Water → (R)-(Z)-4-(3-Amino-4-hydroxy-1-butynyl)-1,3-dihydro-5-fluoro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one

HRID 380882

Reaktionsgleichung

Reaktionsgleichung von HRID 380882
C([N:8]1[C@H:12]([C:13]#[CH:14])[CH2:11][O:10]C1(C)C)(OC(C)(C)C)=O.[F:17][C:18]1[C:19](I)=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])/[C:21]/2=[CH:28]\[C:29]1[NH:30][CH:31]=[CH:32][C:33]=1[O:34][CH3:35].O>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.FC(F)(F)C(O)=O.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[NH2:8][C@@H:12]([CH2:11][OH:10])[C:13]#[C:14][C:19]1[C:18]([F:17])=[CH:26][CH:25]=[C:24]2[C:20]=1/[C:21](=[CH:28]/[C:29]1[NH:30][CH:31]=[CH:32][C:33]=1[O:34][CH3:35])/[C:22](=[O:27])[NH:23]2

Komponenten

11

Edukt 3

HCID 962WaterHCID 11096274tert-Butyl (4R)-4-ethynyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylateHCID 18363902(3Z)-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylidene]-2,3-dihydro-1H-indol-2-one2×

Produkt 1

HCID 23645075(R)-(Z)-4-(3-Amino-4-hydroxy-1-butynyl)-1,3-dihydro-5-fluoro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one

Reagenzien, Katalysatoren, Lösungsmittel 7

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)KatalysatorHCID 178418397HCID 178418397, VerbindungKatalysatorHCID 6228DimethylformamideLösungsmittelHCID 6344DichloromethaneLösungsmittelHCID 6422Trifluoroacetic acidLösungsmittelHCID 8471TriethylamineLösungsmittelHCID 8857Ethyl AcetateLösungsmittel2×

Versuchsvorschrift

Using Method C above, (R)-N-Boc-2,2-dimethyl-4-ethynyl-oxazolidine (141 mg, 0.62 mmol) (Example 91A above) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (80 mg, 0.21 mmol) (Starting Material 6) using (Ph3P)4Pd (24 mg, 0.02 mmol) and a catalylic amount of CuI in a mixture of DMF (4 mL) and Et3N (4 mL) as solvent at 80° C. for 8.5 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4, concentrated and the residue was chromatographed on a silica gel column with a 0-50% THF in hexanes gradient. The intermediate that resulted from this operation was directly dissolved in 6 mL of a 50% trifluoroacetic acid in CH2Cl2 solution that contained 0.6 mL of H2O at 0° C. and stirred for 2 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with ammonium hydroxide. The organic layer was dried over Na2SO4 and concentrated. (R)-(Z)-4-(3-Amino-4-hydroxy-1-butynyl)-1,3-dihydro-5-fluoro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one was obtained after silica gel column chromatography with 0-20% MeOH in CH2Cl2 gradient and precipitation out of THF with excess pentane. (Yield 10 mg, 14%).

Aufarbeitung

  1. extractionextracted with H2O
  2. dry with materialThe organic layer was dried over Na2SO4
  3. concentrationconcentrated
  4. customthe residue was chromatographed on a silica gel column with a 0-50% THF in hexanes gradient
  5. customThe intermediate that resulted from this operation
  6. customat 0° C.
  7. extractionextracted with ammonium hydroxide
  8. dry with materialThe organic layer was dried over Na2SO4
  9. concentrationconcentrated

Quellen und Nachweise

ORD-Eintrag
ord-8af8a456c1e64cb2aae61dd726c6cc1f
Quelldatensatz
uspto-grants-2001_10
Patentnummer
US06303793B1

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