| 89.4% |
Stage #1: 2-chloro-5-methylpyridine With sodium tungstate; sulfuric acid In water for 0.5h;
Stage #2: With dihydrogen peroxide In water at 65 - 100℃; |
1.1 Synthesis of 2-chloro-5-methylpyridine N-oxide
2L flask, 145 g of 2-chloro-5-methylpyridine, 1200 mL of purified water and 12.8 g of sodium tungstate were added in one portion. Dropping 18.4 g of concentrated sulfuric acid, stirring 30 min after addition. Then heated to 65-75 °C, dropping 320 g 30% H2O2, temperature control in the 65-75 °C, dropping time control in 5-6h. After the dropwise addition, the reaction was continued for 40 h and monitored by TLC. When the reaction was not progressed, the temperature rise to 95-100 °C and the reaction was continued for 10 h. After the reaction was completed, the reaction mixture was cooled to room temperature and the pH was adjusted to 8-9. The unreacted starting material was extracted with 500 mL of toluene, and the product was extracted 4-5 times with methylene chloride. Dried and air-dried to obtain 145 g of a dark yellow solid product in a yield of 89.4%. |
| 84% |
Stage #1: 2-chloro-5-methylpyridine With urea hydrogen peroxide adduct; trifluoroacetic acid In dichloromethane at 0 - 20℃; for 49h;
Stage #2: With sodium dithionite In dichloromethane for 4h; |
1.A
182] Step A: 2-chloro-5-methylpyridine 1 -oxideTo a mixture of 2-chloro-5-methylpyridine (200 g, 1.57 mol), and urea hydrogen peroxide addition compound (310 g, 3.29 mol) in dichloromethane (2L) was added anhydrous trifluoroacetic acid (619%, 5.96 mol) dropwise at O0C, and the mixture was stirred at O0C for 1 hour.After stirring for 48 hours while elevating the reaction temperature to room temperature, an aqueous solution of sodium hydrosulfite (326 g, 3.14 mol) was added, and the reaction mixture was stirred for 4 hours. The reaction was neutralized with sodium hydroxide, extracted with dichloromethane, washed with brine, and the organic phase dried over magnesium sulfate.Filtration, and removal of solventunder reduced pressure afforded the title compound(189 g, 84%) as a brown SOhU1H NMR (400MHz, CDCl3) δ 8.21 (s, IH), 7.39 (d, J= 8.4Hz, IH), 7.06 (d, J = 8.4Hz, IH), 2.32 (s, 3H); m/z = 144 [M+l]+. |
| 84% |
With 3-chloro-benzenecarboperoxoic acid In chloroform at 50℃; for 16h; |
15.1 Step 1: 2-chloro-5-methylpyridine 1-oxide
To a solution of 2-chloro-5-methylpyridine (2.0 g, 15.7 mmol) in CHCl3 (20 mL) was added meta-chloroperoxybenzoic acid (3.2 g, 18.89 mmol) portion-wise, then the mixture was heated at 50° C. for 16 h. The reaction mixture was cooled to -10° C., and the solid was filtered through Celite. The filtrate was evaporated and purified by column chromatography over silica gel using 80% ethyl acetate in hexanes as eluent to give 2-chloro-5-methylpyridine 1-oxide (1.9 g, 84%). 1HNMR (400 MHz, DMSO-d6): δ 8.33 (s, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 2.22 (s, 3H). LC-MS calcd exact mass 143.01, found m/z 144.1 [M+H]+. |
| 84% |
With 3-chloro-benzenecarboperoxoic acid In chloroform at 50℃; for 16h; |
15.1 Step 1: 2-chloro-5-methylpyridine 1-oxide
To a solution of 2-chloro-5-methylpyridine (2.0 g, 15.7 mmol) in CHCl3 (20 mL) was added meta-chloroperoxybenzoic acid (3.2 g, 18.89 mmol) portion-wise, then the mixture was heated at 50 °C for 16 h. The reaction mixture was cooled to -10 °C, and the solid was filtered through Celite. The filtrate was evaporated and purified by column chromatography over silica gel using 80% ethyl acetate in hexanes as eluent to give 2-chloro-5-methylpyridine 1-oxide (1.9 g, 84%).1HNMR (400 MHz, DMSO-d6%5 h 3).. Z' ,>%' 2)1/ L' J=8.4 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 2.22 (s, 3H). LC-MS calcd exact mass 143.01, found m/z 144.1 [M+H]+. |
| 82% |
With 3-chloro-benzenecarboperoxoic acid In chloroform at 50℃; for 12h; |
|
| 82% |
With dihydrogen peroxide In water; acetic acid at 80℃; for 8h; |
6.1
Example 6: Synthesis of 3-(2-chlorophenyl)-6-(2, 4-difluoro-phenoxy)-lH-pyrazolo- [4,3-c]pyridine following the procedure of Scheme IV; Step 1. Preparation of2-chloro-5-methylpyridine-l-oxide.; To a solution of 2-chloro-5-methylpyridine (10 mL) in 155 mL of glacial acetic acid was added 19 mL of 30% aqueous hydrogen peroxide. The mixture was stirred at 800C for 8 hours. The mixture was diluted with 100 mL of water and then concentrated in a vacuum. The residue was made strongly alkaline with anhydrous sodium carbonate and shaken with 200 mL of chloroform. The solids were removed via filtration, and the filtrate was dried over sodium sulfate, filtered and concentrated to give 10.8 g of the 2-chloro-5-methyl- pyridine-N- oxide (82%). Mass Spec. M+H = 144. |
| 82% |
With dihydrogen peroxide; acetic acid In water at 80℃; for 8h; |
IV; 6.1
To a solution of 2-chloro-5-methylpyridine (10 mL) in 155 mL of glacial acetic acid was added 19 mL of 30% aqueous hydrogen peroxide. The mixture was stirred at 80° C. for 8 hours. The mixture was diluted with 100 mL of water and then concentrated in a vacuum. The residue was made strongly alkaline with anhydrous sodium carbonate and shaken with 200 mL of chloroform. The solids were removed via filtration, and the filtrate was dried over sodium sulfate, filtered and concentrated to give 10.8 g of the 2-chloro-5-methylpyridine-N-oxide (82%). Mass Spec. M+H=144. |
| 82% |
With dihydrogen peroxide; acetic acid In water at 80℃; for 8h; |
|
| 73% |
Stage #1: 2-chloro-5-methylpyridine With urea hydrogen peroxide adduct; trifluoroacetic acid In dichloromethane at 0 - 20℃; for 1.75h;
Stage #2: With sodium dithionite In dichloromethane; water for 0.25h; |
2.2b
(2b) 2-chloro-5-methylpyridine-1-oxide [Formula 19]; Into a mixture of 2-chloro-5-methylpyridine (27.4 g, 215 mmol),, urea hydrogen peroxide addition compound (42.5 g, 452 mmol), dichloromethane (250 ml) was added dropwise anhydrous trifluoroacetic acid (60.7 ml and 430 mmol) at 0°C, and the reaction mixture was stirred at 0°C for 1 hour. Then, after stirring for 45 minutes while elevating the reaction temperature to room temperature, an aqueous solution (450 ml) of sodium hydrosulfite (45 g) was added, and the reaction mixture was stirred for 15 minutes. 0.5N hydrochloric acid (400 ml) was added and the mixture was extracted with dichloromethane (400 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 (22.5 g, 157 mmol, 73%) as a beige solid. ¹H NMR (400MHz, No. ppm; 2.24(3H, s), 7.16- 7.23(lH, m), 7.66(lH, d, J=8Hz), 8.35(lH, s). |
|
With peracetic acid; acetic acid |
|
|
With dihydrogen peroxide; acetic anhydride In water at 20 - 60℃; for 54h; |
1; II.a
In a manner substantially similar to that of of Z. Talik and A. Puszko, Rocziiiki Chemii Ann. Soc. Chim. Polonorum 1976, 50, 2209, hydrogen peroxide 30% (25 mL) was added in small portions to a suspension of 2-chloro-5-methylpyridine (10 g, 0.078 mo 1) in acetic anhydride (25 mL). This mixture was stirred at room temperature for 24 hours and then heated at 60 °C for 30 hours. After removing excess acetic acid under reduced pressure, the residue was added in small portions to concentrated sulfuric acid (15 mL). The resulting solution was added to a mixture of concentrated sulfuric acid (15 mL) and fuming nitric acid (25 mL) and then heated at 100 °C for 90 minutes. The reaction mixture was poured on ice, neutralized with solid ammonium carbonate and finally with aqueous ammonia until pH basic, resulting in the formation of a precipitate. After filtration, the title compound was isolated as a pale yellow solid (9.4 g, 0.05D mol, HPLC Rt 3.272 min, FIA ES+ 188.9, ES- 188.0). |
|
With dihydrogen peroxide; acetic anhydride In water at 20 - 60℃; for 54h; |
13
2-Chloro-5-methyl-4-nitropyridine N-oxide () : Following the method of Z. Talik, A. Puszko, Roczniki Chemii Ann. Soc. Chim. Polonorum, 1976, 50, 2209, to a suspension of 2-chloro-5-methylpyridine (10 g, 0.078 mol) in acetic anhydride (25 mL), hydrogen peroxide 30% (25 mL) was added in small portions. This mixture was stirred at room temperature for 24 hours and then heated at 60 °C for 30 hours. After removing the excess of acetic acid under reduced pressure, the residue was added in small portions to concentrated sulfuric acid (15 mL). The resulting solution was added to a mixture of concentrated sulfuric acid (15 mL) and fuming nitric acid (25 mL), and then heated at 100 °C for 90 minutes. The reaction mixture was poured on ice, neutralized with solid ammonium carbonate and finally with aqueous ammonia until basic. A precipitate was then formed. After nitration, 10 was isolated as a pale yellow solid (9.4 g, 0. 050 mol, HPLC Rt 3.272 minutes, FIA ES+ 188.9, ES-188.0). |
|
With dihydrogen peroxide; acetic anhydride In water at 20 - 60℃; for 54h; |
4.A
To a suspension of 2-chloro-5-methylpyridine (10.0 g) in Ac2O (25.0 mL) was added 30% aqueous H2O2 (25.0 mL). The mixture was stirred at ambient temperature for 24 h and 60 0C for 30 h. To the mixture was added 2 M aqueous NaOH (200 mL) and the aqueous layer was extracted with CHCl3 three times. The combined organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was dissolved in concentrated H2SO4 (15.0 mL) and the solution was poured into mixture of concentrated H2SO4 (15.0 mL) and fuming HNO3 (25.0 mL). The mixture was stirred at 100 0C for 30 min and poured into ice (500 mL). The solution was alkalized with ammonium hydrogencarbonate (pH = 9) and 28 % aqueous NH3 (pH = 13). The mixture was stirred at ambient temperature for 2 h and the precipitate was collected by filtration, washed with H2O and hexane, and dried at 50 0C under reduced pressure to give 2-chloro-5-methyl-4-nitro-pyridine 1-oxide (10.6 g) as a pale yellow solid.1HNMR (300 MHz, CDCl3, δ): 2.61 (s, 3H), 8.25-8.30 (m, 2H); CI MS m/z 189 (M++., 100%). |
|
With dihydrogen peroxide; acetic anhydride In water at 20 - 60℃; for 54h; |
3
Example 3; [0091] Compound 1-3 was prepared as follows: 2-Chloro-5-methyl-4-nitropyridine N-oxide: The title compound was prepared in a manner substantially similar to that described by Z. Talik, A. Puszko, Roczniki Cheniii Ann. Soc. Chim. Polonorum 1976, 50, 2209, as follows. To a suspension of 2-chloro- 5-methylpyridine (10 g, 0.078 mol) in acetic anhydride (25 mL) was added hydrogen peroxide 30% (25 mL) in small portions. This mixture was stirred at room temperature for 24 hours and then heated at 60 °C for 30 hours. After removing the excess acetic acid under reduced pressure, the residue was added in small portions to concentrated sulfuric acid (15 mL). The resulting solution was added to a mixture of concentrated sulfuric acid (15 mL) and fuming nitric acid (25 mL) and then heated at 100 °C for 90 minutes. The reaction mixture was poured onto ice, neutralized with solid ammonium carbonate and finally with aqueos ammonia until a basic pH was obtained and a precipitate formed. This precipitate was collected by filtration to afford the title compound as a pale yellow solid (9.4 g, 0.050 mol, Rt (min) FIA ES+ 188.9, ES- 188.0). |
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