Ethyl 2-oxocyclopentanecarboxylate → ethyl 7-bromo-3-(3-ethoxy-3-oxopropyl)-4-fluoro-1H-indole-2-carboxylate

HRID 2199743Notes

Reaction equation

HRID 2199743 reaction equation
[Br:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].N([O-])=[O:11].[Na+].[C:14]([O-])(=O)[CH3:15].[K+].[O:19]=[C:20]1[CH2:24][CH2:23][CH2:22][CH:21]1[C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(O)C.Cl>[Br:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[C:5]2[C:3]=1[NH:4][C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:22]2[CH2:23][CH2:24][C:20]([O:19][CH2:14][CH3:15])=[O:11]

Participants

7

Reactant 4

HCID 69136Ethyl 2-oxocyclopentanecarboxylateHCID 517044Potassium AcetateHCID 27733172-Bromo-5-fluoroanilineHCID 23668193Sodium Nitrite

Product 1

HCID 68937923ethyl 7-bromo-3-(3-ethoxy-3-oxopropyl)-4-fluoro-1H-indole-2-carboxylate

Reagents, catalysts & solvents 2

HCID 313Hydrochloric AcidSolventHCID 702EthanolSolvent

Conditions

Temperature
0 °C

Procedure

A mixture of 2-bromo-5-fluoroaniline (5 g) in ethanol (17.5 ml) and 1.6M HCl (50 mL) at −5° C. was treated with 2.5M NaNO2 (10.5 ml). 4.5M potassium acetate (29.2 ml) was then added, followed by ethyl 2-oxocyclopentanecarboxylate (3.8 ml). The reaction mixture was stirred at 0° C. for 15 minutes, warmed to 20° C. over 1.5 hours, extracted with dichloromethane, concentrated and dried in vacuo. The residue was dissolved in 67 ml of (H2SO4/ethanol, 17:50), refluxed for 2 days, cooled to room temperature, quenched with water and extracted with dichloromethane. The combined extracts were washed with brine, dried (MgSO4), filtered and concentrated. The concentrate was purified by column chromatography on silica gel with 5-20% ethyl acetate in hexanes. The product was purified further by trituration with ethanol.

Workup

  1. temperaturewarmed to 20° C. over 1.5 hours
  2. extractionextracted with dichloromethane
  3. concentrationconcentrated
  4. customdried in vacuo
  5. dissolutionThe residue was dissolved in 67 ml of (H2SO4/ethanol, 17:50)
  6. temperaturerefluxed for 2 days
  7. temperaturecooled to room temperature
  8. customquenched with water
  9. extractionextracted with dichloromethane
  10. washThe combined extracts were washed with brine
  11. dry with materialdried (MgSO4)
  12. filtrationfiltered
  13. concentrationconcentrated
  14. customThe concentrate was purified by column chromatography on silica gel with 5-20% ethyl acetate in hexanes
  15. customThe product was purified further by trituration with ethanol

Sources & evidence

ORD record
ord-b1158a16f797485c87214ed43a5aff93
Source dataset
uspto-grants-2016_06
Patent number
US09359296B2

Reaction notes

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