反应详情

Using Method C above, (S)-N-Boc-2-Ethynyl-pyrrolidine (106 mg, 0.55 mmol) (Example 87B) was coupled with (Z)-5-(5-fluoro-4-iodo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (80 mg, 0.18 mmol) (Example 116B) using (Ph3P)4Pd (21 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 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. (S)-(Z)-5-[[5-Fluoro-2-oxo-4-[(pyrrolidin-2-yl)ethynyl]-1,2-dihydro-indol-3-ylidene]methyl]-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester was obtained after silica gel column chromatography with a 0-100% EtOAc in hexanes-30% THF in EtOAc gradient and precipitation out of THF with excess of hexanes. (Yield 21 mg, 28%).

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 0-40% EtOAc in hexanes gradient
5. dissolutionThe resulting intermediate was dissolved in 5 mL of a 50% trifluoroacetic acid in CH2Cl2 solution that
6. customat 0° C.
7. additionUpon completion, the reaction mixture was diluted with EtOAc
8. extractionextracted with ammonium hydroxide
9. dry with materialThe organic layer was dried over Na2SO4
10. concentrationconcentrated