Sodium hydride → 6-fluoro-5-(4-hydroxy-piperidin-1-yl)-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one

HRID 1633784Notes

Reaction equation

HRID 1633784 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][NH:46][CH2:45][CH2:44]1.[H-].[Na+]>CN(C=O)C.C(OCC)(=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:46]1[CH2:47][CH2:48][CH:43]([OH:42])[CH2:44][CH2:45]1

Participants

7

Reactant 3

HCID 24758Sodium hydrideHCID 79341Piperidin-4-olHCID 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 101326296-fluoro-5-(4-hydroxy-piperidin-1-yl)-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

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) (392 mg, 0.69 mmol) and 4-hydroxy-piperidine (Aldrich, 2.12 g, 20.94 mmol) in DMF(6 mL) was treated with NaH. (Aldrich, 250 mg, 10.42 mmol). The mixture was stirred for 30 minutes at room temperature and overnight at 120° C. The reaction mixture was poured in a mixture of ethyl acetate and water. The aqueous layer was extracted a 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, with 0-50% ethyl acetate in hexanes gradient), and further purified by HPLC (silica gel, 50% ethyl acetate in hexanes) and precipitation out of THF with excess of pentane to give 6-fluoro-5-(4-hydroxy-piperidin-1-yl)-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one as a yellow solid. (Yield 85 mg, 38%).

Workup

  1. extractionThe aqueous layer was extracted a few more times with ethyl acetate
  2. dry with materialthe combined organic layer was dried over Na2SO4
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customThe residue was purified by flash chromatography (silica gel, with 0-50% ethyl acetate in hexanes gradient)
  6. customfurther purified by HPLC (silica gel, 50% ethyl acetate in hexanes) and precipitation out of THF with excess of pentane

Sources & evidence

ORD record
ord-1652029c0a6247c69a050365c873c08b
Source dataset
uspto-grants-2003_01
Patent number
US06504034B2

Reaction notes

Loading…