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Sodium acetate (365 g, 5.37 mol) was added to a stirred solution of 2-methoxy-4-methyl-3-nitropyridine (250 g, 1.49 mol) in acetic acid (1 .5 L) at ambient temperature and then Br2(639 g, 4.00 mol) was added dropwise (30 mm). After addition, the mixture was heated at 80°C for 12 h, at which time TLC indicated the reaction had gone to completion. The mixturewas cooled (0 °C) and quenched by sequential addition of 10percent aqueous (1.5 L) and saturatedaqueous sodium sulfate (1.5 L). The resulting solid was collected by filtration, washed withwater, and dried under reduced pressure to give the title compound (302 g, 82.2percent yield) as alight yellow solid. h11 NMR (400 MHz, DMSO-d6): 6 8.25 (s, 1 H), 3.94 (s, 3 H), 2.29 (s, 3H).
82.2%
at 80℃; for 12 h;
Sodium acetate (365 g, 5.37 mol) was added to a stirred solution of 2-methoxy-4 -methyl -3- nitropyridine (250 g, 1.49 mol) in acetic acid (1.5 L) at ambient temperature and then Br2 (639 g, (0447) 4.00 mol) was added dropwise (30 min). After addition, the mixture was heated at 80 °C for 12 h, at which time TLC indicated the reaction had gone to completion. The mixture was cooled (0 (0448) °C) and quenched by sequential addition of 10percent aqueous (1.5 L) and saturated aqueous sodium sulfite (1.5 L). The resulting solid was collected by filtration washed with water, and dried under reduced pressure to give the title compound (302 g, 82.2percent yield) as a light yellow solid. (0449) NM (400 MHz, DMSO-iM): δ 8.25 (s, 1 H), 3.94 (s, 3 H), 2.29 (s, 3 H)
82.2%
at 20 - 80℃; for 12 h;
Sodium acetate (365 g, 5.37 mol) was added to a stirred solution of 2-methoxy-4-methyl-3- nitropyridine (250 g, 1.49 mol) in acetic acid (1.5 L) at ambient temperature and then Br2 (639 g, 4.00 mol) was added dropwise (30 min). After addition, the mixture was heated at 80 °C for 12 h, at which time TLC indicated the reaction had gone to completion. The mixture was cooled (0 °C) and quenched by sequential addition of 10percent aqueous (1.5 L) and saturated aqueous Na2S03 (1.5 L). The resulting solid was collected by filtration washed with water, and dried under reduced pressure to give the title compound (302 g, 82.2percent yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-t 6): δ 8.25 (s, 1 H), 3.94 (s, 3 H), 2.29 (s, 3 H).
82.2%
at 20 - 80℃; for 12 h;
BrSodium acetate (365 g, 5.37 mol) was added to a stirred solution of 2-methoxy-4-methyl-3-nitropyridine (250 g, 1.49 mol) in acetic acid (1.5 L) at ambient temperature, then bromine (639g, 4.00 mol) was added and the reaction was heated at 80 °C for 12 h. The mixture was then quenched by the addition of 10percent aqueous NaOH (1.5 L) and saturated aqueous Na2SO3 (1.5 L) at 0 °C. The resulting solid was collected by filtration and washed with water, dried under vacuum to give the title compound (302 g, 82.2percent yield) as a light yellow solid. ‘H NMR (400MHz, DMSO-d6): ö 8.25 (s, 1 H), 3.94 (s, 3 H), 2.29 (s, 3 H).
Stage #1: at 0℃; for 0.166667 h; Stage #2: at 0 - 25℃; for 5 h;
Part B:; This reaction was conducted under inert gas protection. The reaction vessel was first charged with 2000 mL methanol and cooled to about 0° C. with slight agitation. Then 9.1 kg acetyl chloride was added. The exothermic reaction was then cooled and agitated for 10 minutes. The next addition was 100 g of 2-amino-5-bromo-3-nitro-4-picoline (the compound of formula 2) at 0° C. Then 236.5 g of t-butyl nitrite was added at a rate such that the temperature did not exceed 5° C. The slight evolution of nitrogen gas was noted. After the completion of the reaction, cooling was removed and the reaction mixture within the vessel was allowed to warm to 25° C. in about 30 minutes. The mixture was agitated at 25° C. for about 3-4 hours. After 4-5 hours a clear solution was obtained. Reaction completeness was monitored by HPLC after about 4 hours. The reaction was complete after about 5 hours. The reaction mixture was concentrated in vacuo to about 1000 mL. Then 500 mL of water was added and the product precipitated. Then 250 mL saturated sodium bicarbonate solution was added with good agitation to neutralize the HCl and dissolve the hydroxy impurity. The mixture was agitated at 20-25° C. for about 15 minutes and then the precipitate was collected and washed with 1000 mL of water. The product was then dried at 40° C. in vacuo. Yield was 75.0 g (70.44percent), mp. 132° C. IR (KBr, cm-1): 1633, 1581, 1538, 1512, 1458, 1377, 1344, 1321, 1244, 869, 779. 1H-NMR (DMSO-d6) (δ, ppm): 2.31 (s, 3H), 3.96 (s, 3H), 8.55 (s, 1H): 13C-NMR (DMSO-d6) (δ, ppm): 17.49, 54.91, 99.41, 114.39, 141.02, 149.23, 153.46; HMS calcd for C7H7BrN2O3 245.96401 found (M+1): 246.97184; Elemental Analysis: calcd for C7H7BrN2O3: C, 34.03; H, 2.85; N, 11.34; found: C, 33.81; H, 2.91; N, 11.24.
Part B:; This reaction was conducted under inert gas protection. The reaction vessel was first charged with 2000 mL methanol and cooled to about 0 C. with slight agitation. Then 9.1 kg acetyl chloride was added. The exothermic reaction was then cooled and agitated for 10 minutes. The next addition was 100 g of <strong>[100367-40-6]2-amino-5-bromo-3-nitro-4-picoline</strong> (the compound of formula 2) at 0 C. Then 236.5 g of t-butyl nitrite was added at a rate such that the temperature did not exceed 5 C. The slight evolution of nitrogen gas was noted. After the completion of the reaction, cooling was removed and the reaction mixture within the vessel was allowed to warm to 25 C. in about 30 minutes. The mixture was agitated at 25 C. for about 3-4 hours. After 4-5 hours a clear solution was obtained. Reaction completeness was monitored by HPLC after about 4 hours. The reaction was complete after about 5 hours. The reaction mixture was concentrated in vacuo to about 1000 mL. Then 500 mL of water was added and the product precipitated. Then 250 mL saturated sodium bicarbonate solution was added with good agitation to neutralize the HCl and dissolve the hydroxy impurity. The mixture was agitated at 20-25 C. for about 15 minutes and then the precipitate was collected and washed with 1000 mL of water. The product was then dried at 40 C. in vacuo. Yield was 75.0 g (70.44%), mp. 132 C. IR (KBr, cm-1): 1633, 1581, 1538, 1512, 1458, 1377, 1344, 1321, 1244, 869, 779. 1H-NMR (DMSO-d6) (delta, ppm): 2.31 (s, 3H), 3.96 (s, 3H), 8.55 (s, 1H): 13C-NMR (DMSO-d6) (delta, ppm): 17.49, 54.91, 99.41, 114.39, 141.02, 149.23, 153.46; HMS calcd for C7H7BrN2O3 245.96401 found (M+1): 246.97184; Elemental Analysis: calcd for C7H7BrN2O3: C, 34.03; H, 2.85; N, 11.34; found: C, 33.81; H, 2.91; N, 11.24.
This reaction was conducted under inert gas protection. The reaction vessel was first charged with 2000 ml methanol and cooled to about 0 C. with slight agitation. Then 9.1 kg acetyl chloride was added. The exothermic reaction was then cooled and agitated for 10 minutes. The next addition was 100 g <strong>[100367-40-6]2-amino-5-bromo-3-nitro-4-picoline</strong> (the compound of formula 2 at 0 C. Then 236.5 g of t-butyl nitrite was added at a rate such that the temperature did not exceed 5 C. The slight evolution of nitrogen gas was noted. After the completion of the reaction, cooling was removed and the reaction mixture within the vessel was allowed to warm to 25 C. in about 30 minutes. The mixture was agitated at 25 C. for about 3-4 hours. After 4-5 hours a clear solution was obtained. Reaction completeness was monitored by HPLC after about 4 hours. The reaction was complete after about 5 hours. The reaction mixture was concentrated in vacuo to about 1000 mL. Then 500 ml of water was added and the product precipitated. Then 250 ml saturated sodium bicarbonate solution was added with good agitation to neutralize the HCl and dissolve the hydroxy impurity. The mixture was agitated at 20-25 C. for about 15 minutes and then the precipitate was collected and washed with 1000 ml of water. The product was then dried at 40 C. in vacuo. Yield was 75.0 g. Analytical data: m.p. 132 C. IR (KBr, cm-1): 1633, 1581, 1538, 1512, 1458, 1377, 1344, 1321, 1244, 869, 779. 1H-NMR (DMSO-d6) (delta, ppm): 2.31 (s, 3H), 3.96 (s, 3H), 8.55 (s, 1H): 13C-NMR (DMSO-d6) (delta, ppm): 17.49, 54.91, 99.41, 114.39, 141.02, 149.23, 153.46; HRMS calcd for C7H7BrN2O3 245.96401 found (M+1): 246.97184; Elemental Analysis: calcd for C7H7BrN2O3: C 34.03, H 2.85, N 11.34; found: C 33.81, H 2.91, N 11.24.
With chloro-trimethyl-silane; sodium nitrite;
Thereafter, this compound is then reacted with sodium nitrite (NaN02) andtrimethylsilyl chloride (T -C1) in methanol (MeOH) to yield .
With iron; ammonium chloride In ethanol; water for 2h; Reflux;
118.B
A mixture of 5-bromo-4-methyl-2-(methyloxy)-3-nitropyridine (1.00 g, 4.05 mmol) and ammonium chloride (0.909 g, 17 mmol) in EtOH (3.5 mL) and water (3.5 mL) was stirred as iron (0.949 g, 17 mmol) was added. The mixture was heated to reflux for about 2 hours. The mixture was allowed to cool to room temperature then filtered through Celite. The filtrate was concentrated to yield a light brown solid, The solid was slurried in water and filtered to yield 5- bromo-4-methyl-2-(methyloxy)-3-pyridinamine (761 mg, 87%) as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.50 (s, 1 H) 5.07 (s, 2 H) 3.84 (s, 3 H) 2.17 (s, 3 H).
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