Morpholine → 3-Fluoro-4-morpholinoaniline

Temperature

10 °C

3,4-Difluoronitrobenzene (25.196 g, 158.38 mmol) was added to a mixture of morpholine (60.0 ml, 688 mmol, 4.34 eq) in THF (30 ml) at −14° C. The mixture was permitted to warm to 10° C., then maintained at 10–13° C. for 1 hr. A mixture of citric acid monohydrate (75 g, 357 mmol, 2.25 eq) in water (365 ml) was added with a concomitant exotherm to 28° C. The phases were separated, and the aqueous phase was washed with toluene (95 ml). The organic phase was washed with water (315 ml), then concentrated under reduced pressure. Toluene (46 ml) and methanol (60 ml) were added, followed by palladium on carbon (5%, 50% water wet, 3.1603 g, 0.7426 mmol, 0.00469 eq), and the mixture was sealed in a Parr shaker. Hydrogen pressure (40 psi) was applied and maintained while agitating for 42 min. The catalyst then was removed by filtration under reduced pressure, and washed with toluene (60 ml). Heptane (150 ml) added to the filtrate and the resultant slurry concentrated under reduced pressure. Heptane (300 ml) was added, and the precipitate collected by filtration under reduced pressure, 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); 1H-NMR (Pyridine-d5) δ: 2.95–2.98, 3.80–3.83, 5.38, 6.68, 6.78 and 6.90; CMR (Pyridine-d5) 52.43, 67.33, 103.31, 110.63, 121.29, 130.80, 146.23 and 157.72.

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

ORD record

ord-b3192314ebad42b590dfd55e971cc762

Source dataset

uspto-grants-2006_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06998420B2