Formaldehyde → 4-Fluoro-2,3-dihydroxybenzaldehyde

Temperature

80 °C

To a solution of 3-fluoro-benzene-1,2-diol (20 g, 156 mmol) in anhydrous acetonitrile (400 mL) was added magnesium chloride (37.1 g, 312 mmol), paraformaldehyde (31.6 g) and triethylamine (134 mL, 975 mmol). The reaction mixture was heated at 80° C. for 8 h. The reaction mixture was cooled to room temperature and the solid was collected by filtration. The solid was treated with cold 2 N HCl and the aqueous layer was extracted with EtOAc. The organic layer was concentrated in vacuo yielding 20.4 g of crude. After a second run 40.8 g of crude was dissolved in DMF (1 L), cooled to 0° C., added to Cs2CO3 (340 g, 1.04 mol) portion-wise. Then methyl iodide (330 mL, 5.28 mol) was added. After warming to room temperature and stirring overnight the solution was filtered, ethyl acetate was added and the organic layer was washed with water (3×). After concentration in vacuo the product was purified by Biotage silica gel chromatography (2% to 3% to 10% to 20% EtOAc/hexanes) resulting in 14.8 g of dimethoxy compound. This material was dissolved in DCM and cooled to −30° C. and BCl3 (1 M in DCM, 134 mL, 0.1343 mol) was added to the solution at −30° C. After overnight at room temperature, the solution was cooled to −70° C. and BBr3 (1 M in DCM, 67.25 mL, 0.067 mol) was added. After overnight warming to room temperature, the solution was cooled in an ice bath and slowly ice water was added. The DCM layer was separated and the aqueous layer was extracted with DCM (2×). The combined organic layer was extracted with brine (2×), dried over Na2SO4, filtered and concentrated in vacuo. After triturating the residue obtained with hexanes/DCM (6:4) the 5.60 g (11% yield) of the title compound obtained was a brownish pink solid. This material was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 11.36 (s, 1H), 9.83 (s, 1H), 7.16-7.13 (m, 1H), 6.82-6.78 (m, 1H), 5.48 (brs, 1H). 19F NMR (376 MHz, DMSO-d6 with D2O) δ (ppm): −119.03-−119.08 (m, 1F).

1. temperatureThe reaction mixture was cooled to room temperature
2. filtrationthe solid was collected by filtration
3. additionThe solid was treated with cold 2 N HCl
4. extractionthe aqueous layer was extracted with EtOAc
5. concentrationThe organic layer was concentrated in vacuo
6. customyielding 20.4 g of crude
7. temperaturecooled to 0° C.
8. temperatureAfter warming to room temperature
9. filtrationwas filtered
10. additionethyl acetate was added
11. washthe organic layer was washed with water (3×)
12. concentrationAfter concentration in vacuo the product
13. customwas purified by Biotage silica gel chromatography (2% to 3% to 10% to 20% EtOAc/hexanes)
14. customresulting in 14.8 g of dimethoxy compound
15. temperaturecooled to −30° C.
16. waitAfter overnight at room temperature
17. temperaturethe solution was cooled to −70° C.
18. temperatureAfter overnight warming to room temperature
19. temperaturethe solution was cooled in an ice bath
20. customThe DCM layer was separated
21. extractionthe aqueous layer was extracted with DCM (2×)
22. extractionThe combined organic layer was extracted with brine (2×)
23. dry with materialdried over Na2SO4
24. filtrationfiltered
25. concentrationconcentrated in vacuo
26. customAfter triturating the residue

ORD record

ord-918d2e48ec0040aebbfe71cffdf7f79d

Source dataset

uspto-grants-2014_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08703742B2