Hydroxyamine hydrochloride → 3-fluoro-N'-hydroxy-4-(hydroxymethyl)benzenecarboximidamide

To a mixture of 3-fluoro-4-(hydroxymethyl)benzonitrile (3.51 g, 23.2 mmol) and hydroxylamine hydrochloride (3.23 g, 46.4 mmol) in methanol (100 mL) under nitrogen was added sodium bicarbonate (7.80 g, 93 mmol). The reaction mixture was stirred at room temperature for 5 min. and then immersed in an oil bath and heated at reflux for 2 h. HPLC analysis indicated that the starting material had been consumed. The heterogeneous mixture was filtered, the solid was washed with methanol, and the filtrate was concentrated under reduced pressure. The white solid residue was diluted with ethyl acetate (400 mL) but remained heterogeneous. The mixture was sonicated for 5 min and filtered under reduced pressure. The filtrated was washed with water (60 mL), and washed with a 10% aqueous solution of lithium chloride (60 mL), and washed with brine (60 mL). The combined aqueous layers were extracted with ethyl acetate (100 mL), and the combined organic layers were dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded (Z)-3-fluoro-N′-hydroxy-4-(hydroxymethyl)benzimidamide (3.85 g, 20.9 mmol, 90% yield) as a white solid. The compound had an HPLC time=0.263 min.−Column. CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. MS M+1=184.9. 1H NMR (500 MHz, DMSO-d6) δ ppm 4.54 (d, 2H), 5.28 (t, J=5.83 Hz, 1H), 5.86 (s, 2H), 7.40 (dd, J=11.65, 1.39 Hz, 1H), 7.44 (t, J=7.91 Hz, 1H), 7.51 (dd, J=8.05, 1.66 Hz, 1H), and 9.72 (s, 1H).

1. customimmersed in an oil bath
2. temperatureheated
3. temperatureat reflux for 2 h
4. customhad been consumed
5. filtrationThe heterogeneous mixture was filtered
6. washthe solid was washed with methanol
7. concentrationthe filtrate was concentrated under reduced pressure
8. additionThe white solid residue was diluted with ethyl acetate (400 mL)
9. customThe mixture was sonicated for 5 min
10. filtrationfiltered under reduced pressure
11. washThe filtrated was washed with water (60 mL)
12. washwashed with a 10% aqueous solution of lithium chloride (60 mL)
13. washwashed with brine (60 mL)
14. extractionThe combined aqueous layers were extracted with ethyl acetate (100 mL)
15. dry with materialthe combined organic layers were dried over anhydrous sodium sulfate
16. concentrationConcentration under reduced pressure

ORD record

ord-717b2370222c40fe9a15c0e240fc1698

Source dataset

uspto-grants-2013_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08354398B2