  4. temperaturewas then warmed to room temperature
  5. customquenched with saturated aqueous ammonium chloride
  6. extractionextracted with diethyl ether
  7. dry with materialThe combined organic layers were dried over sodium sulfate
  8. concentrationconcentrated
  9. customThe residue was purified on a PLC plate with hexanes-EtOAc (8:2)
  10. customto afford
  11. additiona mixture of two diastereomers
  12. customThe diastereomers were separated on a PLC plate (hexanes-CH2Cl2 (1:1))
  13. customto give two diastereomer
  14. customOne was purified again by PLC plate (hexanes-CH2Cl2 (1:1))
  15. customto afford 20 mg of the first diastereomer (M+1=408)
  16. customthe second was triturated with hexanes
  17. filtrationthe solid collected by filtration

Sources & evidence

ORD record
ord-80c5a6692e9c4f6382ba405e038461b0
Source dataset
uspto-grants-2010_09
Patent number
US07795272B2

Reaction notes

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