2,2-Difluoro-2-(fluorosulfonyl)acetic acid → (R)-4a-Difluoromethoxymethyl-1-(4-fluorophenyl)-6-(6-morpholin-4-yl-pyridine-3-sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triazacyclopenta[b]naphthalene

HRID 1907294Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1907294
[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([CH2:21][OH:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:23]([C:26]2[CH:27]=[N:28][C:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:30][CH:31]=2)(=[O:25])=[O:24])[CH2:16][CH2:15]4)=[CH:4][CH:3]=1.FS([C:42]([F:47])([F:46])C(O)=O)(=O)=O>[Cu](I)I.C(#N)C>[F:46][CH:42]([F:47])[O:22][CH2:21][C@@:19]12[CH2:18][N:17]([S:23]([C:26]3[CH:27]=[N:28][C:29]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[CH:30][CH:31]=3)(=[O:24])=[O:25])[CH2:16][CH2:15][C:14]1=[CH:13][C:12]1[N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[N:9]=[CH:10][C:11]=1[CH2:20]2

Komponenten

5

Edukt 2

HCID 27375162,2-Difluoro-2-(fluorosulfonyl)acetic acidHCID 66780233[(R)-1-(4-Fluorophenyl)-6-[[6-(4-morpholinyl)-3-pyridinyl]sulfonyl]-1,4,7,8-tetrahydro-1,2,6-triazacyclopenta[b]naphthalen-4a-yl]methanol

Produkt 1

HCID 56848978(R)-4a-Difluoromethoxymethyl-1-(4-fluorophenyl)-6-(6-morpholin-4-yl-pyridine-3-sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triazacyclopenta[b]naphthalene

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 83717Copper iodideKatalysatorHCID 6342AcetonitrileLösungsmittel

Reaktionsbedingungen

Temperatur
50 °C

Versuchsvorschrift

A mixture of [(R)-1-(4-fluorophenyl)-6-[[6-(4-morpholinyl)-3-pyridinyl]sulfonyl]-1,4,7,8-tetrahydro-1,2,6-triazacyclopenta[b]naphthalen-4a-yl]methanol (0.21 g), copper iodide (0.0080 g) and acetonitrile under argon was treated with 2-(fluorosulfonyl)difluoroacetic acid (0.062 mL), and the resulting mixture was heated at 50° C. for 30 hours. The mixture was cooled to room temperature, partitioned between water and ethyl acetate and the aqueous phase extracted with ethyl acetate. The combined organic phase was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (1:0 to 1:1 by volume), and then by preparative reverse-phase HPLC, eluting with a mixture of acetonitrile and water containing 0.1% formic acid (1:1 to 7:3 by volume) to afford the title compound as a white solid (0.021 g). LCMS (Method C): 576 (M+H)+, Retention time 11.6 minutes.

Aufarbeitung

  1. temperatureThe mixture was cooled to room temperature
  2. custompartitioned between water and ethyl acetate
  3. extractionthe aqueous phase extracted with ethyl acetate
  4. dry with materialThe combined organic phase was dried over sodium sulfate
  5. concentrationconcentrated under reduced pressure
  6. customThe residue was purified by column chromatography on silica gel
  7. washeluting with a mixture of cyclohexane and ethyl acetate (1:0 to 1:1 by volume)
  8. washby preparative reverse-phase HPLC, eluting with a mixture of acetonitrile and water containing 0.1% formic acid (1:1 to 7:3 by volume)

Quellen und Nachweise

ORD-Eintrag
ord-0dfa600d94a7402cb4402b7aa72d558f
Quelldatensatz
uspto-grants-2013_12
Patentnummer
US08598154B2

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