(3Z)-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylidene]-2,3-dihydro-1H-indol-2-one → (3Z)-5-fluoro-4-[(3S)-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 1069773Notes

Reaction equation

HRID 1069773 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]>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.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

7

Reactant 2

HCID 18363902(3Z)-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylidene]-2,3-dihydro-1H-indol-2-one2×HCID 21971751(s)-2-(n-Boc-n-methylamino)-1-(tert-butyldimethylsilyloxy)-but-3-yne

Product 1

HCID 15907931(3Z)-5-fluoro-4-[(3S)-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 4

HCID 178418397HCID 178418397, compoundCatalystHCID 6228DimethylformamideSolventHCID 8471TriethylamineSolventHCID 8857Ethyl AcetateSolvent

Procedure

Using Method C above, (S)-2-(N-Boc-N-methylamino)-1-(tert-butyldimethylsilyloxy)-but-3-yne (190 mg, 0.61 mmol) (Example 115C above) 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 5.5 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 resulting intermediate was dissolved directly in 6 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)-1,3-Dihydro-5-fluoro-4-[3-methylamino-4-hydroxy-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 32 mg, 42%).

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. dissolutionThe resulting intermediate was dissolved directly in 6 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

Sources & evidence

ORD record
ord-00c67e705bdc482aab0739f9b08af4ea
Source dataset
uspto-grants-2001_06
Patent number
US06252086B1

Reaction notes

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