Trifluoroacetic acid → 8-Fluoro-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6-dihydro-benzo[i]phenanthridin-2-ol

HRID 1513981Notes

Reaction equation

HRID 1513981 reaction equation
C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([OH:25])[CH:21]=2)[C:16]=1[C:26](=O)[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[CH:29][CH:28]=1)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.[BH4-].[Na+].C([BH3-])#N.[Na+]>ClCCl>[F:14][C:12]1[CH:11]=[CH:10][C:9]2[C:15]3[CH:24]=[CH:23][C:22]4[CH:21]=[C:20]([OH:25])[CH:19]=[CH:18][C:17]=4[C:16]=3[CH:26]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][N:36]4[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]4)=[CH:29][CH:28]=3)[NH:7][C:8]=2[CH:13]=1

Participants

7

Reactant 5

HCID 6422Trifluoroacetic acid2×HCID 7519AnisoleHCID 4311764Sodium borohydride2×HCID 5003444Sodium cyanoborohydride2×HCID 67004793HCID 67004793, compound

Product 1

HCID 575525218-Fluoro-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6-dihydro-benzo[i]phenanthridin-2-olYield 35.2%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a round bottom flask add (5-fluoro-2-{6-hydroxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl}-phenyl)-carbamic acid tert-butyl ester (0.060 g, 0.103 mmol), dichloromethane (1.25 mL), anisole (0.15 mL, 1.39 mmol) and trifluoroacetic acid (0.25 mL). Stir the reaction for 1.5 hour at ambient temperature. Add trifluoroacetic acid (2.0 mL) and sodium borohydride (0.024 g, 0.62 mmol) and stir the reaction at ambient temperature for 1.5 hours. Add more sodium borohydride (0.024 g, 0.62 mmol) and stir the reaction at ambient temperature an additional 2 hours. After aqueous work-up and purification LC/MS showed significant amounts of the (M-2) intermediate, so take this material up in acetic acid (3.0 mL) and to it add sodium cyanoborohydride (0.032 g, 0.51 mmol). Stir this mixture for 1.5 hours at ambient temperature. Add more sodium cyanoborohydride (0.032 g, 0.51 mmol) and stir an additional 1.5 hours at ambient temperature. Quench the reaction with saturated aqueous sodium bicarbonate. Extract the resulting aqueous mixture into ethyl acetate. Wash the combined extracts with saturated aqueous sodium bicarbonate, H2O and brine; then dry (sodium sulfate) and evaporate the filtrate in vacuo. Purify the resulting residue by radial chromatography over silica (5%-10% methanol gradient in dichloromethane) to provide 17 mg (35%) of the title compound: mass spectrum (ion spray) m/z=469 (M+H).

Workup

  1. customthe reaction for 1.5 hour at ambient temperature
  2. customthe reaction at ambient temperature for 1.5 hours
  3. stirringstir
  4. customthe reaction at ambient temperature an additional 2 hours
  5. customAfter aqueous work-up and purification LC/MS
  6. stirringStir this mixture for 1.5 hours at ambient temperature
  7. stirringstir an additional 1.5 hours at ambient temperature
  8. customQuench
  9. customthe reaction with saturated aqueous sodium bicarbonate
  10. extractionExtract the resulting aqueous mixture into ethyl acetate
  11. washWash the combined extracts with saturated aqueous sodium bicarbonate, H2O and brine
  12. dry with materialthen dry (sodium sulfate)
  13. customevaporate the filtrate in vacuo
  14. customPurify the resulting residue by radial chromatography over silica (5%-10% methanol gradient in dichloromethane)

Sources & evidence

ORD record
ord-68e28110e2444bfdb9f6dc0e6c1c24e3
Source dataset
uspto-grants-2012_07
Patent number
US08217032B2

Reaction notes

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