Acetic Acid → 7-(Trifluoromethyl)-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one

HRID 2353962Notes

Reaction equation

HRID 2353962 reaction equation
COC(=O)[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6](C)[C:5]=1[N:15](C(OC(C)(C)C)=O)[CH2:16][CH2:17][CH2:18][C:19]([O:21]C)=O.CC(C)([O-])C.[K+].C(O)(=O)C.O>C1(C)C=CC=CC=1.ClCCl>[F:13][C:10]([F:11])([F:12])[C:8]1[CH:9]=[CH:4][C:5]2[NH:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[C:6]=2[CH:7]=1

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 962WaterHCID 23665647Potassium tert-butoxideHCID 68678532HCID 68678532, compound

Product 1

HCID 686801337-(Trifluoromethyl)-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one

Reagents, catalysts & solvents 2

HCID 1140TolueneSolvent2×HCID 6344DichloromethaneSolvent

Conditions

Temperature
100 °C

Procedure

Add a solution of methyl 2-[tert-Butoxycarbonyl-(3-methoxycarbonyl-propyl)-amino]-5-trifluoromethyl-benzoic acid methyl ester (0.5 g, 1.3 mmol) in toluene (25 mL) to a suspension of potassium tert-butoxide (0.3 g, 2.6 mmol) in toluene (75 mL) at 70° C., under an atmosphere of nitrogen, over a period of 30 min. After 2 h, cool the reaction to room temperature and quench the reaction with acetic acid (2.6 mmol). Dilute the reaction with water (100 mL) and dichloromethane (100 mL). Separate the organic phase, dry over sodium sulfate, and filter. Remove the solvent under vacuum then dissolve the crude intermediate in acetic acid (20 mL). Dilute with conc. HCl (20 mL) and water (10 mL) and heat the mixture to 100° C. for 4 h. After cooling to room temperature neutralize the reaction with 5N NaOH while cooling in an ice bath. Extract the organics with ethyl acetate (3×100 mL), dry over sodium sulfate, and filter. Remove the solvent under vacuum and chromatograph the product over silica gel using ethyl acetate/hexane (5-20%) to elute. This provides the title compound as an off white solid (0.13 g, 45%): H NMR (CDCl3, 400 MHz) δ 2.22-2.29 (m, 2H), 2.88 (t, J=6.4 Hz), 3.35 (t, J=6.8 Hz), 4.96 (bs, 1H), 6.84 (d, J=8.8 Hz, 1H), 7.46 (dd, J=2.0, 8.8 Hz, 1H), 8.02 (s, 1H).

Workup

  1. waitAfter 2 h
  2. temperaturecool
  3. customthe reaction to room temperature
  4. customquench
  5. additionDilute
  6. customSeparate the organic phase
  7. dry with materialdry over sodium sulfate
  8. filtrationfilter
  9. customRemove the solvent under vacuum
  10. dissolutionthen dissolve the crude intermediate in acetic acid (20 mL)
  11. additionDilute with conc. HCl (20 mL) and water (10 mL)
  12. temperatureAfter cooling to room temperature
  13. customthe reaction with 5N NaOH
  14. temperaturewhile cooling in an ice bath
  15. extractionExtract the organics with ethyl acetate (3×100 mL)
  16. dry with materialdry over sodium sulfate
  17. filtrationfilter
  18. customRemove the solvent under vacuum and chromatograph the product over silica gel
  19. washto elute

Sources & evidence

ORD record
ord-65718844619645d88b3aeb4b67702ba3
Source dataset
uspto-grants-2010_07
Patent number
US07749992B2

Reaction notes

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