Hydrochloric Acid → 4-Amino-2,6-difluorobenzaldehyde

Temperature

-78 °C

A solution of 3,5-difluoroaniline (12.9 g, 0.1 mol) in anhydrous THF (400 mL) was cooled at −78° C. and treated with nbutyllithium (2.5 M in hexane, 84 mL, 0.21 mol, 2.1 equv.) dropwise over 25 min. After stirring at −78° C. for 30 min, trimethylsilyl chloride (1.0 M in THF, 210 mL, 0.21 mol, 2.1 equiv.) was added dropwise over 30 min. The temperature was allowed to rise to 23° C. and stirred overnight. After re-cooling to −78° C., additional n-butyllithium (2.5 M in hexane, 44 mL, 0.11 mol, 1.1 equiv.) was added dropwise over 20 min, and the reaction mixture was stirred at that temperature for 5 hours to form the anion. Then dimethylformamide (11.6 ml, 0.15 mol, 1.5 equiv.) was added dropwise over 20 min. The temperature was allowed to rise to 23° C. and stirred overnight. The mixture was cooled in an ice-bah and acidified to pH=1 by slow addition of aqueous HCl (1.0 M, 220 mL, 0.22 mol). After stirring 15 min, the mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed (brine), dried (Na2SO4), filtered and evaporated to dry. The residue was purified by chromatography on a silica gel column, eluting with a gradient increasing in polarity from 0 to 50% ethyl acetate in hexane. Relevant fractions were combined to give the title compound.

1. customto rise to 23° C.
2. stirringstirred overnight
3. temperatureAfter re-cooling to −78° C.
4. stirringthe reaction mixture was stirred at that temperature for 5 hours
5. customto form the anion
6. customto rise to 23° C.
7. stirringstirred overnight
8. stirringAfter stirring 15 min
9. extractionthe mixture was extracted with ethyl acetate (3×200 mL)
10. washThe combined organic layers were washed (brine)
11. dry with materialdried (Na2SO4)
12. filtrationfiltered
13. customevaporated
14. customto dry
15. customThe residue was purified by chromatography on a silica gel column
16. washeluting with
17. temperaturea gradient increasing in polarity from 0 to 50% ethyl acetate in hexane

ORD record

ord-15c503a261c04a1a95b023ab6553c0f8

Source dataset

uspto-grants-2007_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07279494B2