Trimethylsilylacetylene → 2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-(3-oxo-isoxazolidin-2-ylmethyl)-benzamide

HRID 20760

Reaktionsgleichung

Reaktionsgleichung von HRID 20760
[F:1][C:2]1[C:3]([NH:23][C:24]2[CH:29]=[CH:28][C:27](I)=[CH:26][C:25]=2[F:31])=[C:4]([CH:12]=[C:13]([CH2:16][N:17]2[C:21](=[O:22])[CH2:20][CH2:19][O:18]2)[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].[CH:32](N(CC)C(C)C)(C)[CH3:33].C[Si](C#C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CO.C(Cl)Cl.CC#N.CC#N.Cl[Pd]Cl.[Cu](I)I>[C:32]([C:27]1[CH:28]=[CH:29][C:24]([NH:23][C:3]2[C:2]([F:1])=[C:14]([F:15])[C:13]([CH2:16][N:17]3[C:21](=[O:22])[CH2:20][CH2:19][O:18]3)=[CH:12][C:4]=2[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6])=[C:25]([F:31])[CH:26]=1)#[CH:33]

Komponenten

9

Edukt 4

HCID 66111TrimethylsilylacetyleneHCID 81531DiisopropylethylamineHCID 2724141Tetrabutylammonium FluorideHCID 116281803,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(3-oxo-isoxazolidin-2-ylmethyl)-benzamide

Produkt 1

HCID 116980742-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-(3-oxo-isoxazolidin-2-ylmethyl)-benzamideAusbeute 37 %

Reagenzien, Katalysatoren, Lösungsmittel 4

HCID 83717Copper iodideKatalysatorHCID 6093782Bis(acetonitrile)dichloropalladiumKatalysatorHCID 887MethanolLösungsmittelHCID 6344DichloromethaneLösungsmittel

Versuchsvorschrift

3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(3-oxo-isoxazolidin-2-ylmethyl)-benzamide (36.9 mg, 66.9 μmol) obtained in Example 37, bis(acetonitrile)dichloropalladium (II) (3.5 mg, 13.5 μmol), 3,3′,3″-phosphinidine-tris(benzenesulfonic acid) trisodium salt (19.0 mg, 33.4 μmol), and copper iodide (I) (2.6 mg, 13.6 μmol) were suspended in methanol (2.5 ml) under a nitrogen atmosphere. To this suspension, N,N-diisopropylethylamine (14.0 μl, 80.4 μmol) and trimethylsilylacetylene (47.3 μl, 334.7 μmol) were added at room temperature, and the mixture was stirred for 1 hour. The reaction mixture was diluted with methylene chloride (30 ml), and washed with saturated brine (2×15 ml). The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resultant residue was dissolved in THF (2 ml). To this solution, tetrabutylammonium fluoride (1.0 M solution in THF, 0.10 ml, 0.10 mmol) was added, and the mixture was stirred for 1 hour, and then concentrated under reduced pressure. The resultant residue was purified by preparative TLC (EtOAc/MeOH (8:1)) to give 2-(4-ethynyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-5-(3-oxo-isoxazolidin-2-ylmethyl)-benzamide (Compound G-5, 11.1 mg, 37%) as a brown oil.

Aufarbeitung

  1. washwashed with saturated brine (2×15 ml)
  2. dry with materialThe organic layer was dried over anhydrous magnesium sulfate
  3. concentrationconcentrated under reduced pressure
  4. dissolutionThe resultant residue was dissolved in THF (2 ml)
  5. stirringthe mixture was stirred for 1 hour
  6. concentrationconcentrated under reduced pressure
  7. customThe resultant residue was purified by preparative TLC (EtOAc/MeOH (8:1))

Quellen und Nachweise

ORD-Eintrag
ord-f0c318e069ec42ed8da0c134d6664760
Quelldatensatz
uspto-grants-2010_06
Patentnummer
US07745663B2

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