9-Fluoro-3-(4-fluoro-benzoyl)-1,1-dimethyl-1,2,3,6-tetrahydro-azepino[4,5-b]indole-5-carboxylic acid ethyl ester → 3-(4-Fluorobenzoyl)-7-hydroxy-1,2,3,6-tetrahydroazepino[4,5-B] indole-5-carboxylic acid ethyl ester

HRID 37953Notes

Reaction equation

HRID 37953 reaction equation
[CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][C:17](F)=[CH:18][C:19]=3[C:11]=2[C:10](C)(C)[CH2:9][N:8]([C:23](=[O:31])[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH:7]=1)=[O:5])[CH3:2].C([O:34]C(C1C2NC3C=CC(N)=CC=3C=2C(C)(C)CN(C(=O)C2C=CC(F)=CC=2)C=1)=O)C.[H+].[B-](F)(F)(F)F.O>CC#N>[CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[C:15]([OH:34])=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[CH2:10][CH2:9][N:8]([C:23](=[O:31])[C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[CH:7]=1)=[O:5])[CH3:2]

Participants

5

Reactant 3

HCID 100253639-Fluoro-3-(4-fluoro-benzoyl)-1,1-dimethyl-1,2,3,6-tetrahydro-azepino[4,5-b]indole-5-carboxylic acid ethyl esterHCID 111660869-Amino-3-(4-fluoro-benzoyl)-1,1-dimethyl-1,2,3,6-tetrahydro-azepino[4,5-b]indole-5-carboxylic acid ethyl esterHCID 131727260HBF4 water

Product 1

HCID 575591393-(4-Fluorobenzoyl)-7-hydroxy-1,2,3,6-tetrahydroazepino[4,5-B] indole-5-carboxylic acid ethyl ester

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
10 °C

Procedure

For the preparation of 9-fluoro-3-(4-fluoro-benzoyl)-1,1-dimethyl-1,2,3,6-tetrahydro-azepino[4,5-b]indole-5-carboxylic acid ethyl ester, to a stirred solution of 9-amino-3-(4-fluoro-benzoyl)-1,1-dimethyl-1,2,3,6-tetrahydro-azepino[4,5-b]indole-5-carboxylic acid ethyl ester (Example 41C) (0.024 g, 0.055 mmol) in 1.0 mL of MeCN was added 11 μL of 48% HBF4 water solution at ±10° C. under N2 for 10 minutes. 9 μL of tBuONO (90%, 0.066 mmol) was added to the reaction mixture and stirred at ±10° C. for 20 minutes. The reaction mixture was warmed to room temperature for 1 hour and monitored by LC-MS. The solvents were removed in vacuo, and the residue was washed with Et2O/hexane (1:1) once and benzene twice. After having dried in high vacuo for several hours, a brown solid was obtained. The solid in 1.5 mL of xylenes was heated at 145° C. reflux under N2 for 1 hour and then concentrated. The crude product was purified by flash chromatograph on silica gel, eluting with EtOAc-hexane (0-30%) to yield the title compound (0.012 g) as a light yellow solid. 1H-NMR (CDCl3): δ10.68 (1H, s), 7.83 (1H, s), 7.62 (2H, m), 7.44 (1H, dd), 7.29 (1H, m), 7.13 (2H, m), 6.93 (1H, m), 4.23 (2H, q), 1.56 (6H, s), 1.22 (3H, t). MS (ESI): 425 (MH+).

Workup

  1. addition9 μL of tBuONO (90%, 0.066 mmol) was added to the reaction mixture
  2. temperatureThe reaction mixture was warmed to room temperature for 1 hour
  3. customThe solvents were removed in vacuo
  4. washthe residue was washed with Et2O/hexane (1:1) once
  5. customAfter having dried in high vacuo for several hours
  6. customa brown solid was obtained
  7. temperaturereflux under N2 for 1 hour
  8. concentrationconcentrated
  9. customThe crude product was purified by flash chromatograph on silica gel
  10. washeluting with EtOAc-hexane (0-30%)

Sources & evidence

ORD record
ord-3e5669e28fec4a379e6dbf57f77b06ec
Source dataset
uspto-grants-2013_09
Patent number
US08524704B2

Reaction notes

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