Ethyl Acetate → 6-fluoro-5-(3-hydroxy-piperidin-1-yl)-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one

HRID 1861011Notes

Reaction equation

HRID 1861011 reaction equation
C(OC([N:8]1[C:16]2[C:11](=[C:12]([C:18]#[C:19][C:20]([C:22]3[N:23](C(OC(C)(C)C)=O)[CH:24]=[CH:25][CH:26]=3)=O)[C:13]([F:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[O:34]C(OC(C)(C)C)=O)=O)(C)(C)C.[OH:42][CH:43]1[CH2:48][CH2:47][CH2:46][NH:45][CH2:44]1.[H-].[Na+].C(OCC)(=O)C>CN(C=O)C.O>[F:17][C:13]1[C:12]2[C:11]3[C:16](=[CH:15][CH:14]=1)[NH:8][C:9](=[O:34])[C:10]=3[C:20]([C:22]1[NH:23][CH:24]=[CH:25][CH:26]=1)=[CH:19][C:18]=2[N:45]1[CH2:46][CH2:47][CH2:48][CH:43]([OH:42])[CH2:44]1

Participants

7

Reactant 4

HCID 8857Ethyl AcetateHCID 232933-HydroxypiperidineHCID 24758Sodium hydrideHCID 102315682-tert-Butoxycarbonyloxy-4-[3-(1-tert-butoxycarbonyl-1H-pyrrol-2-yl)-3-oxo-prop-1-ynyl]-5-fluoro-indole-1-carboxylic acid tert-butyl ester

Product 1

HCID 99683216-fluoro-5-(3-hydroxy-piperidin-1-yl)-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
120 °C

Procedure

A mixture of 2-tert-butoxycarbonyloxy-4-[3-(1-tert-butoxycarbonyl-1H-pyrrol-2-yl)-3-oxo-prop-1-ynyl]-5-fluoro-indole-1-carboxylic acid tert-butyl ester (from Example 4 above) (230 mg, 0.40 mmol) and 3-hydroxy-piperidine (Aldrich, 1.23 g, 12.13 mmol) in DMF (15 ml) was heated to 120° C. for 1.5 hours. The mixture was cooled and NaH (Aldrich, 140 mg, 5.83 mmol) was added in small portions with stirring. After 30 minutes at room temperature and then 20 hours at 120° C. the mixture was cooled and poured into a mixture of ethyl acetate and water. The aqueous layer was extracted few more times with ethyl acetate and the combined organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 60% ethyl acetate in hexanes) and further purified by HPLC (silica gel, 35% ethyl acetate in hexanes) and a precipitation out of THF with excess of pentane to give 6-fluoro-5-(3-hydroxy-piperidin-1-yl)-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one as a yellow solid. (Yield 45 mg, 31%).

Workup

  1. temperatureThe mixture was cooled
  2. temperature20 hours at 120° C. the mixture was cooled
  3. extractionThe aqueous layer was extracted few more times with ethyl acetate
  4. dry with materialthe combined organic layer was dried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe residue was purified by flash chromatography (silica gel, 60% ethyl acetate in hexanes)
  8. customfurther purified by HPLC (silica gel, 35% ethyl acetate in hexanes)
  9. customa precipitation out of THF with excess of pentane

Sources & evidence

ORD record
ord-60d67f7752624b06882d3c1dd468bd61
Source dataset
uspto-grants-2003_03
Patent number
US06531598B1

Reaction notes

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