1-Methyl-3-(trifluoroacetyl)-1H-indole → 2,2,2-Trifluoro-1-[1-(4-fluorophenyl)-2-methyl-1H-benzimidazol-5-yl]-1-(1-methyl-1H-indol-3-yl)ethanol

HRID 244469

反応式

HRID 244469 の反応式
Br[C:2]1[CH:18]=[CH:17][C:5]2[N:6]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[C:7]([CH3:9])=[N:8][C:4]=2[CH:3]=1.C([Li])CCC.[F:24][C:25]([F:39])([F:38])[C:26]([C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]([CH3:37])[CH:29]=1)=[O:27]>C1COCC1>[F:39][C:25]([F:24])([F:38])[C:26]([C:2]1[CH:18]=[CH:17][C:5]2[N:6]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[C:7]([CH3:9])=[N:8][C:4]=2[CH:3]=1)([C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]([CH3:37])[CH:29]=1)[OH:27]

参加物

5

反応物 3

HCID 35243881-Methyl-3-(trifluoroacetyl)-1H-indoleHCID 594373055-bromo-1-(4-fluorophenyl)-2-methyl-1H-benzimidazoleHCID 178418339Butyllithium

生成物 1

HCID 594372782,2,2-Trifluoro-1-[1-(4-fluorophenyl)-2-methyl-1H-benzimidazol-5-yl]-1-(1-methyl-1H-indol-3-yl)ethanol収率 17.8%

試薬・触媒・溶媒 1

HCID 8028Tetrahydrofuran溶媒2 回

実験手順

To a chilled (−78° C.) solution of 5-bromo-1-(4-fluorophenyl)-2-methyl-1H-benzimidazole (210 mg, 0.68 mmol) in anhydrous THF (3 mL) was added n-butyllithium (1 mmol, 400 μL of a 2.5 M solution in hexanes) over a 1 minute period followed by a chilled (−78° C.) solution of 2,2,2-trifluoro-1-(1-methyl-1H-indol-3-yl)ethanone (200 mg, 0.88 mmol) in 1 mL of anhydrous THF. After 30 minutes, the mixture was quenched with ammonium chloride solution and extracted with methylene chloride. The organic layer was concentrated to afford a yellow oil. The residue was purified by column chromatography over silica gel eluting with 0-50% ethyl acetate in hexanes. The product rich fractions were collected and concentrated in vacuo to afford a light yellow oil. A second purification by reverse phase HPLC (C-18 column) using a gradient of 20-100% acetonitrile (0.1% TFA) in water (0.1% TFA) over 15 minutes and fractions corresponding to an earlier eluting peak (M+H 455) were collected. The acetonitrile was concentrated in vacuo, the residue was made basic with aqueous sodium bicarbonate, and extracted with methylene chloride. The organic layer was concentrated to afford 55 mg of the title compound as an off-white solid. MS m/z 455 (MH+).

後処理

  1. customthe mixture was quenched with ammonium chloride solution
  2. extractionextracted with methylene chloride
  3. concentrationThe organic layer was concentrated
  4. customto afford a yellow oil
  5. customThe residue was purified by column chromatography over silica gel eluting with 0-50% ethyl acetate in hexanes
  6. customThe product rich fractions were collected
  7. concentrationconcentrated in vacuo
  8. customto afford a light yellow oil
  9. customA second purification by reverse phase HPLC (C-18 column)
  10. customover 15 minutes
  11. washfractions corresponding to an earlier eluting peak (M+H 455)
  12. customwere collected
  13. concentrationThe acetonitrile was concentrated in vacuo
  14. extractionextracted with methylene chloride
  15. concentrationThe organic layer was concentrated

出典と根拠

ORDレコード
ord-a29d6e01f86b479988aae6245f0a7b8a
出典データセット
uspto-grants-2014_02
特許番号
US08658637B2

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