Sodium hydride → (S)-3-[6-fluoro-2-oxo-3-(1H-pyrrol-2-yl)-1,2-dihydro-benzo[cd]indol-5-ylsulfanyl]-pyrrolidine-1-carboxylic acid tert-butyl ester

HRID 1861024Notes

Reaction equation

HRID 1861024 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([SH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]1[C:16](/[C:25](/I)=[CH:26]/[C:27](=O)[C:28]2[NH:29][CH:30]=[CH:31][CH:32]=2)=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH2:18]2.[H-].[Na+].[H][H]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([S:13][C:25]2[CH:26]=[C:27]([C:28]3[NH:29][CH:30]=[CH:31][CH:32]=3)[C:18]3[C:19](=[O:24])[NH:20][C:21]4[C:17]=3[C:16]=2[C:15]([F:14])=[CH:23][CH:22]=4)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

5

Reactant 4

HCID 24758Sodium hydrideHCID 10135347(Z)-5-fluoro-4-[1-iodo-3-oxo-3-(1H-pyrrol-2-yl)-propenyl]-1,3-dihydro-indol-2-oneHCID 59032356tert-Butyl (3S)-3-sulfanylpyrrolidine-1-carboxylateHCID 178418361HCID 178418361, compound

Product 1

HCID 12042976(S)-3-[6-fluoro-2-oxo-3-(1H-pyrrol-2-yl)-1,2-dihydro-benzo[cd]indol-5-ylsulfanyl]-pyrrolidine-1-carboxylic acid tert-butyl ester

Conditions

Temperature
120 °C

Procedure

To a mixture of (S)-3-mercapto-pyrrolidine-1-carboxylic acid tert-butyl ester (from Example 55 above) (1.35 g, 5.81 mmol) and (Z)-5-fluoro-4-[1-iodo-3-oxo-3-(1H-pyrrol-2-yl)-propenyl]-1,3-dihydro-indol-2-one (from Example 8 above) (100 mg, 0.20 mmol) was added NaH (48 mg, 2.01 mmol) in small portions at room temperature. After the evolution of hydrogen ceased, the mixture was heated to 120° C. for 1 hour then cooled and partitioned between ethyl acetate and water. The water layer was extracted with ethyl acetate (3×) and the combined organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by HPLC (silica gel, 25% ethyl acetate in hexanes) followed by a precipitation out of THF with excess of pentane to give (S)-3-[6-fluoro-2-oxo-3-(1H-pyrrol-2-yl)-1,2-dihydro-benzo[cd]indol-5-ylsulfanyl]-pyrrolidine-1-carboxylic acid tert-butyl ester as a yellow solid. (Yield 57 mg; 62%).

Workup

  1. temperaturethen cooled
  2. custompartitioned between ethyl acetate and water
  3. extractionThe water layer was extracted with ethyl acetate (3×)
  4. dry with materialthe combined organic layer was dried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe residue was purified by HPLC (silica gel, 25% ethyl acetate in hexanes)
  8. customfollowed by a precipitation out of THF with excess of pentane

Sources & evidence

ORD record
ord-db865d124d944b559719898f81000333
Source dataset
uspto-grants-2003_03
Patent number
US06531598B1

Reaction notes

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