Formaldehyde → 4-Fluoro-2-hydroxybenzaldehyde

Temperature

25 °C

Magnesium methoxide (13 g, 150 mmol, 6% in methanol) in methanol (50 mL) was treated with 3-fluorophenol (22.4 g, 200 mmol). The solution was heated to reflux and approximately half the methanol distilled off. Toluene (300 mL) was added and the reaction mixture was heated with azeotropic removal of solvent until the temperature of the distillate reached 95° C. A slurry of paraformaldehyde powder (22 g, 720 mmol) in toluene (20 mL) was added in small portions over 1 hour to the reaction with concurrent removal of volatile materials by distillation. The mixture was stirred was at 95° C. for 1 hour, cooled to 25° C., quenched by slow addition to 10% sulfuric acid and stirred at 30-40° C. for 2 hours. The layers were separated and the aqueous portion extracted with toluene (2×50 mL). The organic layers were combined, washed with 10% sulfuric acid, washed with water, dried with sodium sulfate, filtered and the solvent was evaporated. The resulting yellow oil was purified by flash chromatography over silica gel eluting with hexane:ethyl acetate (5:1) to provide 9.7 g of the title compound as a white solid.

1. temperatureThe solution was heated
2. temperatureto reflux
3. distillationapproximately half the methanol distilled off
4. additionToluene (300 mL) was added
5. temperaturethe reaction mixture was heated with azeotropic removal of solvent until the temperature of the distillate
6. customreached 95° C
7. customquenched by slow addition to 10% sulfuric acid
8. stirringstirred at 30-40° C. for 2 hours
9. customThe layers were separated
10. extractionthe aqueous portion extracted with toluene (2×50 mL)
11. washwashed with 10% sulfuric acid
12. washwashed with water
13. dry with materialdried with sodium sulfate
14. filtrationfiltered
15. customthe solvent was evaporated
16. customThe resulting yellow oil was purified by flash chromatography over silica gel eluting with hexane:ethyl acetate (5:1)

ORD record

ord-7828702f8551411ca2098c8bf270b5de

Source dataset

uspto-grants-2003_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06642222B2