(S)-N-Boc-2-ethynylpyrrolidine → (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

HRID 1069783Notes

Reaction equation

HRID 1069783 reaction equation
C([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]#[CH:14])(OC(C)(C)C)=O.[CH2:15]([O:17][C:18]([C:20]1[C:24]([CH3:25])=[C:23](/[CH:26]=[C:27]2\[C:28](=[O:38])[NH:29][C:30]3[C:35]\2=[C:34](I)[C:33]([F:37])=[CH:32][CH:31]=3)[NH:22][CH:21]=1)=[O:19])[CH3:16]>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>[CH2:15]([O:17][C:18]([C:20]1[C:24]([CH3:25])=[C:23](/[CH:26]=[C:27]2\[C:28](=[O:38])[NH:29][C:30]3[C:35]\2=[C:34]([C:14]#[C:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)[C:33]([F:37])=[CH:32][CH:31]=3)[NH:22][CH:21]=1)=[O:19])[CH3:16]

Participants

7

Reactant 2

HCID 11030701(S)-N-Boc-2-ethynylpyrrolidineHCID 20667774(Z)-5-(5-Fluoro-4-iodo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester

Product 1

HCID 15907936(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

Reagents, catalysts & solvents 4

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

Procedure

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%).

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 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

Sources & evidence

ORD record
ord-6515143b580f4dc4940f1e6138a8506a
Source dataset
uspto-grants-2001_06
Patent number
US06252086B1

Reaction notes

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