| 78% |
With sulfuric acid; nitric acid at 0 - 90℃; for 1.5h; |
10
2,6-Dimethyl-3-piperidin-4-yl-3H-imidazo[4,5-c]pyridine; A solution of 5-bromo-2-methyl-pyridine (1.47 g, 8.54 mmol) in CH2Cl2 (5 mL) was treated with a cold solution of 30% hydrogen peroxide (4.6 mL) in acetic acid (13.8 mL) at 0° C. The reaction mixture was stirred at 50° C. for 18 h and poured into ice water (5 mL). The resulting mixture was adjusted to pH=9 by addition of K2CO3. The mixture was stirred at rt for 15 min and diluted with CH2Cl2 (10 mL). The aqueous layer was extracted three times with CH2Cl2. The combined extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 5-bromo-2-methyl-pyridine N-oxide as a white solid (1.6 g, 99%) which was used without further purification. A solution of 5-bromo-2-methyl-pyridine N-oxide (536 mg, 2.85 mmol) in concentrated H2SO4 (3.0 mL) was added dropwise a solution of fuming HNO3 (2.4 mL) in concentrated H2SO4 (3.2 mL) at 0° C. The reaction mixture was heated at 90° C. for 1.5 h. The reaction mixture was cooled to rt and poured into ice (50 g). The mixture was extracted with CH2Cl2 (3×20 mL). The combined extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 5-bromo-2-methyl-4-nitro-pyridine N-oxide as a yellow solid (520 mg, 78%) which was used without further purification 5-Bromo-2-methyl-4-nitro-pyridine N-oxide (520 mg, 2.23 mmol) was mixed with 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.56 g, 7.80 mmol) in a microwave tube. The reaction mixture was irradiated in a microwave oven at 140° C. for 1 h. The mixture was dissolved in CH2Cl2 (5 mL). Flash chromatography (10/1 CH2Cl2/CH3OH) afforded 4-(6-methyl-4-nitro-pyridin-N-oxide-3-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (380 mg, 48%) as a red solid. A solution of 4-(6-methyl-4-nitro-pyridin-N-oxide-3-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (40 mg, 0.113 mmol) in acetic acid (1 mL) was treated with iron powder (80 mg). The reaction mixture was stirred at 115° C. for 5 h and then was treated with acetic anhydride (2 mL). The resulting mixture was heated at 140° C. for 18 h. The solvent was evaporated and the mixture was diluted with water (10 mL). The mixture was adjusted to pH=10 by addition of solid sodium hydroxide. The aqueous mixture was extracted three times with CH2Cl2. The combined extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Flash chromatography (10/1 CH2Cl2/CH3OH) afforded 1-[4-(2,6-dimethyl-imidazo[4,5-c]-pyridin-3-yl)-piperidin-1-yl]-ethanone (20 mg, 65%) as a brown solid. A solution of 1-[4-(2,6-dimethyl-imidazo[4,5-c]-pyridin-3-yl)-piperidin-1-yl]-ethanone (20 mg, 0.074 mmol) in ethanol (0.5 mL) was treated with concentrated HCl (0.5 mL). The reaction mixture was heated at 100° C. for 18 h. The solvent was evaporated and the mixture was diluted with water (2 mL). The mixture was washed twice with diethyl ether and the aqueous phase was adjusted to pH=10 by addition of a solution of 25% aqueous NaOH. The aqueous mixture was extracted with CH2Cl2 (5×10 mL). The combined extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford 2,6-dimethyl-3-piperidin-4-yl-3H-imidazo[4,5-c]pyridine (13 mg, 77%) as a light yellow solid which was used without further purification. 1H-NMR (300 MHz, CDCl3): δ 8.85 (s, 1H), 7.41 (s, 1H), 4.25 (m, 1H), 3.34 (d, 2H, J=10.2 Hz), 2.82 (t, 2H, J=12.3 Hz), 2.65 (s, 3H), 2.35 (m, 2H), 1.93 (d, 2H, J=10.2 Hz). |
| 78% |
With sulfuric acid; nitric acid at 110℃; for 3h; |
|
| 78% |
With sulfuric acid; nitric acid at 115℃; for 3h; Cooling with ice; |
1.2 2) Synthesis of 2-methyl-4-nitro-5-bromopyridine oxide, ie, compound 2 in the route;
To the reaction flask was added 2-methyl-5-bromopyridine oxynitride (13.0 g, 69.2 mmol) obtained in the step 1), cooled in an ice bath, and stirred.Concentrated sulfuric acid (98%, 40 ml) and fuming nitric acid (95%, 30 ml) were slowly added dropwise; after the addition, the ice bath was removed, and the mixture was heated to reflux at 115 ° C for 3 h, and the reaction was completed. Dilute the reaction solution to 100 ml of ice water.Extracted with dichloromethane,Washed with potassium carbonate solution,Dry over anhydrous sodium sulfate,Filter, spin dry,The yellow solid 2-methyl-4-nitro-5-bromopyridine oxynitride was obtained in a yield of 78%. |
| 65% |
With sulfuric acid; nitric acid at 0 - 90℃; for 5h; |
26.AAX Procedure AAX: Preparation of 5-bromo-2 -methyl -4-nitropyridine 1-oxide
To a solution of 5-bromo-2-methylpyridine 1-oxide (5.10 g, 27.1 mmol) in concentrated sulphuric acid (8.90 mL, 0.18 mol) at 0 °C was added fuming nitric acid (6.80 mL, 0.14 mol). The resulting mixture was then stirred at 90 "C for 5 h. After cooling to rt, the reaction mixture was poured into ice/water, and the resulting solid was filtered, washed with water, and dried to afford 5-bromo-2 -methyl -4-nitropyridine 1-oxide (4.10 g, 65%) as a light yellow solid. 1H-NMR (300 MHz, CDC13): δ ppm: 8.52 (s, 1 H), 2.50 (s, 3H). |
|
With sulfuric acid; nitric acid at 80℃; |
|
| 360 mg |
With sulfuric acid; nitric acid at 90℃; for 20h; |
5.B B) 5-bromo-2-methyl-4-nitropyridine 1-oxide
B) 5-bromo-2-methyl-4-nitropyridine 1-oxide 5-Bromo-2-methylpyridine 1-oxide (5.36 g) was added to a mixture of conc. nitric acid (10.1 mL) and conc. sulfuric acid (8.94 mL), and the mixture was stirred at 90°C for 20 hr. The reaction mixture was poured into ice water, and the resulting pale-yellow precipitate was collected by filtration. The crude crystals were washed with water to give the title compound (3.83 g) as a pale-yellow solid. The filtrate was neutralized with 8N aqueous sodium hydroxide solution at room temperature, and extracted with a mixed solvent of ethyl acetate and THF. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (360 mg) as a pale-yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 2.36 (3H, s), 8.39 (1H, s), 8.88 (1H, s). |
|
With sulfuric acid; nitric acid at 0 - 90℃; for 48h; |
1.J
A mixture of 5-bromo-2-methyl-pyridine (10.0 g, 58.0 mmol), hydrogen peroxide (28 ml_, 30% in water) in acetic acid (28 mL) was heated to 90 0C for 2 days, then additional hydrogen peroxide (14 mL) was added. The mixture was heated for another 1 day. Upon cooling to room temperature, it was extracted with CHCI3 three times. The organic solution was then dried over MgSO4, and concentrated to yield the crude pyridine oxide. MS: 187.7 (M+H)+; tR=2.22 min. (method 1 ).The above pyridine oxide was added into a mixture of HNO3 (18 mL) and H2SO4 (16 ml) at O0C. The mixture was then heated to 9O0C for 48 hrs, allowed to cool to room temperature and poured into iced water resulting in a precipitation. The solid was filtered and dried to afford 5-bromo-2-methyl-4-nitropyridine oxide (7.32g). MS: 232.7 (M+H)+; tR=1.94 min. (method 1 ). |
|
With sulfuric acid; nitric acid at 0 - 90℃; for 48h; |
1.J
The above pyridine oxide was added into a mixture of HNO3 (18 mL) and H2SO4 (16 mL) at O0C. The mixture was then heated to 9O0C for 48 hrs, allowed to cool to rt and poured into iced water resulting in a precipitation. The solid was filtered and dried to afford 5-bromo-2-methyl-4-nitropyridine oxide (7.32g). MS: 232.7 (M+H)+; tR=1.94 min. (method 1). |
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