2-fluoro-4-iodobenzonitrile

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

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-fluoro-4-iodobenzonitrile (4000 mg, 16.19 mmol), 5-chloro-4-hydroxypyridin-2(1H)-one (2357 mg, 16.19 mmol), 4,7-dimethoxy-1,10-phenanthroline (778 mg, 3.24 mmol), copper(I) iodide (617 mg, 3.24 mmol) and potassium carbonate (4476 mg, 32.4 mmol) in DMSO (40 mL) was stirred at 140° C. under N2 for 3 hrs. After cooling to room temperature, the reaction mixture was diluted with H2O (50 mL) and 1N HCl was added to adjust the pH to ˜2 (pH paper). The resulting mixture was extracted with EtOAc (400 mL, 2×). The combined extracts were dried (Na2SO4) and evaporated under reduced pressure to give black oil. The residue was purified by flash chromatography on silica gel (0-7% MeOH/CH2Cl2) to give brown oil (3.2 g, 43.3%). MS (ESI) 265 (M+H). After cooling to room temperature was added The resulting mixture was extracted with EtOAc (400 mL, 2×) The combined extracts were dried (Na2SO4) evaporated under reduced pressure to give black oil The residue was purified by flash chromatography on silica gel (0-7% MeOH/CH2Cl2)

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

Procedure: 27 g of sodium nitrite was dissolved in 205 ml of sulfuric acid and cooled to 10° C. or less, and then 238 ml of acetic acid was added. At 20° to 25° C., 65 g of 2-fluoro-4-iodoaniline was added to the solution, and then the solution was agitated for one hour. A second solution was made by dissolving 82.5 g of copper sulfate pentahydrate in 20.5 ml of water, to which was added 140 g of ice, and this solution was added to the first. A third solution containing 88 g of potassium cyanide dissolved in 207 ml of water, 500 g of sodium bicarbonate, and 206 ml of benzene was added to the first solution, and a diazonium salt sulfuric acid solution was added therein. After agitation at room temperature for 3 hours, a sodium hydroxide aqueous solution was added to dissolve the crystals. After being extracted with chloroform, the crystals were washed three times alternating with a 10% sodium hydroxide solution and water. After distillation of the chloroform, the residue was extracted with hexane, and the hexane was distilled off. This residue was subjected to vacuum distillation (95° to 110° C./15 mmHg), and further recrystallized to obtain 20 g of 1-cyano-2-fluoro-4-iodobenzene. cooled to 10° C. or less this solution was added to the first After agitation at room temperature for 3 hours to dissolve the crystals After being extracted with chloroform the crystals were washed three times After distillation of the chloroform the residue was extracted with hexane the hexane was distilled off This residue was subjected to vacuum distillation (95° to 110° C./15 mmHg) further recrystallized

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

Procedure: 27 g of sodium nitrite was dissolved in 205 ml of sulfuric acid and cooled to 10° C. or less, and then 238 ml of acetic acid was added. At 20° to 25° C., 65 g of 2-fluoro-4-iodoaniline was added to the solution, and then the solution was agitated for one hour. A second solution was made by dissolving 82.5 g of copper sulfate pentahydrate in 20.5 ml of water, to which was added 140 g of ice, and this solution was added to the first. A third solution containing 88 g of potassium cyanide dissolved in 207 ml of water, 500 g of sodium bicarbonate, and 206 ml of benzene was added to the first solution, and a diazonium salt sulfuric acid solution was added therein. After agitation at room temperature for 3 hours, a sodium hydroxide aqueous solution was added to dissolve the crystals. After being extracted with chloroform, the crystals were washed three times alternating with a 10% sodium hydroxide solution and water. After distillation of the chloroform, the residue was extracted with hexane, and the hexane was distilled off. This residue was subjected to vacuum distillation (95° to 110° C./15 mmHg), and further recrystallized to obtain 20 g of 1-cyano-2-fluoro-4-iodobenzene. cooled to 10° C. or less this solution was added to the first After agitation at room temperature for 3 hours to dissolve the crystals After being extracted with chloroform the crystals were washed three times After distillation of the chloroform the residue was extracted with hexane the hexane was distilled off This residue was subjected to vacuum distillation (95° to 110° C./15 mmHg) further recrystallized

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

Procedure: 2.1 g of this 1-cyano-2-fluoro-4-iodobenzene was dissolved in 14 ml of N,N-dimethylformamide to which was added 3 mg of bis(triphenylphosphine) palladium (II) chloride and 13 mg of cuprous iodide. Next, 1.2 g of the 4-propylphenylacetylene obtained in step 2 was added and allowed to react at 50 to 60° C for 0.5 hour. After completion of the reaction, 35 ml of 9% hydrochloric acid was added to the reaction solution. After being extracted with chloroform, the crystals were washed with water three times to distill off the chloroform. The residue was purified by silica gel-chloroform column chromatography, followed by recrystallization with a mixed solvent of acetone and methanol to obtain 0.5 g of 4-propyl-3'-fluoro-4'-cyanotolan. The melting point of this compound (hereinafter referred to as the C-I point) was 67.2° C. to react at 50 to 60° C for 0.5 hour was added to the reaction solution After being extracted with chloroform the crystals were washed with water three times to distill off the chloroform The residue was purified by silica gel-chloroform column chromatography followed by recrystallization with a mixed solvent of acetone and methanol

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

Procedure: 27 g of sodium nitrite was dissolved in 205 ml of sulfuric acid and cooled to 10° C. or less, and then 238 ml of acetic acid was added. At 20° to 25° C., 65 g of 2-fluoro-4-iodoaniline was added to the solution, and then the solution was agitated for one hour. A second solution was made by dissolving 83 g of copper sulfate pentahydrate in 20.5 ml of water, to which was added 140 g of ice, and this solution was added to the first. A third solution containing 88 g of potassium cyanide dissolved in 200 ml of water, 500 g of sodium bicarbonate, and 200 ml of benzene was added to the first solution, and a diazonium salt sulfuric acid solution was added therein. After agitation at room temperature for 3 hours, a sodium hydroxide aqueous solution was added to dissolve the crystals. After being extracted with chloroform, the crystals were washed three times alternating with a 10% sodium hydroxide solution and water. After distillation of the chloroform, the residue was extracted with hexane, and the hexane was distilled off. This residue was subjected to vacuum distillation (95° to 110° C./15 mmHg), and further recrystallized to obtain 20 g of 1-cyano-2-fluoro-4-iodobenzene. cooled to 10° C. or less this solution was added to the first After agitation at room temperature for 3 hours to dissolve the crystals After being extracted with chloroform the crystals were washed three times After distillation of the chloroform the residue was extracted with hexane the hexane was distilled off This residue was subjected to vacuum distillation (95° to 110° C./15 mmHg) further recrystallized

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

Procedure: 27 g of sodium nitrite was dissolved in 205 ml of sulfuric acid and cooled to 10° C. or less, and then 238 ml of acetic acid was added. At 20° to 25° C., 65 g of 2-fluoro-4-iodoaniline was added to the solution, and then the solution was agitated for one hour. A second solution was made by dissolving 83 g of copper sulfate pentahydrate in 20.5 ml of water, to which was added 140 g of ice, and this solution was added to the first. A third solution containing 88 g of potassium cyanide dissolved in 200 ml of water, 500 g of sodium bicarbonate, and 200 ml of benzene was added to the first solution, and a diazonium salt sulfuric acid solution was added therein. After agitation at room temperature for 3 hours, a sodium hydroxide aqueous solution was added to dissolve the crystals. After being extracted with chloroform, the crystals were washed three times alternating with a 10% sodium hydroxide solution and water. After distillation of the chloroform, the residue was extracted with hexane, and the hexane was distilled off. This residue was subjected to vacuum distillation (95° to 110° C./15 mmHg), and further recrystallized to obtain 20 g of 1-cyano-2-fluoro-4-iodobenzene. cooled to 10° C. or less this solution was added to the first After agitation at room temperature for 3 hours to dissolve the crystals After being extracted with chloroform the crystals were washed three times After distillation of the chloroform the residue was extracted with hexane the hexane was distilled off This residue was subjected to vacuum distillation (95° to 110° C./15 mmHg) further recrystallized

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

Procedure: To a stirred solution of 4-iodo-2-fluorobenzonitrile (2.5 g, 10.12 mmol) in 10.12 ml THF under argon, a solution of isopropylmagnesium chloride. LiCl in THF (10.12 ml, 13.16 mmol) was added at 0° C. The reaction mixture was stirred at this temperature for 5 min to afford the title compound, which was used immediately in the next step as a stock solution (˜0.5M in THF).

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

Procedure: To a stirred solution of 4-iodo-2-fluorobenzonitrile (2.5 g, 10.12 mmol) in 10.12 ml THF under argon, a solution of isopropylmagnesium chloride. LiCl in THF (10.12 ml, 13.16 mmol) was added at 0° C. The reaction mixture was stirred at this temperature for 5 min to afford the title compound, which was used immediately in the next step as a stock solution (˜0.5M in THF).

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-fluoro-4-iodobenzonitrile (4000 mg, 16.19 mmol), 5-chloro-4-hydroxypyridin-2(1H)-one (2357 mg, 16.19 mmol), 4,7-dimethoxy-1,10-phenanthroline (778 mg, 3.24 mmol), copper(I) iodide (617 mg, 3.24 mmol) and potassium carbonate (4476 mg, 32.4 mmol) in DMSO (40 mL) was stirred at 140° C. under N2 for 3 hrs. After cooling to room temperature, the reaction mixture was diluted with H2O (50 mL) and 1N HCl was added to adjust the pH to ˜2 (pH paper). The resulting mixture was extracted with EtOAc (400 mL, 2×). The combined extracts were dried (Na2SO4) and evaporated under reduced pressure to give black oil. The residue was purified by flash chromatography on silica gel (0-7% MeOH/CH2Cl2) to give brown oil (3.2 g, 43.3%). MS (ESI) 265 (M+H). After cooling to room temperature was added The resulting mixture was extracted with EtOAc (400 mL, 2×) The combined extracts were dried (Na2SO4) evaporated under reduced pressure to give black oil The residue was purified by flash chromatography on silica gel (0-7% MeOH/CH2Cl2)

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

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-fluoro-4-iodobenzonitrile (4000 mg, 16.19 mmol), 5-chloro-4-hydroxypyridin-2(1H)-one (2357 mg, 16.19 mmol), 4,7-dimethoxy-1,10-phenanthroline (778 mg, 3.24 mmol), copper(I) iodide (617 mg, 3.24 mmol) and potassium carbonate (4476 mg, 32.4 mmol) in DMSO (40 mL) was stirred at 140° C. under N2 for 3 h. After cooled to rt, the reaction mixture was diluted with H2O (50 mL) and added 1N HCl to adjust the pH to ˜2 (pH paper). The resulting mixture was extracted with EtOAc (400 mL, 2×). The combined extracts were dried (Na2SO4) and evaporated under reduced pressure to give black oil. The residue was purified by flash chromatography (SiO2, 0 to 7% MeOH/CH2Cl2) to give brown oil (3.2 g, 43.3%). MS (ESI) 265 (M+H). After cooled to rt The resulting mixture was extracted with EtOAc (400 mL, 2×) The combined extracts were dried (Na2SO4) evaporated under reduced pressure to give black oil The residue was purified by flash chromatography (SiO2, 0 to 7% MeOH/CH2Cl2)