1-oxidopyridin-1-ium-4-carbonitrile

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

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-cyanopyridine-N-oxide (10.0 g) was added to phosphorus oxychloride (85 mL) and heated to 110° C. for 2.5 h. The mixture was cooled to room temperature and the excess phosphorus oxychloride removed under reduced pressure. The residue was dissolved in water and made basic with concentrated ammonia. The product was extracted into methylene chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Column chromatography on silica gel (100 mL) using methylene chloride as eluent to give 7.19 g of the title compound: 1H NMR (CDCl3) δ 7.48, 7.6, 8.6. The mixture was cooled to room temperature the excess phosphorus oxychloride removed under reduced pressure The residue was dissolved in water The product was extracted into methylene chloride dried over anhydrous magnesium sulfate concentrated under reduced pressure

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

Procedure: A mixture of 4-cyanopyridine N-oxide (30 g, 0.25 mol), phosphorous oxychloride (96 ml, 0.35 mol) and phosphorous pentachloride (72 g, 0.38 mol) was refluxed at 120°-130° C. for 6 hours and then stirred at room temperature for 12 hours. The reaction mixture was slowly poured into a mixture of ice/Na2CO3 /K2CO3 and was extracted with chloroform (4×250 ml). The solvent was removed in vacuo and the residue was purified by column chromatography on silica eluting with 50% ether/hexanes to afford 8.4 g (24%) of 2-chloro-4-cyanopyridine, m.p. 69.5°-70.5° C. and 10.5 g (30%) of 3-chloro-4-cyanopyridine, m.p. 71.5°-72° C. was refluxed at 120°-130° C. for 6 hours was extracted with chloroform (4×250 ml) The solvent was removed in vacuo the residue was purified by column chromatography on silica eluting with 50% ether/hexanes

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-cyanopyridine-N-oxide (10.0 g) was added to phosphorus oxychloride (85 mL) and heated to 110° C. for 2.5 h. The mixture was cooled to room temperature and the excess phosphorus oxychloride removed under reduced pressure. The residue was dissolved in water and made basic with concentrated ammonia. The product was extracted into methylene chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Column chromatography on silica gel (100 mL) using methylene chloride as eluent to give 7.19 g of the title compound: 1H NMR (CDCl3) δ 7.48, 7.6, 8.6. The mixture was cooled to room temperature the excess phosphorus oxychloride removed under reduced pressure The residue was dissolved in water The product was extracted into methylene chloride dried over anhydrous magnesium sulfate concentrated under reduced pressure

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-cyanopyridine-N-oxide (10.0 g) was added to phosphorus oxychloride (85 mL) and heated to 110° C. for 2.5 h. The mixture was cooled to room temperature and the excess phosphorus oxychloride removed under reduced pressure. The residue was dissolved in water and made basic with concentrated ammonia. The product was extracted into methylene chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Column chromatography on silica gel (100 mL) using methylene chloride as eluent to give 7.19 g of the title compound: 1H NMR (CDCl3) δ 7.48, 7.6, 8.6. The mixture was cooled to room temperature the excess phosphorus oxychloride removed under reduced pressure The residue was dissolved in water The product was extracted into methylene chloride dried over anhydrous magnesium sulfate concentrated under reduced pressure

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-cyanopyridine-N-oxide (10.0 g) was added to phosphorus oxychloride (85 mL) and heated to 110° C. for 2.5 h. The mixture was cooled to room temperature and the excess phosphorus oxychloride removed under reduced pressure. The residue was dissolved in water and made basic with concentrated ammonia. The product was extracted into methylene chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Column chromatography on silica gel (100 mL) using methylene chloride as eluent to give 7.19 g of the title compound: 1H NMR (CDCl3) δ 7.48, 7.6, 8.6. The mixture was cooled to room temperature the excess phosphorus oxychloride removed under reduced pressure The residue was dissolved in water The product was extracted into methylene chloride dried over anhydrous magnesium sulfate concentrated under reduced pressure

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-cyanopyridine-N-oxide (10.0 g) was added to phosphorus oxychloride (85 mL) and heated to 110° C. for 2.5 h. The mixture was cooled to room temperature and the excess phosphorus oxychloride removed under reduced pressure. The residue was dissolved in water and made basic with concentrated ammonia. The product was extracted into methylene chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Column chromatography on silica gel (100 mL) using methylene chloride as eluent to give 7.19 g of the title compound: 1H NMR (CDCl3) δ 7.48, 7.6, 8.6. The mixture was cooled to room temperature the excess phosphorus oxychloride removed under reduced pressure The residue was dissolved in water The product was extracted into methylene chloride dried over anhydrous magnesium sulfate concentrated under reduced pressure

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

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

Procedure: This example illustrates the use of catalytic activity of the product obtained in Example 1. A typical oxidation of substituted pyridine to substituted pyridine N-oxide was carried out as follows. 0.5 g. of the material obtained according to example 1, (x=0.064) were added to a mixture containing 10.0 g 4-Cyano pyridine and 40 ml methanol under stirring. The temperature of this reaction mixture was kept at 60° C. and then 19.8 g. of H2O2 (30%) were added drop wise to the reaction mixture under stirring. The progress of the reaction followed by Thin Layer Chromatography. Then this reaction was carried out for 24 hours. Once the reaction was complete the catalyst was removed by filtration and the solvent was distilled off under vacuum. The isolated product by this procedure contained, exclusively the corresponding N-oxide is observed from the 1HNMR and mass spectra. 4-Cyanopyridne gave 9.6 g of coresponding 4-Cyanopyridine N-oxide without any trace of byproduct. of the material obtained were added to a mixture was kept at 60° C. under stirring was removed by filtration the solvent was distilled off under vacuum

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

Procedure: 4-cyanopyridine was reacted with 1 equivalent of HOF.MeCN to yield 59% of 4-cyanopyridine-N-oxide.

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

Procedure: To a solution of 4-cyanopyridine N-oxide (600 g) in ahydrous methanol (250 ml) was added sodium methoxide (1.35 g), and this solution was stirred for 0.5 hour at room temperature. To this solution were added aminomalonamide (3.51 g) and acetic acid, and this mixture was stirred for 2 hours under reflux. After cooling the reaction mixture to 0°-5° C., the precipitated product was separated by filtration, washed with ethanol, isopropylether and dried under vacuum to give yellow crystal of 4-(4-carbamoyl-5-hydroxyimidazole-2yl)-pyridine-N-oxide (5.96 g). this mixture was stirred for 2 hours under reflux After cooling the reaction mixture to 0°-5° C. the precipitated product was separated by filtration washed with ethanol, isopropylether dried under vacuum

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

Procedure: To a solution of 4-cyanopyridine N-oxide (100 mg) in methanol (4 mL) were added sodium methoxide (13.5 mg), and the mixture was stirred at room temperature for 24 hrs. To the reaction mixture was added methanesulfonic acid (104 mg), and the reaction mixture was stirred at room temperature for an additional 10 minutes. To the 3.5 ml of this solution was added to the solution (2 mL) of (2S)-1-(4-fluorophenyl)-1-(6-fluoro-3-pyridyl)-1,2-propanediamine described in Reference Example 5-1, and the mixture was stirred at room temperature for 15 hrs. After concentrating the reaction mixture in vacuo, the obtained residue was dissolved in ethyl acetate, washed with saturated sodium hydrogen carbonate aqueous solution and saturated sodium chloride aqueous solution in this order, and dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, and the organic solvent was evaporated in vacuo. The obtained residue was purified by silica gel column chromatography (C-300; chloroform:methanol=9:1) to give 2-(1-oxido-pyridin-4-yl)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-methyl-2-imidazoline (172 mg) as colorless oil. To the solution (5 ml) of the obtained N-oxide compound in acetonitrile was added trimethylsilylcyanide (140 mg) and triethylamine (142 mg), and the mixture was stirred at 90° C. for 17 hrs. To the mixture was added trimethylsilylcyanide (140 mg) and triethylamine (142 mg), and the mixture was stirred at 90° C. for 2 hrs, and concentrated in vacuo. The obtained residue was dissolved in chloroform, washed with saturated sodium hydrogen carbonate aqueous solution, water and saturated sodium chloride aqueous solution in this order, and dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, and the organic solvent was evaporated in vacuo. The obtained residue was purified by silica gel column chromatography (C-300; hexane:ethyl acetate=1:1) and treated with 4N hydrogen chloride-ethyl acetate solution to give the title compound (108 mg). the reaction mixture was stirred at room temperature for an additional 10 minutes the mixture was stirred at room temperature for 15 hrs After concentrating the reaction mixture in vacuo the obtained residue was dissolved in ethyl acetate washed with saturated sodium hydrogen carbonate aqueous solution and saturated sodium chloride aqueous solution in this order dried over anhydrous sodium sulfate Sodium sulfate was removed by filtration the organic solvent was evaporated in vacuo The obtained residue was purified by silica gel column chromatography (C-300; chloroform:methanol=9:1)