Water → (3Z)-5-fluoro-4-{2-[(2S,4R)-4-hydroxypyrrolidin-2-yl]ethynyl}-3-[(3-methoxy-1H-pyrrol-2-yl)methylidene]-2,3-dihydro-1H-indol-2-one

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Reaction Steps

Using Method C above, (3R,5S)-N-Boc-3-Hydroxy-5-ethynyl-pyrrolidine (98 mg, 0.47 mmol) (Example 99C above) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (60 mg, 0.16 mmol) (Starting Material 6) using (Ph3P)4Pd (18 mg, 0.02 mmol) and a catalytic amount of Cul in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80° C. for 6 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 0-100% EtOAc in hexanes gradient. The intermediate that resulted from this operation was directly dissolved in 5 mL of a 50% trifluoroacetic acid in CH2Cl2 solution that contained 0.2 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. (Z)-1,3-Dihydro-5-fluoro-4-[(2S,4R)-(4-hydroxy-pyrrolidin-2-yl)-ethynyl]-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 of pentane. (Yield 12 mg, 31%).

Provenance & Evidence