Morpholine → 3-Fluoro-4-morpholinoaniline

HRID 1166696Notes

Reaction equation

HRID 1166696 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[CH:5]=[CH:6][C:7]=1F.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[H][H]>C1COCC1.O.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[NH2:9]

Participants

8

Reactant 4

HCID 8083MorpholineHCID 222302-Hydroxy-1,2,3-propanetricarboxylic acid hydrate (1:1)HCID 1230531,2-Difluoro-4-nitrobenzeneHCID 178418361HCID 178418361, compound

Product 1

HCID 14853303-Fluoro-4-morpholinoaniline

Reagents, catalysts & solvents 3

HCID 23938PalladiumCatalystHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

3,4-Difluoronitrobenzene (25.196 g, 158.38 mmol) is added to a mixture of morpholine (60.0 ml, 688 mmol, 4.34 eq) in THF (30 ml) at −14°. The mixture is permitted to warm to 10° then maintained at 10-13° for 1 hr. A mixture of citric acid monohydrate (75 g, 357 mmol, 2.25 eq) in water (365 ml) is added with concomitant exotherm to 28°. The phases are separated and the aqueous phase is washed with toluene (95 ml). The organic phase is washed with water (315 ml) and concentrated under reduced pressure. Toluene (46 ml) and methanol (60 ml) are added followed by palladium on Carbon (5%, 50% water wet, 3.1603 g, 0.7426 mmol, 0.00469 eq) and the mixture sealed in a Parr shaker. Hydrogen pressure (40 psi) is applied and maintained while agitating for 42 min. The catalyst is then removed by filtration under reduced pressure and washed with toluene (60 ml). Heptane (150 ml) is added to the filtrate and the resultant slurry concentrated under reduced pressure. Heptane (300 ml) is added and the precipitate collected by filtration under reduced pressure and washed with heptane and dried to give the title compound, HPLC (stationary phase is 4.6×250 mm zorbax RX C-8 column; mobile phase is acetonitrile (650 ml), triethylamine (1.85 ml) and acetic acid (1.30 ml) and water of sufficient amount to make 1,000 ml; flow rate=3.0 ml/min; UV detection at 254 nm) RT=1.08 min, >99.3 area); NMR (Pyridine-D5) 2.95-2.98, 3.80-3.83, 5.38, 6.68, 6.78 and 6.90 δ; CMR (Pyridine-D5) 52.43, 67.33, 103.31, 110.63, 121.29, 130.80, 146.23 and 157.72 δ.

Workup

  1. temperatureto warm to 10°
  2. temperaturethen maintained at 10-13° for 1 hr
  3. additionis added with concomitant exotherm to 28°
  4. customThe phases are separated
  5. washthe aqueous phase is washed with toluene (95 ml)
  6. washThe organic phase is washed with water (315 ml)
  7. concentrationconcentrated under reduced pressure
  8. additionToluene (46 ml) and methanol (60 ml) are added
  9. customthe mixture sealed in a Parr shaker
  10. temperaturemaintained
  11. customThe catalyst is then removed by filtration under reduced pressure
  12. washwashed with toluene (60 ml)
  13. additionHeptane (150 ml) is added to the filtrate
  14. concentrationthe resultant slurry concentrated under reduced pressure
  15. additionHeptane (300 ml) is added
  16. filtrationthe precipitate collected by filtration under reduced pressure
  17. washwashed with heptane
  18. customdried

Sources & evidence

ORD record
ord-3195a61972a64ac080e34b60bd03b9ec
Source dataset
uspto-grants-2003_09
Patent number
US06613944B2

Reaction notes

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