Formic Acid → 5-Fluorobenzimidazole

Under ice cooling, 4 mol/L hydrochloric acid (200 mL) and formic acid (38.3 g) were sequentially added to 4-fluoro-1,2-phenylenediamine (21.0 g), and the mixture was heated to reflux for 90 minutes while being stirred. Under ice cooling, the reaction mixture was basified with a 10% aqueous solution of sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was washed with diisopropyl ether, and 5-fluorobenzimidazole (19.7 g) was obtained. 5-Fluorobenzimidazole (19.7 g) thus obtained was dissolved in toluene (500 mL), and methyl orthoformate (38.7 g) and benzenesulfonic acid monohydrate (1.0 g) were sequentially added thereto. The mixture was heated to reflux for 40 hours while being stirred. After distilling off the solvent and methyl orthoformate under reduced pressure, the residue was diluted with toluene. Diisopropylamine (1 mL) and a saturated aqueous solution of sodium hydrogen carbonate were sequentially added thereto under ice cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by basic silica gel chromatography (20% to 100% ethyl acetate/hexane), and thus the title compound (25.2 g) was obtained.

1. temperaturethe mixture was heated
2. temperatureto reflux for 90 minutes
3. extractionextracted with ethyl acetate
4. washThe organic layer was washed with saturated brine
5. dry with materialdried over anhydrous sodium sulfate
6. distillationAfter distilling off the solvent under reduced pressure
7. washthe residue was washed with diisopropyl ether

ORD-Eintrag

ord-67bc9e2d90534d9aa6be0da581d02835

Quelldatensatz

uspto-grants-2015_08

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US09096531B2