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1.6: 2-Fluoro-6-hvdroxybenzo?itrile (analogous to WO 99/14187):151 g (1 mol) of <strong>[94088-46-7]2-fluoro-6-methoxybenzonitrile</strong> and 346.5 g (3 mol) of pyridinium hy? drochloride were introduced into a 2 I flask and then slowly heated to 1900C under a protective gas atmosphere and then stirred at this temperature for 5 h. The mixture was cooled by slowly stirring to room temperature overnight. Then 1000 ml of water were added, and the mixture was heated to 8O0C. After adding 1000 ml of methyl tert.-butyl ether, the phases were separated and the aqueous phase was back-extracted twice with 500 ml of methyl tert.-butyl ether. The combined methyl tert.-butyl ether phases were washed once with 800 ml of 10% strength aqueous sodium hydroxide solution and once with 400 ml of water. The two aqueous phases were combined, adjusted to pH 2 with concentrated hydrochloric acid and washed three times with 500 ml of methylene chloride. Then, the combined organic phases were washed once with 10% strength hydrochloric acid. The organic phase was dried over sodium sulfate. Finally, the solvent was distilled off in vacuo. Yield: 12O g (87% of theory) of the desired product of purity >99% according to GC.1H NMR (in D6 dimethylsulfoxide): delta = 6.85 ppm (m, 2H, arom. H), 7.55 ppm (q, 1H, arom. H), 11.7 ppm (s, 1H1 OH).
With pyridine hydrochloride; at 20 - 190℃;
1.2. 2-Fluoro-6-hydroxybenzonitrile:; 151 g (1 mol) of <strong>[94088-46-7]2-fluoro-6-methoxybenzonitrile</strong> and 346.5 g (3 mol) of pyridinium hydrochloride have been introduced into a 2 I flask and then slowly heated to 190C under a protective gas atmosphere and then stirred at this temperature for 5 h. The mixture has been cooled with slow stirring to room temperature overnight. Then 1000 ml of water have been added, and the mixture has been heated to 80C. After adding 1000 ml of methyl tert-butyl ether, the phases have been are separated and the aqueous phase has been back-extracted twice with 500 ml of methyl tert-butyl ether. The combined methyl tert-butyl ether phases have been washed once with 800 ml of 10% strength NaOH and once with 400 ml of water. The two aqueous phases have been combined, adjusted to pH 2 with concentrated hydrochloric acid and washed three times with 500 ml of methylene chloride. Then, the combined organic phases <n="246"/>have been washed once with 10% strength hydrochloric acid. The organic phase has been dried over sodium sulfate. Finally, the solvent has been distilled off in vacuo to give 120 g (870 mmol) of the desired product.
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere;
a) 2-Ethoxy-6-fluorobenzonitrile I52 A mixture of 2-fluoro-6-hydroxybenzonitrile (2.0 g, 14.6 mmol), K2CO3 (6.04 g, 43.8 mmol) and bromoethane (2.38 g, 21.9 mmol) in DMF (4 ml.) was stirred at RT under N2 overnight. The mixture was diluted with EtOAc (300 ml_), washed with water (100 ml. x 5), brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Pet. ether/EtOAc = 100/1 to 5/1) to give the title compound (1.6 g, 67%) as a white solid. LCMS-E: Rt5.24 min; m/z 166.1 [M+H]+.
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