3-fluoro-4-hydroxybenzonitrile

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c) and 3-fluoro-4-hydroxybenzonitrile (commercially available) and replacing di-ethyl azodicarboxylate by di-tert-butyl azodicarboxylate. The resulting solid was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane and ethyl acetate (100:0 to 50:50) to give the desired compound as a colorless foam (89%). MS (Turbo Spray): m/z=510.3 [M+H]. The resulting solid was purified by silica gel chromatography eluting with a gradient of n-heptane and ethyl acetate (100:0 to 50:50)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Potassium iodide (7.97 g, 48 mmol) was dissolved in 125 ml of DMF with stirring, and 4-cyano-2-fluorophenol (16a; 5.56 g 48 mmol) and chloramine-T in 75 ml of DMF were added dropwise with stirring. The reaction mixture was poured into 650 ml of water, acidified with 6N HCl, and extracted with ethyl acetate. The organic layer was washed with 10% NaHSO3, water and brine and dried over magnesium sulfate. The organic solution was concentrated in vacuo and the yellow solid residue was treated with 200 ml of 1N NaOH solution, filtered through supercel, and the filtrate was acidified with conc. HCl solution. The solid product was filtered, dried, dissolved in ether, and the organic layer was dried over magnesium sulfate. The organic solution was concentrated in vacuo and the residue was recrystallized from ethylene chloride to afford 5.93 g (55.6%) of the title compounds. with stirring extracted with ethyl acetate The organic layer was washed with 10% NaHSO3, water and brine dried over magnesium sulfate The organic solution was concentrated in vacuo the yellow solid residue was treated with 200 ml of 1N NaOH solution filtered through supercel The solid product was filtered dried dissolved in ether the organic layer was dried over magnesium sulfate The organic solution was concentrated in vacuo the residue was recrystallized from ethylene chloride

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Potassium iodide (7.97 g, 48 mmol) was dissolved in 125 ml of DMF with stirring, and 4-cyano-2-fluorophenol (16a; 5.56 g 48 mmol) and chloramine-T in 75 ml of DMF were added dropwise with stirring. The reaction mixture was poured into 650 ml of water, acidified with 6N HCl, and extracted with ethyl acetate. The organic layer was washed with 10% NaHSO3, water and brine and dried over magnesium sulfate. The organic solution was concentrated in vacuo and the yellow solid residue was treated with 200 ml of 1N NaOH solution, filtered through supercel, and the filtrate was acidified with conc. HCl solution. The solid product was filtered, dried, dissolved in ether, and the organic layer was dried over magnesium sulfate. The organic solution was concentrated in vacuo and the residue was recrystallized from ethylene chloride to afford 5.93 g (55.6%) of the title compounds. with stirring extracted with ethyl acetate The organic layer was washed with 10% NaHSO3, water and brine dried over magnesium sulfate The organic solution was concentrated in vacuo the yellow solid residue was treated with 200 ml of 1N NaOH solution filtered through supercel The solid product was filtered dried dissolved in ether the organic layer was dried over magnesium sulfate The organic solution was concentrated in vacuo the residue was recrystallized from ethylene chloride

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Bromo-2-fluorophenol (10 ml, 91 mmol) and 9.85 g (0.11 mol) of CuCN were combined in 75 ml of NMP with stirring under nitrogen, and the mixture was heated at 150° C. for 5 h. The mixture was diluted with 200 ml of ether, stirred, and decanted. The residue was diluted again with 200 ml of ether, heated, and decanted. The combined decantates were washed with water, 1N HCl solution, water, and brine, and dried over magnesium sulfate. The organic solution was concentrated in vacuo to provide 12 g of a white solid which was triturated in carbon tetrachloride and filtered to afford 7.29 g (72.1%) of the title compound. stirred decanted The residue was diluted again with 200 ml of ether heated decanted The combined decantates were washed with water, 1N HCl solution, water, and brine dried over magnesium sulfate The organic solution was concentrated in vacuo

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Bromo-2-fluorophenol (10 ml, 91 mmol) and 9.85 g (0.11 mol) of CuCN were combined in 75 ml of NMP with stirring under nitrogen, and the mixture was heated at 150° C. for 5 h. The mixture was diluted with 200 ml of ether, stirred, and decanted. The residue was diluted again with 200 ml of ether, heated, and decanted. The combined decantates were washed with water, 1N HCl solution, water, and brine, and dried over magnesium sulfate. The organic solution was concentrated in vacuo to provide 12 g of a white solid which was triturated in carbon tetrachloride and filtered to afford 7.29 g (72.1%) of the title compound. stirred decanted The residue was diluted again with 200 ml of ether heated decanted The combined decantates were washed with water, 1N HCl solution, water, and brine dried over magnesium sulfate The organic solution was concentrated in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 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%

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 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%