Trifluoroacetic acid → HCID 67265137, compound

HRID 1687506Notes

Reaction equation

HRID 1687506 reaction equation
FC(F)(F)C(O)=O.[N+]([O-])([O-])=O.[K+].[CH3:13][O:14][C:15]1[C:20]2[CH2:21][CH2:22][CH2:23][CH:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH2:25][C:19]=2[CH:18]=[CH:17][C:16]=1[N+:32]([O-])=O>C(#N)C.C(O)C.[Pd]>[CH3:13][O:14][C:15]1[C:20]2[CH2:21][CH2:22][CH2:23][CH:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH2:25][C:19]=2[CH:18]=[CH:17][C:16]=1[NH2:32]

Participants

7

Reactant 3

HCID 6422Trifluoroacetic acidHCID 24434Potassium NitrateHCID 67263902HCID 67263902, compound

Product 1

HCID 67265137HCID 67265137, compoundYield 61%

Reagents, catalysts & solvents 3

HCID 23938PalladiumCatalystHCID 702EthanolSolventHCID 6342AcetonitrileSolvent

Procedure

The reductive amination product obtained above (5.46 g, 20.87 mmol) was dissolved in dry acetonitrile (35 mL) and trifluoroacetic acid (30 mL) and cooled to −5° C. Potassium nitrate (2.11 g, 20.9 mmol) was added in one portion and the mixture was stirred for three hours while warming to room temperature. The resulting mixture was poured in ice water was extracted with dichloromethane. The dichloromethane extract was washed with saturated sodium bicarbonate solution, was dried (sodium sulfate), and was concentrated. ISCO chromatography was effected in several batches (stepwise gradient: 35 to 40 to 45 to 50 to 55 to 60% followed by 100% ethyl acetate:dichloromethane) to afford two regioisomers in order of elution: 4-(1-Methoxy-4-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-morpholine (2.41 g, 38%) and 4-(1-Methoxy-2-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-morpholine (1.41 g, 22%). The latter nitro isomer, 4-(1-Methoxy-2-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-morpholine (1.51 g, 4.939 mmol) was dissolved in ethanol (100 mL) and hydrogenated over 10% palladium on carbon (151 mg) at 50 psi using a Parr shaker for 3 hours. The palladium was removed by filtration and the ethanol was concentrated to afford a brown foam which was purified via ISCO chromatography (gradient elution: 2 to 8% methanol:dichloromethane) to afford 1-methoxy-6-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine (830 mg, 61%) as a brown solid.

Workup

  1. customThe reductive amination product obtained above (5.46 g, 20.87 mmol)
  2. extractionwas extracted with dichloromethane
  3. extractionThe dichloromethane extract
  4. washwas washed with saturated sodium bicarbonate solution
  5. dry with materialwas dried (sodium sulfate)
  6. concentrationwas concentrated
  7. customdichloromethane) to afford two regioisomers
  8. washin order of elution
  9. customfor 3 hours
  10. customThe palladium was removed by filtration
  11. concentrationthe ethanol was concentrated
  12. customto afford a brown foam which
  13. customwas purified via ISCO chromatography (gradient elution: 2 to 8% methanol:dichloromethane)

Sources & evidence

ORD record
ord-d39de0dd1fc94b058eefd6a5b5947ec3
Source dataset
uspto-grants-2012_04
Patent number
US08148391B2

Reaction notes

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