Water → (R)-(Z)-1,3-Dihydro-5-fluoro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-4-[(pyrrolidin-2-yl)ethynyl]-2 H-indol-2-one

Using Method C above, (R)-N-Boc-2-ethynyl-pyrrolidine (100 mg, 0.52 mmol) (Example 89B) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (50 mg, 0.13 mmol) (Starting Material 6) using (Ph3P)4Pd (15 mg, 0.01 mmol) and a catalytic amount of Cul (2 mg) in a mixture of DMF (4 mL) and Et3N (4 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 40-70% EtOAc in hexanes gradient. The intermediate that was obtained from this operation was directly dissolved at 0° C., in 5 mL of a solution of 50% trifluoroacetic acid in CH2Cl2 that contained 0.3 mL of H2O 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)-1,3-Dihydro-5-fluoro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-4-[(pyrrolidin-2-yl)ethynyl]-2H-indol-2-one was obtained after reverse phase column chromatography with 0-90% MeOH in H2O gradient, a silica gel column chromatography with neat THF and a precipitatiion out of THF with excess of hexanes. (Yield 14 mg, 31%).

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 40-70% EtOAc in hexanes gradient
5. customThe intermediate that was obtained from this operation
6. extractionextracted with ammonium hydroxide
7. dry with materialThe organic layer was dried over Na2SO4
8. concentrationconcentrated

ORD record

ord-9cd6093364d746e1abf77d1490151e1a

Source dataset

uspto-grants-2001_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06252086B1