Water → (3Z)-5-fluoro-4-[(3R)-4-hydroxy-3-(methylamino)but-1-yn-1-yl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylidene]-2,3-dihydro-1H-indol-2-one

HRID 1069762Notes

Reaction equation

HRID 1069762 reaction equation
C([N:8]([C@H:10]([C:20]#[CH:21])[CH2:11][O:12][Si](C(C)(C)C)(C)C)[CH3:9])(OC(C)(C)C)=O.[F:22][C:23]1[C:24](I)=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])/[C:26]/2=[CH:33]\[C:34]1[NH:35][CH:36]=[CH:37][C:38]=1[O:39][CH3:40].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>[F:22][C:23]1[C:24]([C:21]#[C:20][C@@H:10]([NH:8][CH3:9])[CH2:11][OH:12])=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])/[C:26]/2=[CH:33]\[C:34]1[NH:35][CH:36]=[CH:37][C:38]=1[O:39][CH3:40]

Participants

10

Reactant 3

HCID 962WaterHCID 18363902(3Z)-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylidene]-2,3-dihydro-1H-indol-2-one2×HCID 21971749(R)-2-(N-Boc-N-methylamino)-1-(tert-butyldimethylsilyloxy)-but-3-yne

Product 1

HCID 23645076(3Z)-5-fluoro-4-[(3R)-4-hydroxy-3-(methylamino)but-1-yn-1-yl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylidene]-2,3-dihydro-1H-indol-2-one

Reagents, catalysts & solvents 6

HCID 178418397HCID 178418397, compoundCatalystHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 6422Trifluoroacetic acidSolventHCID 8471TriethylamineSolventHCID 8857Ethyl AcetateSolvent2×

Procedure

Using Method C above, (R)-2-(N-Boc-N-methylamino)-1-(tert-butyldimethylsilyloxy)-but-3-yne (130 mg, 0.42 mmol) (Example 104C) 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 catalytic amount of Cul in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80 IC 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 40-100% EtOAc in hexanes gradient. The intermediate that resulted from this operation was dissolved directly in 10 mL of a 50% trifluoroacetic acid in CH2Cl2 solution that contained 0.5 mL of H2O at 0 °C. and stirred for 2.5 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-4-[4-hydroxy-3-methylamino-1-butynyl]-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 of pentane. (Yield 28 mg, 38%).

Workup

  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 40-100% EtOAc 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

Sources & evidence

ORD record
ord-56885a3203944d2a943b833bc08f366e
Source dataset
uspto-grants-2001_06
Patent number
US06252086B1

Reaction notes

Loading…