Trifluoroacetic acid → 2-[(4-Chloro-2-fluorophenyl){5-fluoro-7-[(methylsulfonyl)methyl]-1H-indol-3-yl}methyl]cyclopropanecarbonitrile

HRID 561692Notes

Reaction equation

HRID 561692 reaction equation
[Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19](O)[CH:20]2[CH2:22][CH:21]2[C:23]#[N:24])=[C:15]([F:26])[CH:14]=1.[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[C:35]([CH2:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:36]=1)[NH:33][CH:32]=[CH:31]2>ClCCl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:31]2[C:30]3[C:34](=[C:35]([CH2:37][S:38]([CH3:41])(=[O:39])=[O:40])[CH:36]=[C:28]([F:27])[CH:29]=3)[NH:33][CH:32]=2)[CH:20]2[CH2:22][CH:21]2[C:23]#[N:24])=[C:15]([F:26])[CH:14]=1

Participants

6

Reactant 4

HCID 6422Trifluoroacetic acidHCID 159675indium(III)chlorideHCID 583922222-[(4-Chloro-2-fluorophenyl)(hydroxy)methyl]cyclopropanecarbonitrileHCID 583923185-Fluoro-7-[(methylsulfonyl)methyl]-1H-indole

Product 1

HCID 445484752-[(4-Chloro-2-fluorophenyl){5-fluoro-7-[(methylsulfonyl)methyl]-1H-indol-3-yl}methyl]cyclopropanecarbonitrile

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

471 mg (2.13 mmol) of indium(III) chloride and 0.25 ml (3.19 mmol) of trifluoroacetic acid were added to 400 mg (1.77 mmol) of the compound from Example 165A and 483 mg (2.13 mmol) of the compound from Example 87A under argon in 18 ml of dichloromethane, and the mixture was heated under reflux for 3 days. It was concentrated and the residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) and another RP18 separation with acetonitrile/water 55:45 to result in 131 mg (17% of theory) of diastereomer 1 and 127 mg (17% of theory) of diastereomer 2 of the title compound.

Workup

  1. temperaturethe mixture was heated
  2. temperatureunder reflux for 3 days
  3. concentrationIt was concentrated
  4. washwashed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution
  5. dry with materialdried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid)
  9. customanother RP18 separation with acetonitrile/water 55:45

Sources & evidence

ORD record
ord-d5461ad93425465f84daecf7db8ac971
Source dataset
uspto-grants-2011_11
Patent number
US08063234B2

Reaction notes

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