Dimethylformamide → 2-chloro-3-(1-cyanocyclopropyl)-N-(2,4-difluoro-5-hydroxyphenyl)benzamide

To a solution of 2-chloro-3-(1-cyanocyclopropyl)benzoic acid (4.42 g, 20 mmol) produced in Example C62(ii) in oxalyl chloride (10 mL) was added N,N-dimethylformamide (100 μL)), and the mixture was stirred at room temperature for 1 hr, and concentrated to dryness under reduced pressure. This was dissolved in tetrahydrofuran (10 mL), and the solution was added dropwise with vigorous stirring to a two-layer mixture of a solution of 5-amino-2,4-difluorophenol (2.90 g, 20 mmol) in tetrahydrofuran (5 mL) and a solution (10 mL) of sodium hydrogen carbonate (2.70 g, 30 mmol) in water under ice-cooling. The reaction mixture was stirred at room temperature for 1 hr, and poured into water (200 mL), and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→50/50) to give the title compound (4.90 g, 70%) as white crystals.

1. concentrationconcentrated to dryness under reduced pressure
2. dissolutionThis was dissolved in tetrahydrofuran (10 mL)
3. additionthe solution was added dropwise
4. stirringThe reaction mixture was stirred at room temperature for 1 hr
5. extractionthe mixture was extracted with ethyl acetate (100 mL×2)
6. dry with materialdried over anhydrous sodium sulfate
7. filtrationThe insoluble material was filtered off
8. concentrationthe filtrate was concentrated under reduced pressure
9. customThe obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→50/50)

ORD record

ord-604edac178f54e0d84ff4d590eaa51ad

Source dataset

uspto-grants-2013_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08344135B2