(3Z)-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylidene]-2,3-dihydro-1H-indol-2-one → (Z)-1,3-Dihydro-5-fluoro-4-[(3R,4R)-4-hydroxy-3-methylamino-1-pentynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one

Participants

Reaction Steps

Using Method C above, (2R,3R)-3-(N-Boc-N-methylamino)-2-(tert-butyldimethylsilyloxy)-pent-4-yne (370 mg, 1.13 mmol) (Example 117C above) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (150 mg, 0.39 mmol) (Starting Material 6) using (Ph3P)4Pd (45 mg, 0.04 mmol) and a catalytic amount of Cul in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80° C. for 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 0-40% EtOAc in hexanes gradient. The resulting intermediate was dissolved in 5 mL of a 50% trifluoroacetic acid in CH2Cl2 solution that contained 0.5 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-[(3R,4R)-4-hydroxy-3-methylamino-1-pentynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one was obtained after silica gel column chromatography with a 0-10% MeOH in CH2Cl2 gradient and precipitation out of THF with excess pentane. (Yield 53 mg, 37%).

Provenance & Evidence