2-chloro-3-methyl-1-oxidopyridin-1-ium

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

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of the compound from Step 1 2-chloro-3-methylpyridine 1-oxide (14.5 g, 101 mmol) and tert-butyl (3R)-3-aminopiperidine-1-carboxylate (24.27 g, 121.2 mmol) in n-BuOH (120 mL) were added diisopropylethyl amine (14.35 g, 111 mmol) and DMAP (1.22 g, 9.99 mmol) slowly at 0° C. The resulting mixture was heated at 100° C. for 36 h. The reaction was cooled, and water was added. The mixture was then extracted with EtOAc (3×50 mL). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude compound was purified by silica gel chromatography eluting with a gradient of petroleum ether:EtOAc (80:20 to 50:50) to afford the title compound (7.9 g, 25%) as a yellow oil. The reaction was cooled The mixture was then extracted with EtOAc (3×50 mL) The combined organic layers were dried over Na2SO4 filtered the filtrate was concentrated under reduced pressure The crude compound was purified by silica gel chromatography eluting with a gradient of petroleum ether:EtOAc (80:20 to 50:50)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of the compound from Step 1 2-chloro-3-methylpyridine 1-oxide (14.5 g, 101 mmol) and tert-butyl (3R)-3-aminopiperidine-1-carboxylate (24.27 g, 121.2 mmol) in n-BuOH (120 mL) were added diisopropylethyl amine (14.35 g, 111 mmol) and DMAP (1.22 g, 9.99 mmol) slowly at 0° C. The resulting mixture was heated at 100° C. for 36 h. The reaction was cooled, and water was added. The mixture was then extracted with EtOAc (3×50 mL). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude compound was purified by silica gel chromatography eluting with a gradient of petroleum ether:EtOAc (80:20 to 50:50) to afford the title compound (7.9 g, 25%) as a yellow oil. The reaction was cooled The mixture was then extracted with EtOAc (3×50 mL) The combined organic layers were dried over Na2SO4 filtered the filtrate was concentrated under reduced pressure The crude compound was purified by silica gel chromatography eluting with a gradient of petroleum ether:EtOAc (80:20 to 50:50)

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

Procedure: To a mixture of 2-chloro-3-methylpyridine (15 g, 118 mmol) and urea hydrogen peroxide (44.07 g, 468.5 mmol) in DCM (300 mL) was added trifluoroacetic anhydride (98.55 g, 469.2 mmol) dropwise at 0° C. The mixture was stirred at room temperature for 20 h. The mixture was then poured into water (150 mL), and the layers were separated. The organic layer was washed with saturated aqueous Na2S2O3 (20 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (DCM:MeOH, 100:0 to 10:1) to afford the title compound (14.5 g, 86%) as a colorless solid. the layers were separated The organic layer was washed with saturated aqueous Na2S2O3 (20 mL) dried over Na2SO4 filtered the filtrate was concentrated under reduced pressure The crude product was purified by silica gel flash chromatography (DCM:MeOH, 100:0 to 10:1)

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

Procedure: 2-Chloro-3-methylpyridine 1-oxide (9.00 g, 62.7 mmol) and triethylamine (10.4 ml, 75.2 mmol) were dissolved in dichloromethane (70 ml), and a solution of phosphorus oxychloride (7 ml, 75.3 mmol) in dichloromethane (40 ml) was added dropwise at 0° C. After stirring for 3 hours while elevating reaction temperature to room temperature, the reaction mixture was stirred under reflux for 1 hour. After the reaction was completed, water (30 ml) was added and the reaction mixture was neutralized with a sodium hydroxide solution, and after extracted with dichloromethane (70 ml), dried over magnesium sulfate. The solvent was evaporated and purified by silica gel column chromatography (eluting solvent: ethyl acetate/n-hexane=3/100), thereby yielding the title compound (3.47 g) as a white solid 10:3 mixture with 2,4-dichloro-3-methylpyridine. the reaction mixture was stirred under reflux for 1 hour after extracted with dichloromethane (70 ml) dried over magnesium sulfate The solvent was evaporated purified by silica gel column chromatography (eluting solvent: ethyl acetate/n-hexane=3/100)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into a mixture of 2-chloro-3-methylpyridine (12.8 g, 100 mmol), urea hydrogen peroxide addition compound ((NH2)2CO.H2O2, 19.8 g, 210 mmol) and dichloromethane (130 ml) was added dropwise anhydrous trifluoroacetic acid (28.2 ml, 200 mmol) at 0° C. under nitrogen flow, and the reaction mixture was stirred at 0° C. for 1 hour. Then, after stirring for 30 minutes and elevating the reaction temperature to room temperature, an aqueous solution (200 ml) of sodium hydrosulfite (20 g) was added, and the reaction mixture was stirred for 15 minutes. 2N hydrochloric acid (50 ml) was added and the mixture was extracted with dichloromethane (120 ml), and after washed with sodium bicarbonate solution, the mixture was dried over magnesium sulfate and the solvent was evaporated, thereby yielding the title compound (9.00 g, 62.7 mmol, 63%) as a pale yellow solid. Then, after stirring for 30 minutes to room temperature the reaction mixture was stirred for 15 minutes the mixture was extracted with dichloromethane (120 ml) after washed with sodium bicarbonate solution the mixture was dried over magnesium sulfate the solvent was evaporated

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

Procedure: A solution of 2-chloro-3-methylpyridine 1-oxide (11.37 g, 79.2 mmol) and triethylamine (13.1 ml, 94.0 mmol) in dichloromethane (90 mL) at 0° C. was slowly treated with a solution of phosphorus oxychloride (8.8 ml, 96.1 mmol) in dichloromethane (35 mL) and stirred for a further 2 hours then heated to reflux for 1 hour. Water (40 mL) was added to the reaction mixture then it was basified with 2N sodium hydroxide (150 mL). The mixture was extracted with dichloromethane (3×100 mL) and the combined extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The product was purified by flash column chromatography on silica gel (160 g) 100% dichloromethane to afford 2,6-dichloro-3-methylpyridine as a white solid (2.64 g, 21%). 400 M Hz 1H NMR (DMSO-d6) δ: 7.86 (d, J=8.4 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 2.30 (s, 3H). then heated to reflux for 1 hour The mixture was extracted with dichloromethane (3×100 mL) the combined extracts were dried over anhydrous sodium sulfate filtered concentrated under reduced pressure The product was purified by flash column chromatography on silica gel (160 g) 100% dichloromethane

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

Procedure: To a mixture of 2-chloro-3-methylpyridine (12.8 g, 100 mmol), urea hydrogen peroxide (19.8 g, 210 mmol) and dichloromethane (130 mL) was added dropwise anhydrous trifluoroacetic acid (28.2 mL, 200 mmol) at 0° C. The reaction was stirred for a further 1.5 hours, warmed to room temperature and then treated with 9% w/w aqueous sodium hydrosulfite (200 mL). The mixture was stirred for a further 15 minutes then 2N hydrochloric acid (50 ml) was added and the mixture was extracted with dichloromethane (2×120 mL). The combined extracts were washed with saturated aqueous sodium hydrogen carbonate (2×100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield 2-chloro-3-methylpyridine 1-oxide as a yellow solid (11.45 g; 89% purity by UV). The mixture was stirred for a further 15 minutes the mixture was extracted with dichloromethane (2×120 mL) The combined extracts were washed with saturated aqueous sodium hydrogen carbonate (2×100 mL) dried over anhydrous sodium sulfate filtered concentrated under reduced pressure

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of the compound from Step 1 2-chloro-3-methylpyridine 1-oxide (14.5 g, 101 mmol) and tert-butyl (3R)-3-aminopiperidine-1-carboxylate (24.27 g, 121.2 mmol) in n-BuOH (120 mL) were added diisopropylethyl amine (14.35 g, 111 mmol) and DMAP (1.22 g, 9.99 mmol) slowly at 0° C. The resulting mixture was heated at 100° C. for 36 h. The reaction was cooled, and water was added. The mixture was then extracted with EtOAc (3×50 mL). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude compound was purified by silica gel chromatography eluting with a gradient of petroleum ether:EtOAc (80:20 to 50:50) to afford the title compound (7.9 g, 25%) as a yellow oil. The reaction was cooled The mixture was then extracted with EtOAc (3×50 mL) The combined organic layers were dried over Na2SO4 filtered the filtrate was concentrated under reduced pressure The crude compound was purified by silica gel chromatography eluting with a gradient of petroleum ether:EtOAc (80:20 to 50:50)

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

Procedure: To a mixture of 2-chloro-3-methylpyridine (15 g, 118 mmol) and urea hydrogen peroxide (44.07 g, 468.5 mmol) in DCM (300 mL) was added trifluoroacetic anhydride (98.55 g, 469.2 mmol) dropwise at 0° C. The mixture was stirred at room temperature for 20 h. The mixture was then poured into water (150 mL), and the layers were separated. The organic layer was washed with saturated aqueous Na2S2O3 (20 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (DCM:MeOH, 100:0 to 10:1) to afford the title compound (14.5 g, 86%) as a colorless solid. the layers were separated The organic layer was washed with saturated aqueous Na2S2O3 (20 mL) dried over Na2SO4 filtered the filtrate was concentrated under reduced pressure The crude product was purified by silica gel flash chromatography (DCM:MeOH, 100:0 to 10:1)

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

Procedure: 2-Chloro-3-methylpyridine 1-oxide (9.00 g, 62.7 mmol) and triethylamine (10.4 ml, 75.2 mmol) were dissolved in dichloromethane (70 ml), and a solution of phosphorus oxychloride (7 ml, 75.3 mmol) in dichloromethane (40 ml) was added dropwise at 0° C. After stirring for 3 hours while elevating reaction temperature to room temperature, the reaction mixture was stirred under reflux for 1 hour. After the reaction was completed, water (30 ml) was added and the reaction mixture was neutralized with a sodium hydroxide solution, and after extracted with dichloromethane (70 ml), dried over magnesium sulfate. The solvent was evaporated and purified by silica gel column chromatography (eluting solvent: ethyl acetate/n-hexane=3/100), thereby yielding the title compound (3.47 g) as a white solid 10:3 mixture with 2,4-dichloro-3-methylpyridine. the reaction mixture was stirred under reflux for 1 hour after extracted with dichloromethane (70 ml) dried over magnesium sulfate The solvent was evaporated purified by silica gel column chromatography (eluting solvent: ethyl acetate/n-hexane=3/100)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into a mixture of 2-chloro-3-methylpyridine (12.8 g, 100 mmol), urea hydrogen peroxide addition compound ((NH2)2CO.H2O2, 19.8 g, 210 mmol) and dichloromethane (130 ml) was added dropwise anhydrous trifluoroacetic acid (28.2 ml, 200 mmol) at 0° C. under nitrogen flow, and the reaction mixture was stirred at 0° C. for 1 hour. Then, after stirring for 30 minutes and elevating the reaction temperature to room temperature, an aqueous solution (200 ml) of sodium hydrosulfite (20 g) was added, and the reaction mixture was stirred for 15 minutes. 2N hydrochloric acid (50 ml) was added and the mixture was extracted with dichloromethane (120 ml), and after washed with sodium bicarbonate solution, the mixture was dried over magnesium sulfate and the solvent was evaporated, thereby yielding the title compound (9.00 g, 62.7 mmol, 63%) as a pale yellow solid. Then, after stirring for 30 minutes to room temperature the reaction mixture was stirred for 15 minutes the mixture was extracted with dichloromethane (120 ml) after washed with sodium bicarbonate solution the mixture was dried over magnesium sulfate the solvent was evaporated