* 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.
With hydrazine In 1,2-dimethoxyethane at 40℃; for 4 h; Heating / reflux
λ/-Methyl-3-nitropyridin-2-amine (58.14 g, 0.38 mol) was dissolved in 1 ,2 dimethoxyethane (400 mL) under vigorous stirring. The obtained solution was refluxed with activated charcoal (2.9 g) for 2 h and kept overnight at room temperature. The reaction apparatus was flushed with dry nitrogen, and the catalyst (Pd/C 10percent, 1.75 g) was added. The mixture was heated to 40 0C. Hydrazine monohydrate (54 mL, 1.08 mol) was added dropwise to the suspension within 2 h. The obtained mixture was refluxed for 2 h, cooled, and passed through Celite (upper layer, 3 cm) and silica gel (lower layer, 5 cm, diameter 13 cm) to remove the catalyst. The layers were washed with 1 ,2-dimethoxyethane (300 mL). The filtrate was concentrated under reduced pressure to afford λ/2-methylpyridine-2,3-diamine in 98percent (46.2 g) yield as a brown crystalline solid. The product was used for the next stage without additional purification.
91.04%
With iron(III) chloride; hydrazine hydrate In ethanol at 80℃; for 5 h;
A solution of 1 g (4 mmol) of N-methyl-3-nitro-2-aminopyridine, 1.57 mL of hydrazine hydrate and 0.33 g of ferric chloride448mL ethanol, add a small amount of activated carbon, reflux at 80 for 5h, hot filter, the filtrate steamed, dark green solid production0.8 g (yield: 91.04percent).
78.25%
With hydrazine In ethanol; water at 20℃; for 2.33333 h; Inert atmosphere
Palladium (0.924 g, 0.868 mmol) was added to a three necked 1 L round bottom flask equipped with a condenser and flow of N2, and it was wet by adding a few mL of water. Then, N-methyl-3-nitropyridin-2-amine (19.0 g, 124 mmol) dissolved in ethanol (130 mL) was added. Hydrazine (15.41 ml, 496 mmol) was added to the above solution dropwise over a period of 20 minutes with continuous stirring. The reaction was exothermic, and 3/4 gas evolved during the reaction. The reaction mixture was stirred at room temperature for about 2 h. The color of the reaction changed from yellow to colorless. Completion of the reaction was checked by TLC. Pd was filtered on a tightly packed Celite.(R). plug. The Celite.(R). was first washed with DCM, and Pd was filtered off. A little bit of Celite.(R). was placed on the top of Pd for safety, and it was washed with DCM until all the product was washed off of the Celite.(R).. Combined solvent was concentrated and residue was taken in EtOAc washed with 3/4(). NaCl solid was added to remove any left over hydrazine. EtOAc was dried on Na2SC>4, filtered and concentrated to give a dark brown solid (11.95 g; 78.25percent).
Reference：
[1] Chemistry - A European Journal, 2017, vol. 23, # 57, p. 14173 - 14176
[2] Open Medicinal Chemistry Journal, 2018, vol. 12, # 1, p. 74 - 83
[3] Patent: WO2008/12622, 2008, A2, . Location in patent: Page/Page column 57
[4] Patent: CN106831776, 2017, A, . Location in patent: Paragraph 0100; 0101; 0102
[5] Patent: WO2012/121936, 2012, A2, . Location in patent: Page/Page column 93-94
[6] Bulletin de la Societe Chimique de France, 1992, # 1, p. 79 - 84
[7] Farmaco, 1994, vol. 49, # 4, p. 259 - 265
[8] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 21, p. 4790 - 4793
[9] Patent: US5624935, 1997, A,
[10] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 5, p. 1696 - 1701
[11] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 20, p. 5493 - 5496
[12] Organic and Biomolecular Chemistry, 2013, vol. 11, # 14, p. 2335 - 2347
[13] Australian Journal of Chemistry, 2016, vol. 69, # 6, p. 618 - 630
2
[ 4093-88-3 ]
[ 7440-05-3 ]
[ 5028-20-6 ]
Reference：
[1] Patent: US2012/228583, 2012, A1,
3
[ 4093-88-3 ]
[ 6332-56-5 ]
Reference：
[1] Chemische Berichte, 1928, vol. 61, p. 1230[2] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1928, vol. 60, p. 975
4
[ 5470-18-8 ]
[ 74-89-5 ]
[ 4093-88-3 ]
Yield
Reaction Conditions
Operation in experiment
100%
at 80℃; for 8 h; Sealed tube
To a solution of 3-nitro-2-chloropyridine (4.0 g, 25.2 mmol) in 15 mL 2-methoxyethanol was added methylamine (2.0 M in THF, 32 mL). The reactionwas stirred for 8 hr at 80 °C in a sealed tube. After cooling to rt, the reaction mixture was evaporated to afford 15 quantitatively (3.6 g, 23.2 mmol). 1H NMR (500 MHz, CDCl3) δ 8.47 – 8.37 (m, 2H), 8.20 (s, 1H), 6.64 (dd, J = 8.3, 4.4 Hz, 1H), 3.17 (d, J = 4.8 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 156.0, 153.5, 135.4, 111.7, 28.4. HRMS (ESI+) m/z calcd for C6H8N3O2+ 154.0617, found 154.0610.
98.5%
at 0 - 20℃; for 3 h;
Methylamine (33percent in EtOH) (1 10 mL, 883 mmol) was placed in a 500 mL three necked round bottom flask. It was cooled to 0 °C using ice bath. 2-chloro-3-nitropyridine (20 g, 126 mmol) was added to the above solution in portions as this is an exothermic reaction. After the addition was complete the reaction mixture was stirred for 2 h at 0 °C and later 1 h at room temperature. Solvent was concentrated and residue was taken in 500 mL of water and extracted with EtOAc 3 x 150 mL. Combine organic layer was dried over Na2SC"4, filtered and concentrated to give a bright orangish yellow solid(19 g , 98.5percent).
95.76%
With triethylamine In dichloromethane at 20℃; for 5 h;
24 mL of methylamine, 39.5 mL of triethylamine was added to 240 mL of dichloromethane, and 30 g(0.18 mol) of 2-chloro-3-nitropyridine, and the reaction was completed at room temperature for 5 h. After completion of the reaction, the reaction solution was washed three times with waterInto anhydrous sodium sulfate in addition to water, suction filtration, steaming, yellow crystalline solid product 44.8g (yield 95.76percent).
86%
With sodium acetate In water; acetonitrile at 20℃; Heating / reflux
2-chloro-3-nitropyridine 70.0 g, 0.44 mol) was dissolved in recently distilled acetonitrile (400 mL) under stirring. Sodium acetate (55.2 g, 0.67 mol) and 30percent aqueous solution of methylamine (111 mL) were added under vigorous stirring. The obtained suspension was stirred at room temperature for 30 min, refluxed for 1 h, and kept overnight at room temperature. The yellow reaction mixture was concentrated under reduced pressure to remove approximately 300 mL of the solvent. The residue was diluted with 20percent aqueous solution of K2CO3 (1 L) under stirring. The yellow precipitate was filtered off, washed with water (3° * 200 mL), and dried to afford W-Methyl-3-nitropyridin-2-amine in 86percent (58.14 g, 0.38 mol) yield as bright yellow crystals.
Reference：
[1] Tetrahedron Letters, 2015, vol. 56, # 44, p. 6097 - 6099
[2] Patent: WO2012/121936, 2012, A2, . Location in patent: Page/Page column 93
[3] Patent: CN106831776, 2017, A, . Location in patent: Paragraph 0097; 0098; 0099
[4] European Journal of Organic Chemistry, 2009, # 22, p. 3753 - 3764
[5] Acta Chemica Scandinavica, 1993, vol. 47, # 8, p. 805 - 812
[6] Patent: WO2008/12622, 2008, A2, . Location in patent: Page/Page column 57
[7] Open Medicinal Chemistry Journal, 2018, vol. 12, # 1, p. 74 - 83
[8] Chemistry - A European Journal, 2017, vol. 23, # 57, p. 14173 - 14176
[9] Patent: US4520196, 1985, A,
[10] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 5, p. 1696 - 1701
[11] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 20, p. 5493 - 5496
5
[ 5470-18-8 ]
[ 4093-88-3 ]
Yield
Reaction Conditions
Operation in experiment
98.5%
With methylamine In ethanol; water
Synthesis of N-methyl-3-nitropyridin-2-amine Methylamine (33percent in EtOH) (110 mL, 883 mmol) was placed in a 500 mL three necked round bottom flask. It was cooled to 0° C. using ice bath. 2-chloro-3-nitropyridine (20 g, 126 mmol) was added to the above solution in portions as this is an exothermic reaction. After the addition was complete the reaction mixture was stirred for 2 h at 0° C. and later 1 h at room temperature. Solvent was concentrated and residue was taken in 500 mL of water and extracted with EtOAc 3*150 mL. Combine organic layer was dried over Na2SO4, filtered and concentrated to give a bright orangish yellow solid (19 g, 98.5percent).
Reference：
[1] Patent: US2012/228583, 2012, A1,
6
[ 5470-18-8 ]
[ 4093-88-3 ]
[ 33742-70-0 ]
Reference：
[1] Patent: US5624935, 1997, A,
7
[ 74-89-5 ]
[ 4093-88-3 ]
[ 73895-39-3 ]
Reference：
[1] Advanced Synthesis and Catalysis, 1999, vol. 341, # 1, p. 75 - 78
8
[ 1480-87-1 ]
[ 74-89-5 ]
[ 4093-88-3 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 21, p. 4790 - 4793
9
[ 123-39-7 ]
[ 5470-18-8 ]
[ 4093-88-3 ]
Reference：
[1] Journal of the Brazilian Chemical Society, 2010, vol. 21, # 8, p. 1439 - 1445
10
[ 79-16-3 ]
[ 5470-18-8 ]
[ 4093-88-3 ]
Reference：
[1] Journal of the Brazilian Chemical Society, 2010, vol. 21, # 8, p. 1439 - 1445
11
[ 4214-75-9 ]
[ 74-88-4 ]
[ 4093-88-3 ]
Reference：
[1] Chemische Berichte, 1928, vol. 61, p. 1230[2] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1928, vol. 60, p. 975
[3] Chemische Berichte, 1928, vol. 61, p. 1230[4] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1928, vol. 60, p. 975
12
[ 90819-94-6 ]
[ 7664-93-9 ]
[ 4093-89-4 ]
[ 4093-88-3 ]
Reference：
[1] Chemische Berichte, 1928, vol. 61, p. 1230[2] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1928, vol. 60, p. 975
[3] Chemische Berichte, 1925, vol. 58, p. 1717
In 2-methoxy-ethanol; at 80℃; for 8.0h;Sealed tube;
To a solution of 3-nitro-2-chloropyridine (4.0 g, 25.2 mmol) in 15 mL 2-methoxyethanol was added methylamine (2.0 M in THF, 32 mL). The reactionwas stirred for 8 hr at 80 C in a sealed tube. After cooling to rt, the reaction mixture was evaporated to afford 15 quantitatively (3.6 g, 23.2 mmol). 1H NMR (500 MHz, CDCl3) delta 8.47 - 8.37 (m, 2H), 8.20 (s, 1H), 6.64 (dd, J = 8.3, 4.4 Hz, 1H), 3.17 (d, J = 4.8 Hz, 3H). 13C NMR (126 MHz, CDCl3) delta 156.0, 153.5, 135.4, 111.7, 28.4. HRMS (ESI+) m/z calcd for C6H8N3O2+ 154.0617, found 154.0610.
98.5%
In ethanol; at 0 - 20℃; for 3.0h;
Methylamine (33% in EtOH) (1 10 mL, 883 mmol) was placed in a 500 mL three necked round bottom flask. It was cooled to 0 C using ice bath. 2-chloro-3-nitropyridine (20 g, 126 mmol) was added to the above solution in portions as this is an exothermic reaction. After the addition was complete the reaction mixture was stirred for 2 h at 0 C and later 1 h at room temperature. Solvent was concentrated and residue was taken in 500 mL of water and extracted with EtOAc 3 x 150 mL. Combine organic layer was dried over Na2SC"4, filtered and concentrated to give a bright orangish yellow solid(19 g , 98.5%).
95.76%
With triethylamine; In dichloromethane; at 20℃; for 5.0h;
24 mL of methylamine, 39.5 mL of triethylamine was added to 240 mL of dichloromethane, and 30 g(0.18 mol) of 2-chloro-3-nitropyridine, and the reaction was completed at room temperature for 5 h. After completion of the reaction, the reaction solution was washed three times with waterInto anhydrous sodium sulfate in addition to water, suction filtration, steaming, yellow crystalline solid product 44.8g (yield 95.76%).
86%
With sodium acetate; In water; acetonitrile; at 20℃;Heating / reflux;
2-chloro-3-nitropyridine 70.0 g, 0.44 mol) was dissolved in recently distilled acetonitrile (400 mL) under stirring. Sodium acetate (55.2 g, 0.67 mol) and 30% aqueous solution of methylamine (111 mL) were added under vigorous stirring. The obtained suspension was stirred at room temperature for 30 min, refluxed for 1 h, and kept overnight at room temperature. The yellow reaction mixture was concentrated under reduced pressure to remove approximately 300 mL of the solvent. The residue was diluted with 20% aqueous solution of K2CO3 (1 L) under stirring. The yellow precipitate was filtered off, washed with water (3 * 200 mL), and dried to afford W-Methyl-3-nitropyridin-2-amine in 86% (58.14 g, 0.38 mol) yield as bright yellow crystals.
80%
In N-methyl-acetamide;
A. 2-Methylamino-3-nitropyridine 25 g (0.16M) of 2-chloro-3-nitropyridine is dissolved in 200 ml dimethylformamide. For three hours monomethylamine is bubbled into the solution. The mixture is heated to reflux overnight. After the solvent is removed the oily residue is triturated with water and the solid is collected and air dried. The crude material is recrystallized from hexane to give 19.5 g (80% yield) of title compound, melting point 62-3 C. Analysis for: C6 H7 N3 O2: Calculated: C, 47.05; H, 4.61; N, 27.44. Found: C, 46.92; H, 4.73; N, 27.13.
With hydrazine;palladium 10% on activated carbon; In 1,2-dimethoxyethane; at 40℃; for 4.0h;Heating / reflux;
lambda/-Methyl-3-nitropyridin-2-amine (58.14 g, 0.38 mol) was dissolved in 1 ,2 dimethoxyethane (400 mL) under vigorous stirring. The obtained solution was refluxed with activated charcoal (2.9 g) for 2 h and kept overnight at room temperature. The reaction apparatus was flushed with dry nitrogen, and the catalyst (Pd/C 10%, 1.75 g) was added. The mixture was heated to 40 0C. Hydrazine monohydrate (54 mL, 1.08 mol) was added dropwise to the suspension within 2 h. The obtained mixture was refluxed for 2 h, cooled, and passed through Celite (upper layer, 3 cm) and silica gel (lower layer, 5 cm, diameter 13 cm) to remove the catalyst. The layers were washed with 1 ,2-dimethoxyethane (300 mL). The filtrate was concentrated under reduced pressure to afford lambda/2-methylpyridine-2,3-diamine in 98% (46.2 g) yield as a brown crystalline solid. The product was used for the next stage without additional purification.
91.04%
With iron(III) chloride; hydrazine hydrate; In ethanol; at 80℃; for 5.0h;
A solution of 1 g (4 mmol) of N-methyl-3-nitro-2-aminopyridine, 1.57 mL of hydrazine hydrate and 0.33 g of ferric chloride448mL ethanol, add a small amount of activated carbon, reflux at 80 for 5h, hot filter, the filtrate steamed, dark green solid production0.8 g (yield: 91.04%).
78.25%
With hydrazine;palladium; In ethanol; water; at 20℃; for 2.33333h;Inert atmosphere;
Palladium (0.924 g, 0.868 mmol) was added to a three necked 1 L round bottom flask equipped with a condenser and flow of N2, and it was wet by adding a few mL of water. Then, <strong>[4093-88-3]N-methyl-3-nitropyridin-2-amine</strong> (19.0 g, 124 mmol) dissolved in ethanol (130 mL) was added. Hydrazine (15.41 ml, 496 mmol) was added to the above solution dropwise over a period of 20 minutes with continuous stirring. The reaction was exothermic, and ¾ gas evolved during the reaction. The reaction mixture was stirred at room temperature for about 2 h. The color of the reaction changed from yellow to colorless. Completion of the reaction was checked by TLC. Pd was filtered on a tightly packed Celite plug. The Celite was first washed with DCM, and Pd was filtered off. A little bit of Celite was placed on the top of Pd for safety, and it was washed with DCM until all the product was washed off of the Celite. Combined solvent was concentrated and residue was taken in EtOAc washed with ¾(). NaCl solid was added to remove any left over hydrazine. EtOAc was dried on Na2SC>4, filtered and concentrated to give a dark brown solid (11.95 g; 78.25%).
In 1,4-dioxane; palladium;
PREPARATION 105 3-Amino-2-methylaminopyridin A procedure similar to that described in Example 6 was repeated, except that 5.00 g of 2-methylamino-3nitropyridine (prepared as described in Preparation 104) were hydrogenated in 80 ml of 1,4-dioxane in the presence of 1.00 g of 10 % w/w palladium-on-charcoal. After working up the product as described in Example 6, 3.87 g of the title compound, melting at 90-92 C. were obtained.
PREPARATION 104 2-Methylamino-3-nitropyridine A procedure similar to that described in Preparation 66 was repeated, except that 24.9 g of 2-chloro-3-nitropyridine, 41.7 g of sodium carbonate, 22.7 ml of a 30 % ethanolic solution of methylamine were reacted in 250 ml of toluene. After working up the product as described in Preparation 66, the resulting crude product was crystallized by trituration with isopropanol, to give 24.0 g of the title compound, melting at 52-53 C.
With sodium chloride; hydrazine; In ethanol; ethyl acetate;
Synthesis of N2-methylpyridine-2,3-diamine Palladium (0.924 g, 0.868 mmol) was added to a three necked 1 L round bottom flask equipped with a condenser and flow of N2, and it was wet by adding a few mL of water. Then, <strong>[4093-88-3]N-methyl-3-nitropyridin-2-amine</strong> (19.0 g, 124 mmol) dissolved in ethanol (130 mL) was added. Hydrazine (15.41 ml, 496 mmol) was added to the above solution dropwise over a period of 20 minutes with continuous stirring. The reaction was exothermic, and H2 gas evolved during the reaction. The reaction mixture was stirred at room temperature for about 2 h. The color of the reaction changed from yellow to colorless. Completion of the reaction was checked by TLC. Pd was filtered on a tightly packed Celite plug. The Celite was first washed with DCM, and Pd was filtered off. A little bit of Celitewas placed on the top of Pd for safety, and it was washed with DCM until all the product was washed off of the Celite. Combined solvent was concentrated and residue was taken in EtOAc washed with H2O. NaCl solid was added to remove any left over hydrazine. EtOAc was dried on Na2SO4, filtered and concentrated to give a dark brown solid (11.95 g; 78.25%).
Synthesis of N-methyl-3-nitropyridin-2-amine Methylamine (33% in EtOH) (110 mL, 883 mmol) was placed in a 500 mL three necked round bottom flask. It was cooled to 0 C. using ice bath. 2-chloro-3-nitropyridine (20 g, 126 mmol) was added to the above solution in portions as this is an exothermic reaction. After the addition was complete the reaction mixture was stirred for 2 h at 0 C. and later 1 h at room temperature. Solvent was concentrated and residue was taken in 500 mL of water and extracted with EtOAc 3*150 mL. Combine organic layer was dried over Na2SO4, filtered and concentrated to give a bright orangish yellow solid (19 g, 98.5%).
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