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

HRID 561693Notes

Reaction equation

HRID 561693 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.[CH3:27][S:28]([CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:40]=1[NH:39][CH:38]=[CH:37]2)(=[O:30])=[O:29]>ClCCl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:37]2[C:36]3[C:40](=[C:32]([CH2:31][S:28]([CH3:27])(=[O:30])=[O:29])[CH:33]=[CH:34][CH:35]=3)[NH:39][CH:38]=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 583922947-[(Methylsulfonyl)methyl]-1H-indole

Product 1

HCID 583922862-[(4-Chloro-2-fluorophenyl){7-[(methylsulfonyl)methyl]-1H-indol-3-yl}methyl]cyclopropane-carbonitrile

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

1.76 g (7.98 mmol) of indium(III) chloride and 0.92 ml (12.0 mmol) of trifluoroacetic acid were added to 1.50 g (6.65 mmol) of the compound from Example 165A and 1.67 g (7.98 mmol) of the compound from Example 86A under argon in 69 ml of dichloromethane, and the mixture was heated under reflux for three 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 isocratic RP18 separation with acetonitrile/water 1:1 to result in 283 mg (10% of theory) of diastereomer 1 and 145 mg (5% of theory) of diastereomer 2 of the title compound.

Workup

  1. temperaturethe mixture was heated
  2. temperatureunder reflux for three 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 isocratic RP18 separation with acetonitrile/water 1:1

Sources & evidence

ORD record
ord-0a6376f4034742a480ed9d8e35815822
Source dataset
uspto-grants-2011_11
Patent number
US08063234B2

Reaction notes

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