3,5-difluoro-4-hydroxybenzonitrile

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Example 32, intermediate b), 3,5-difluoro-4-hydroxybenzonitrile (commercially available), triphenylphosphine and di-tert-butyl azodicarboxylate. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 70:30). Colorless foam. MS (Turbo Spray): m/z=492.4 [M+H]. The compound was purified by silica gel chromatography eluting with a gradient of n-heptane:ethyl acetate (100:0 to 70:30)

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A stirred reaction vessel charged with 4-cyanophenol (11.9 g, 0.1 mol) and 96% formic acid (200 cm3) was purged with nitrogen and cooled to 10° C. Fluorine (0.2 mol), diluted with nitrogen to 10%, was passed through the cooled, stirred solution over a period of about 6 hours. The vessel was purged with nitrogen and allowed to warm to ambient temperature. The reaction mixture was poured into water and extracted with diethyl ether. The extracts were dried and the solvent was removed by distillation to leave a tan solid (12.4 g). Short path distillation of the crude product (3.9 g) at reduced pressure gave an off white solid (3.4 g) which was shown to comprise three main compounds by nmr and GC analysis. The mixture was shown to contain 4-cyano-2-fluorophenol (δF -134.7 ppm[d6 -Me2CO]) and 4-cyano-2,6-difluorophenol (δF -131.0 ppm[d6 -Me2CO]) in yields of 64% and 10%, respectively, with a conversion of 84%. (NB The chemical shifts in this and all other examples were relative to CFCl3.) in yields of 64% and 10%

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A stirred reaction vessel charged with 4-cyanophenol (11.9 g, 0.1 mol) and 96% formic acid (200 cm3) was purged with nitrogen and cooled to 10° C. Fluorine (0.2 mol), diluted with nitrogen to 10%, was passed through the cooled, stirred solution over a period of about 6 hours. The vessel was purged with nitrogen and allowed to warm to ambient temperature. The reaction mixture was poured into water and extracted with diethyl ether. The extracts were dried and the solvent was removed by distillation to leave a tan solid (12.4 g). Short path distillation of the crude product (3.9 g) at reduced pressure gave an off white solid (3.4 g) which was shown to comprise three main compounds by nmr and GC analysis. The mixture was shown to contain 4-cyano-2-fluorophenol (δF -134.7 ppm[d6 -Me2CO]) and 4-cyano-2,6-difluorophenol (δF -131.0 ppm[d6 -Me2CO]) in yields of 64% and 10%, respectively, with a conversion of 84%. (NB The chemical shifts in this and all other examples were relative to CFCl3.) in yields of 64% and 10%

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Example 32, intermediate b), 3,5-difluoro-4-hydroxybenzonitrile (commercially available), triphenylphosphine and di-tert-butyl azodicarboxylate. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 70:30). Colorless foam. MS (Turbo Spray): m/z=492.4 [M+H]. The compound was purified by silica gel chromatography eluting with a gradient of n-heptane:ethyl acetate (100:0 to 70:30)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 4-bromo-2,6-difluorophenol (4.00 g, 19.0 mmol), copper (I) cyanide (1.72 g, 19.0 mmol), and dimethylformamide (40 mL) was refluxed for 6 hours, cooled to room temperature, diluted with water (150 mL), and filtered. The tan solids obtained were washed with water and retained. The combined filtrates were acidified (1N HCl) and extracted with ethyl acetate. The combined organic extracts were dried (MgSO4), concentrated in vacuo, and purified by flash chromatography (Silica Gel 60, 20% ethyl acetate in hexanes) to give 1.03 g of pure title compound as an off-white solid, mp 195°-197° C. was refluxed for 6 hours filtered The tan solids obtained were washed with water extracted with ethyl acetate The combined organic extracts were dried (MgSO4) concentrated in vacuo purified by flash chromatography (Silica Gel 60, 20% ethyl acetate in hexanes)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 4-bromo-2,6-difluorophenol (4.00 g, 19.0 mmol), copper (I) cyanide (1.72 g, 19.0 mmol), and dimethylformamide (40 mL) was refluxed for 6 hours, cooled to room temperature, diluted with water (150 mL), and filtered. The tan solids obtained were washed with water and retained. The combined filtrates were acidified (1N HCl) and extracted with ethyl acetate. The combined organic extracts were dried (MgSO4), concentrated in vacuo, and purified by flash chromatography (Silica Gel 60, 20% ethyl acetate in hexanes) to give 1.03 g of pure title compound as an off-white solid, mp 195°-197° C. was refluxed for 6 hours filtered The tan solids obtained were washed with water extracted with ethyl acetate The combined organic extracts were dried (MgSO4) concentrated in vacuo purified by flash chromatography (Silica Gel 60, 20% ethyl acetate in hexanes)

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A suspension of 3,5-difluoro-4-hydroxybenzonitrile (10 g, 0.0649 mol; see Preparation B(iv) above), anhydrous K2CO3 (17.94 g, 0.1298 mol) and 1,2-dibromoethane (73.2 g, 0.389 mol) in dry DMF (100 mL) was stirred at 60° C. overnight under a nitrogen atmosphere. The reaction mixture was filtered through Celite® and the solvent was then evaporated under reduced pressure. The residue was purified by column chromatography over silica gel, using 1.5% ethyl acetate in petroleum ether as eluent, to yield 12 g of the sub-title compound as a white solid. The reaction mixture was filtered through Celite® the solvent was then evaporated under reduced pressure The residue was purified by column chromatography over silica gel

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 3,5-difluoro-4-hydroxybenzonitrile (2.1 g, 0.0136 mol; see step (iv) above), K2CO3 (3.76 g, 0.0272 mol) and 1,3-dibromopropane (16.48 g, 0.0816 mol) in dry DMF (50 mL) was stirred at 60° C. overnight under a nitrogen atmosphere. The reaction mixture was filtered through Celite® and partitioned between water and ethyl acetate. The organic layer was washed with water and brine and then dried over sodium sulfate. Solvent evaporation under reduced pressure provided a residue that was purified by column chromatography over silica gel, using 2.5% ethyl acetate in petroleum ether as eluent, to yield 1.5 g (20%) of the sub-title compound as a yellow liquid. The reaction mixture was filtered through Celite® partitioned between water and ethyl acetate The organic layer was washed with water and brine dried over sodium sulfate Solvent evaporation under reduced pressure provided a residue that was purified by column chromatography over silica gel