* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Russian Journal of Organic Chemistry, 2009, vol. 45, # 1, p. 115 - 118
2
[ 7598-26-7 ]
[ 24638-29-7 ]
Yield
Reaction Conditions
Operation in experiment
98%
With 10% palladium on activated charcoal; hydrogen In methanol at 20℃; for 5 h;
Pd/C (50 mg, 0.47 mmol) was added to a stirred solution of 2-amino-5-methyl-3- nitropyridine (500 mg, 3.27 mmol) was in MeOH (7 ml). The reaction was then evacuated of air 3 times and filled with H2 gas. The reaction was then stirred under this atmosphere at 20°C for 5 h after which the reaction was filtered through Celite and washed with further MeOH (30 ml). The solution was concentrated in vacuo to give WIN-321 -195-01 (395 mg, 98percent). 1H NMR (MeOD): δ 7.22 (dd, J 2.0, 0.9 Hz, 1 H), 6.81 (dd, J 2.0, 0.7 Hz, 1 H), 2.13 (t, J 0.7 Hz, 3H). MS, m/z = 124 (100).
82%
With 10% palladium on activated carbon; Degussa type; hydrogen In methanol; ethyl acetate at 20℃; for 8 h;
5-Methyl-3-nitropyridin-2-amine (50000.0 mg, 0.33 mol) was dissolved in MeOH/ EtOAc (1000.0 mL), and 10percent of Pd/C (5000.0 mg) was added thereto. The flask was substituted with hydrogen. The reaction mixture was reacted at room temperature for 8 hours, then filtered through celite and evaporated under reduced pressure to obtain brown solid compound of 5-methylpyridin-2,3-diamine (98000.0 mg, 82percent). [0755] 1H-NMR (300 MHz, CDCl3); δ: 7.48 (s, 1H), 6.74 (s, 1H), 4.06 (bs, 2H), 3.27 (bs, 2H), 2.16 (s, 3H)
Reference：
[1] Journal of Medicinal Chemistry, 1997, vol. 40, # 22, p. 3679 - 3686
[2] Patent: WO2017/219083, 2017, A1, . Location in patent: Page/Page column 73; 74
[3] Patent: US2014/315888, 2014, A1, . Location in patent: Paragraph 0754-0755
[4] Journal of the American Chemical Society, 1950, vol. 72, p. 2806
[5] Patent: US5620978, 1997, A,
3
[ 1603-41-4 ]
[ 7598-26-7 ]
Yield
Reaction Conditions
Operation in experiment
27%
Stage #1: at -10 - 20℃; for 1 h; Stage #2: With nitric acid In water at 55 - 60℃; for 0.5 h; Stage #3: With sodium hydroxide In water at 0℃;
Example 170: 5-methyl-3-nitro-pyridin-2-ylamine; [00577] Sulfuric acid (97percent, 100 mL) was placed in a -10 °C bath and when the internal temperature reached to 5 °C, 2-amino-picoline (25 g, 231.2 mmol) was added in small portions with stirring (in1 h). The suspension was stirred at ambient temperature to dissolve rest of the solid. The resulting solution was heated to 55 °C and 70percent cone. HNO3 (15.6 mL) was added dropwise while maintaining the internal temperature between 55-60 °C. The mixture was stirred further 30 min after the addition, poured into crushed ice (800 g), stirred to get solution and treated with 40percent aqueous NaOH solution at 0 °C to reach pH 9 and extracted with CHCb (3 x 250 mL). Combined organic layers were washed with brine (2 x 200 mL), dried (anhydrous Na2SO4) and concentrated under reduced pressure to afford 5-methyl-3-nitro-pyridin-2-ylamine (9.49 g) as yellow solid in 27percent yield. ESMS m/z (relative intensity): 154 (M+H)+ (100).
Reference：
[1] Patent: WO2006/76644, 2006, A2, . Location in patent: Page/Page column 204
[2] Journal of Medicinal Chemistry, 1997, vol. 40, # 22, p. 3679 - 3686
[3] Journal of the American Chemical Society, 1951, vol. 73, p. 3504
[4] Journal of the American Chemical Society, 1950, vol. 72, p. 2806
[5] Journal of the American Chemical Society, 1955, vol. 77, p. 3154
4
[ 1603-41-4 ]
[ 7598-26-7 ]
Reference：
[1] Patent: US5620978, 1997, A,
5
[ 91752-76-0 ]
[ 71090-35-2 ]
[ 7598-26-7 ]
Reference：
[1] Archiv der Pharmazie, 1992, vol. 325, # 12, p. 785 - 789
Stage #1: With hydrogen bromide In water at -10 - 0℃; Stage #2: With bromine; sodium nitrite In water at -10 - 0℃; for 1 h; Stage #3: With sodium hydroxide In water at 0 - 20℃; for 1 h;
Example 171 : 2-Bromo-5-methyl-3-nitro-pyridine:; [00578] To concentrated HBr (48percent, 28.6 mL) was added 5-methyl-3-nitro- pyridin-2-ylamine (5 g, 32.6 mmol) in portions at 0 °C temperature with stirring. The mixture was stirred until the internal temperature reached to -10 °C, then bromine was added drop wise. A solution of NaNO2 (7.6 g, 110.84 mmol) in water (11 mL) was added slowly to maintain the reaction mixture temperature below 0 °C. The dark mixture (gas evolution was observed) was stirred for 1 h at 0 °C then was carefully treated (slow addition) with a solution of NaOH (12 g, 300 mmol) in water (17 mL) while maintaining the internal temperature below 20 °C. EPO <DP n="207"/>The mixture was stirred for an additional 1 h, then was filtered, dried under vacuum for 6 h and purified by recrystalization using 95percent EtOH to get pure 2- bromo-5-methyl-3-nitro-pyridine (1.96 g) as yellow solid in 28percent first crop yield. ESMS m/z (relative intensity): 217 (M+H)+ (100).
Example 170: 5-methyl-3-nitro-pyridin-2-ylamine; [00577] Sulfuric acid (97%, 100 mL) was placed in a -10 C bath and when the internal temperature reached to 5 C, 2-amino-picoline (25 g, 231.2 mmol) was added in small portions with stirring (in1 h). The suspension was stirred at ambient temperature to dissolve rest of the solid. The resulting solution was heated to 55 C and 70% cone. HNO3 (15.6 mL) was added dropwise while maintaining the internal temperature between 55-60 C. The mixture was stirred further 30 min after the addition, poured into crushed ice (800 g), stirred to get solution and treated with 40% aqueous NaOH solution at 0 C to reach pH 9 and extracted with CHCb (3 x 250 mL). Combined organic layers were washed with brine (2 x 200 mL), dried (anhydrous Na2SO4) and concentrated under reduced pressure to afford 5-methyl-3-nitro-pyridin-2-ylamine (9.49 g) as yellow solid in 27% yield. ESMS m/z (relative intensity): 154 (M+H)+ (100).
With palladium on activated charcoal; hydrogen; In methanol; at 20℃; for 5h;
Pd/C (50 mg, 0.47 mmol) was added to a stirred solution of 2-amino-5-methyl-3- nitropyridine (500 mg, 3.27 mmol) was in MeOH (7 ml). The reaction was then evacuated of air 3 times and filled with H2 gas. The reaction was then stirred under this atmosphere at 20C for 5 h after which the reaction was filtered through Celite and washed with further MeOH (30 ml). The solution was concentrated in vacuo to give WIN-321 -195-01 (395 mg, 98%). 1H NMR (MeOD): delta 7.22 (dd, J 2.0, 0.9 Hz, 1 H), 6.81 (dd, J 2.0, 0.7 Hz, 1 H), 2.13 (t, J 0.7 Hz, 3H). MS, m/z = 124 (100).
82%
With palladium 10% on activated carbon; hydrogen; In methanol; ethyl acetate; at 20℃; for 8h;
5-Methyl-3-nitropyridin-2-amine (50000.0 mg, 0.33 mol) was dissolved in MeOH/ EtOAc (1000.0 mL), and 10% of Pd/C (5000.0 mg) was added thereto. The flask was substituted with hydrogen. The reaction mixture was reacted at room temperature for 8 hours, then filtered through celite and evaporated under reduced pressure to obtain brown solid compound of 5-methylpyridin-2,3-diamine (98000.0 mg, 82%). [0755] 1H-NMR (300 MHz, CDCl3); delta: 7.48 (s, 1H), 6.74 (s, 1H), 4.06 (bs, 2H), 3.27 (bs, 2H), 2.16 (s, 3H)
81%
With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; for 2h;
The compound 5-methyl-3-nitropyridin-2-amine 38a (306 mg, 2 mmol), 10% palladium carbon (15 mg) and methanol (30 ml) were mixed and then stirred at room temperature for 2 hr under hydrogen atmosphere. The solvent was removed by filtration palladium on carbon, the filtrate was removed under reduced pressure, To give the desired product 5-methylpyridine-2,3-diamine 38b (200 mg, brown solid), yield: 81%.
629 mg (99%)
Pd-C; In methanol;
2,3-Diamino-5-methylpyridine (39) A mixture of 38 (790 mg, 5.17 mmol), methanol (60 mL), and 5% Pd-C (70 mg) was shaken under H2 (20-30 psi) for 3 h, then filtered and evaporated to give 629 mg (99%) of the diamine 39 as a black thick oil. 1 H NMR (CDCl3) delta2.160 (s, 3H), 3.308 (bs, 2H), 4.160 (bs, 2H), 6.740 (s, 1H), 7.459 (s, 1H). It was used for the next reaction without further purification.
Example 171 : 2-Bromo-5-methyl-3-nitro-pyridine:; [00578] To concentrated HBr (48%, 28.6 mL) was added 5-methyl-3-nitro- pyridin-2-ylamine (5 g, 32.6 mmol) in portions at 0 C temperature with stirring. The mixture was stirred until the internal temperature reached to -10 C, then bromine was added drop wise. A solution of NaNO2 (7.6 g, 110.84 mmol) in water (11 mL) was added slowly to maintain the reaction mixture temperature below 0 C. The dark mixture (gas evolution was observed) was stirred for 1 h at 0 C then was carefully treated (slow addition) with a solution of NaOH (12 g, 300 mmol) in water (17 mL) while maintaining the internal temperature below 20 C. EPO <DP n="207"/>The mixture was stirred for an additional 1 h, then was filtered, dried under vacuum for 6 h and purified by recrystalization using 95% EtOH to get pure 2- bromo-5-methyl-3-nitro-pyridine (1.96 g) as yellow solid in 28% first crop yield. ESMS m/z (relative intensity): 217 (M+H)+ (100).
2-Amino-5-methyl-3-nitropyridine (38) 2-Amino-5-methylpyridine (2.16 g, 20.0 mmol) was added into 10 mL of conc H2 SO4 in portions at room temperature with stirring. To the resulting solution was added 70% (HNO3 2.0 mL, 31.5 mmol) at room temperature dropwise with stirring. The mixture was then stirred at 55 C. (bath) for 2 h, cooled to room temperature and poured into crushed ice (about 100 g). The mixture was basified to pH 9 in ice-water bath by the addition of 40% aq. NaOH dropwise and the mixture was extracted with CHCl3 (5*25 mL). The CHCl3 extracts were combined, washed with brine (20 mL), dried (MgSO4), and rota-evaporated to dryness to give 770 mg (25%) of 38 as a bright yellow powder, mp 175-6 C. 1 H NMR (CDCl3) delta2.291 (s, 3H), 6.556 (bs, 2H), 8.219 (s, 1H), 8.237 (s, 1H).
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