Hydrochloric Acid → 5-cyano-1-{2-[4-(trifluoromethoxy)phenoxy]ethyl}-1H-indole-2-carboxylic acid

HRID 513200Notes

Reaction equation

HRID 513200 reaction equation
C(C1C=C2C(=CC=1)NC(C(OCC)=O)=C2)#N.FC(F)(F)OC1C=CC(OCCO)=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:65]([C:67]1[CH:68]=[C:69]2[C:73](=[CH:74][CH:75]=1)[N:72]([CH2:76][CH2:77][O:78][C:79]1[CH:84]=[CH:83][C:82]([O:85][C:86]([F:89])([F:88])[F:87])=[CH:81][CH:80]=1)[C:71]([C:90]([O:92]CC)=[O:91])=[CH:70]2)#[N:66].[OH-].[Na+].Cl>C1(C)C=CC=CC=1.CCOC(C)=O.C1COCC1.O.CO>[C:65]([C:67]1[CH:68]=[C:69]2[C:73](=[CH:74][CH:75]=1)[N:72]([CH2:76][CH2:77][O:78][C:79]1[CH:80]=[CH:81][C:82]([O:85][C:86]([F:87])([F:88])[F:89])=[CH:83][CH:84]=1)[C:71]([C:90]([OH:92])=[O:91])=[CH:70]2)#[N:66]

Participants

13

Reactant 7

HCID 313Hydrochloric AcidHCID 11776TriphenylphosphineHCID 14798Sodium HydroxideHCID 4714953Ethyl 5-cyanoindole-2-carboxylateHCID 5363146Diisopropyl azodicarboxylateHCID 211086172-[4-(Trifluoromethoxy)phenoxy]ethanolHCID 71212567ethyl 5-cyano-1-{2-[4-(trifluoromethoxy)phenoxy]ethyl}-1H-indole-2-carboxylate

Product 1

HCID 712121305-cyano-1-{2-[4-(trifluoromethoxy)phenoxy]ethyl}-1H-indole-2-carboxylic acidYield 85.8%

Reagents, catalysts & solvents 5

HCID 887MethanolSolventHCID 962WaterSolventHCID 1140TolueneSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution Ethyl 5-cyano-1H-indole-2-carboxylate (37 mg, 0.173 mmol), 2-[4-(trifluoromethoxy) phenoxy]ethanol (42 mg, 0.19 mmol) and Triphenylphosphine (227 mg, 0.518 mmol) in toluene (1 mL) was add DIAD (0.044 ml, 0.225 mmol) dropwise at RT. The reaction was let to stir overnight. The mixture was diluted with EtOAc and quenched with water. The two layers were separated, and the aqueous phase was further extracted twice with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by normal phase silica chromatography. The eluting solvent was 0-30% EtOAc in Hexanes. The isolated ethyl 5-cyano-1-{2-[4-(trifluoromethoxy)phenoxy]ethyl}-1H-indole-2-carboxylate (15 mg, 0.04 mmol) was dissolved in THF (1 mL), MeOH (300 uL) and 1M NaOH (200 uL). The reaction went to completion in 5 hr. Water was added, the pH was adjusted to 3 with 1N HCl, and the solvent was removed in vacuo. EtOAc was added to the resulting aqueous solution. The two layers were separated, and the aqueous phase was further extracted twice with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to yield 13.4 mg of the title product. HRMS: Calc for C19H13F3N2O4 413.0720. Found 413.0718

Workup

  1. customquenched with water
  2. customThe two layers were separated
  3. extractionthe aqueous phase was further extracted twice with EtOAc
  4. washThe combined organic layers were washed with brine
  5. dry with materialdried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe residue was purified by normal phase silica chromatography
  9. waitThe reaction went to completion in 5 hr
  10. customthe solvent was removed in vacuo
  11. additionEtOAc was added to the resulting aqueous solution
  12. customThe two layers were separated
  13. extractionthe aqueous phase was further extracted twice with EtOAc
  14. washThe combined organic layers were washed with brine
  15. dry with materialdried (Na2SO4)
  16. filtrationfiltered
  17. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-715a5af52da54067a6b3f7b777a2190d
Source dataset
uspto-grants-2015_08
Patent number
US09102673B2

Reaction notes

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