* 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] Liebigs Annalen der Chemie, 1991, # 9, p. 875 - 878
3
[ 19798-80-2 ]
[ 6980-08-1 ]
Yield
Reaction Conditions
Operation in experiment
85%
Cooling with ice
The compound 4-chloro-2-aminopyridine (6.4 g, 50 mmol) was slowly added to fuming nitric acid (50 mL) under ice-cooling. The reaction system was gradually warmed to room temperature and poured into water containing crushed ice. The residue was filtered and separated by flash column chromatography (dichloromethane: methanol = 100: 1) to give the title compound as a white solid. L: 4-chloro-3-nitro Yl-2-aminopyridine (7.4 g, yield 85percent).
70%
at 0 - 70℃; for 21 h;
4-chloropyridin-2-amine (100 g, 0.77 mol) dissolved in 1.0 L H2SO4 and cooled to 0 degree and H2SO4(30mL) and HNO3(58.2g) was added dropwise a mixed solution slowly for 15 minutes. Raise the reaction solution to room temperature and stir for 20 hours. The temperature was increased to 50 ~ 70 and then was stirred for one hour. When the reaction was completed, the reaction mixture cooled to room temperature, ice-water and 10percent NaOH was slowly added dropwise to adjust the pH to 7.5 and filtered to result in yellow solid product. the resultant yellow solid product was purified by silica gel column chromatography to give the desired compound 4-chloro-3-nitropyridin-2-amine (80g, yield:70percent)
36%
Stage #1: With sulfuric acid; nitric acid In water at 0℃; for 1 h; Stage #2: With ammonium hydroxide In water
To a solution of 2-amino-4-chloropyridine (5.00 g, 0.0389 mol) in sulfuric acid (40.8 mL) with stirring at 0° C. was added a solution of nitric acid (2.72 g, 0.0389 mol) and sulfuric acid (3.89 g, 0.0389 mol). The mixture was stirred (1 hr) then poured into 200 g ice and 100 ml water. The solid was filtered and collected. The solution was neutralized with 28percent NH3 in water to pH 5. The solution was extracted with EtOAc (3.x.300 ml). The solid also was dissolved in EtOAc and neutralized with 28percent NH3 in H2O. The organic layers were combined, concentrated with 30 g silica gel, and purified by flash chromatography (20 to 60percent EtOAc/hexanes) to afford the title compound (2.40 g, 36percent) as a yellow solid.
35%
at 0℃; for 16 h;
4-chloro-3-nitropyridin-2-amine A nitrating mixture (HNO3:H2SO4, 5 mL) was added to 4-chloropyridin-2-amine (2.56 g, 20 mmol) at 0° C. and stirred for 16 h. After completion of the reaction, the mixture was diluted with water and ethyl acetate, extracted with ethyl acetate, washed with water, brine, dried over anhydrous Na2SO4, and then concentrated under reduced pressure. The resulting crude product was purified by flash chromatography to afford 4-chloro-3-nitropyridin-2-amine as a yellow solid (1.211 g, 35percent yield). HPLC: 97.2percent purity. MS: 74.0 [M+H]+. 1H NMR: 400 MHz, DMSO-d6: δ 8.11 (d, J=5.24 Hz, 1H), 7.23 (s, 2H), 6.85 (d, -=5.24 Hz, 1H).
33%
at 0 - 20℃; for 1 h;
To a stirred solution of 2-amino-4-chloropyridine (5.00 g, 0.0389 mol) in concentrated sulfuric acid (40.8 mL) was added dropwise concentrated nitric acid (5.00 g, 0.0389 mol) and concentrated sulfuric acid (3.89 g) at 0°C. 0.0389 mol). After addition, the mixture was allowed to warm to room temperature and stirred for 1 h. The reaction was then poured into a mixture of 200 g of ice and 100 mL of water. A large amount of a yellow solid precipitated and the solids were collected by filtration. The filtrate was neutralized with 28percent ammonia to a pH of 9, and extracted three times with ethyl acetate and the organic phase was collected. The solid obtained by filtration was also dissolved in ethyl acetate, and the pH was adjusted to 9 with aqueous ammonia. The separated organic phase was combined with the foregoing organic phase, dried over anhydrous sodium sulfate, concentrated, and the residue was subjected to column chromatography to give the title compound (2.233 g, Yield 33percent) is a yellow solid.
32%
Stage #1: for 0.0833333 h; Cooling with ice Stage #2: at 0 - 55℃; for 1.16667 h; Cooling with ice
[00116] To a 100 ml. round-bottomed flask containing 2-amino-4-chloropyridine (0.480 g, 3.75 mmol) cooled in an ice bath was added concentrated sulphuric acid (5.4 g). The reaction mixture was stirred for 5 min and then nitric acid (70percent; 0.36 g) was added dropwise. The reaction mixture was stirred at 0 °C for 10 min, then heated to 55 °C and stirred at this temperature for 1 h. It was cooled to room temperature and diluted with ice- water. The pH was carefully adjusted to ~ 7.5 with 10percent aqueous NaOH whereupon a yellow precipitate formed. This was filtered off, washed with water and dried in vacuo over P205. The product was purified by silica column chromatography (elution with dichloromethane) to provide in order of elution: 4-Chloro-3-nitropyridin-2-amine as a yellow solid (0.210 g, 32percent), 1 H-NMR (500 MHz, DMSO-d6) 6.87 (d, J = 5.2 Hz, 1 H, pyridine C-H), 7.21 (s, 2H, NH2), 8.1 1 (d, J = 5.2 Hz, 1 H, pyridine C-H).
1.2 g
Stage #1: at 0 - 20℃; for 2 h; Stage #2: With sodium hydroxide In water
To a solution of 4- chloro-pyridin-2-ylamine (5 g) in 96percent aq H2SO4 (20 mL) at 0 °C was added a mixture solution of 70percent aq HN03 (2.5 mL) and 96percent aq H2S04 (10 mL) drop-wise. After the addition was completed, the mixture was stirred at room temperature for 2h. The solution was poured onto ice/water and 6M aq. NaOH was added drop-wise to adjust pH to 9. Then the solid was filtered off, washed with water, and dried before it was purified by chromatography on alumina (eluent: pentane:EtOAc 2:1) to afford 4-chloro-3-nitro-pyridin-2-ylamine (1.2 g). 200 mg of this material was dissolved methanol (3mL) and NaOMe (125 mg) was added before the mixture was stirred at 60 °C for 16h. 37percent> aq HC1 was added drop-wise to adjust pH to 6. The mixture was cooled to 0 °C, and the precipitated solid was filtered off, washed with water, and dried to afford 4-methoxy-3-nitro-pyridin-2-ylamine (180 mg). This material was dissolved in methanol (20 mL) and treated with hydrogen gas (1 bar) in the presence of 10percent> palladium on charcoal at room temperature for 2h. The mixture was filtered and the filtrate was concentrated in vacuo to afford 4-methoxy-pyridine-2,3-diamine (50 mg). This procedure was repeated to produce more material. In the next step, 4-methoxy-pyridine-2,3-diamine (6.8 g) was dissolved in ethanol (200 mL). To this solution was slowly added methyl pyruvate (4.9 mL) at room temperature, and the mixture was stirred at ambient temperature for 3h before the volatiles were removed in vacuo. The residue was purified by chromatography on silica gel (eluent: pentane:EtOAc 5: 1 to 0: 1) to give afford 8-methoxy-2-methyl-4H-pyrido[2,3- b]pyrazin-3-one (6.1 g). To a suspension of 3 g of this material in DMF (12 mL) was added PyBroP (7.65 g) followed by DBU (3.58 g). The mixture was stirred overnight before the precipitated solid was filtered off, washed with ethanol, and dried to afford 3-(benzotriazol-l- yloxy)-8-methoxy-2-methyl-pyrido[2,3-b]pyrazine (3.5 g). 1.5 g of this material was dissolved in a mixture of ethanol (lOmL) and DCM (60mL). Hydrazine monohydrate (3.6g) was added, and the mixture was stirred overnight at ambient temperature before the volatiles were removed in vacuo. The residual solid was triturated from ethanol, filtered off, washed with ethanol, and dried to afford (8-methoxy-2-methyl-pyrido[2,3-b]pyrazin-3-yl)- hydrazine He (0.9 g).
Stage #1: at -8 - 20℃; for 0.333333 h; Salt-ice bath Stage #2: With ammonia In water at 0 - 25℃;
Example 13(a) 4-Chloro-3-nitropyridin-2-amine(Aust. J. Chem. 1982, 35, 2025.)4-Chloro-2-aminopyridine (10 g, 77.5 mmol) was dissolved in concentrated sulfuric acid (10OmL) and using a salt-ice bath, was cooled to ca. -8 0C. Fuming nitric acid was slowly added whilst stirring and at such a rate that a temperature < 0 °C was maintained. The reaction mixture was then stirred for 20 minutes at ambient temperature and carefully poured onto ice. Ammonium hydroxide (32percent) was carefully added. Ice was used to maintain temperature < 25 0C until the solution reached pH 3. The solid product was filtered, washed with water and re-crystallised from 1:1 wateπEtOH. The solid was added in small portions to ice-cold concentrated sulfuric acid (200 mL) at a rate allowing a temperature of <4 °C to be maintained. Once addition was complete, the reaction mixture was allowed to reach ambient temperature. After 2.5 h at room temperature, 2 regioisomers (1:1), the 3 and 5-nitro compounds were observed (LCMS). The reaction mixture was poured onto ice and basifed with ammonium hydroxide (32percent). Filtration and subsequent washing with water provided the mixture of the 2 regioisomers. The products were dissolved in ethyl acetate to which was added heptane to effect trituration of the undesired regioisomer. Filtration of this isomer and evaporation of the ethyl acetate provided the desired product along with 15-20percent of the undesired isomer. These isomers could also be separated using silica flash chromatography (Combiflash.(R). system) with a suitable EtOAC/heptane gradient. (5 g, 37 percent). MS (ESI) m/z 172 (M-I), 174. RT (LCMS, 254nm) 2.2 min
32%
Stage #1: for 0.0833333 h; Cooling with ice Stage #2: at 0 - 55℃; for 1.16667 h;
To a 100 ml round-bottomed flask containing 2-amino-4-chloropyridine (0.480g, 3.75 mmol) cooled in an ice bath was added concentrated sulphuric acid (5.4 g). Thereaction mixture was stirred for 5 min and then nitric acid (70percent; 0.36 g) was addeddropwise. The reaction mixture was stirred at 0 °C for 10 min, then heated to 55 °C andstirred at this temperature for 1 h. It was cooled to room temperature and diluted with ice-1 0 water. The pH was carefully adjusted to ~ 7.5 with 10percent aqueous NaOH whereupon ayellow precipitate formed. This was filtered off, washed with water and dried in vacuoover P205. The product was purified by silica column chromatography (elution withdichloromethane) to provide in order of elution: 4-Chloro-3-nitropyridin-2-amine as ayellow solid (0.21 0 g, 32percent), 1 H-NMR (500 MHz, DMSO-d6) 6.87 (d, J = 5.2 Hz, 1 H,15 pyridine C-H), 7.21 (s, 2H, NH2), 8.11 (d, J = 5.2 Hz, 1 H, pyridine C-H). [00118] 4-chloro-5-nitropyridin-2-amine (0.080 g, 12percent): 1H-NMR (500 MHz, DMSO-d6)6.58 (s, 1 H, pyridine C-H) 7.58 (s, 2H, NH2), 8.79 (s, 1 H, pyridine C-H).
Reference：
[1] Tetrahedron Letters, 2012, vol. 53, # 42, p. 5597 - 5601
[2] Patent: WO2007/40438, 2007, A2, . Location in patent: Page/Page column 59
[3] Journal of Medicinal Chemistry, 2012, vol. 55, # 20, p. 8721 - 8734,14
[4] Journal of Medicinal Chemistry, 2012, vol. 55, # 20, p. 8721 - 8734
[5] Patent: WO2013/190320, 2013, A1, . Location in patent: Paragraph 00117; 00118
[6] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 8, p. 2512 - 2515
The compounds were prepared as described in the literature with major modifications. To a solution of 4-chloropyridin-2-amine 9 (2.60 g, 0.02 mol) in sulfuric acid (96percent, 40 mL) was slowly added fuming nitric acid (20 mL) under intensively stirring at 0 C over a period of 6 h. The reaction mixture was allowed to stay at 0-5 C for 3 days and then poured into ice water (120 g).The mixture was adjusted to pH 3-5 with ammonium hydroxide (25percent, 160 mL) and the yellow precipitate filtered, washed with cooled water, and dried at room temperature to give 4-chloro-2-nitraminopyridine intermediate (3.46 g, 99percent) as yellow crystals; mp 204-205 C. The crude nitramine (2.73 g, 0.016 mol) was carefully dissolved in small portions into cooled sulfuric acid (96percent,54 mL) under constant stirring. The solution was allowed to warm to room temperature and stirred for further 3 h. After that, the reaction mixture was poured into ice water (60 g) and adjusted topH 6-7 with ammonium hydroxide (25percent, 150 mL) until a yellow crystalline precipitate was formed. The cooled product (mixture of 3- and 5-nitro isomers) was filtered under normal pressure, dried at room temperature over night, and washed several times with ethyl acetate (170 mL) until the color of the crystalline precipitate had turned to a slight yellow. The residue left after filtration was dissolved in ethanol (100 mL), boiled for 15 min, filtered to removethe insoluble precipitate, and recrystallized from dichloromethane/petroleum ether (50percent, 50 mL) to give the pure product 11 (Fraction 1). The combined ethyl acetate layers were evaporated to dryness and purified by repeated column chromatography on silica gel using 50percent dichloromethane/ethyl acetate as eluent. Chromatographically purified products were additionally recrystallized from dichloromethane/petroleum ether (50percent, each 50 mL), evaporated, and dried at 70 C to give pure product 10 (Fractions 2and 4) and 11 (Fraction 3, for details, see Supplementary data,Fig. S2).4.2.1. 4-Chloro-3-nitropyridin-2-amine (10). Slight yellow needles (1.47 g, 42percent over two steps); mp 176-177 C; Rf (50percent CH2Cl2/EtOAc) 0.69; 1H NMR (500 MHz, DMSO-d6) dH: 6.85 (1H, d,J5.36 Hz, H-5), 7.21 (2H, br s, NH2), 8.11 (1H, d, J5.36 Hz, H-6); 13CNMR (125 MHz, DMSO-d6) dC: 113.2 (C5), 129.5 (C3), 136.0 (C4),152.1 (C6), 152.8 (C2); LC/ESI-MS calcd for C5H4ClN3O2 m/z 173.0,found 171.9 [MH]e, 174.9 [MH].4.2.2. 4-Chloro-5-nitropyridin-2-amine (11).22b Yellow crystals(1.05 g, 30percent over two steps); mp 260-261 C; Rf (50percent CH2Cl2/EtOAc)0.48; 1H NMR (500 MHz, DMSO-d6) dH: 6.58 (1H, s, H-3), 7.59 (2H,br s, NH2), 8.79 (1H, s, H-6); 13C NMR (125 MHz, DMSO-d6) dC: 108.4(C3), 133.5 (C5), 137.1 (C4), 149.7 (C6), 162.7 (C2); LC/ESI-MS calcd for C5H4ClN3O2 m/z 173.0, found 171.9 [MH]
Reference：
[1] Australian Journal of Chemistry, 1982, vol. 35, # 10, p. 2025 - 2034
[2] Australian Journal of Chemistry, 1982, vol. 35, # 10, p. 2035 - 2040
[3] Tetrahedron, 2016, vol. 72, # 41, p. 6455 - 6466
7
[ 13091-23-1 ]
[ 1681-37-4 ]
[ 6980-08-1 ]
[ 40497-64-1 ]
[ 24484-96-6 ]
Reference：
[1] Liebigs Annalen der Chemie, 1991, # 9, p. 875 - 878
8
[ 19798-80-2 ]
[ 6980-08-1 ]
[ 24484-96-6 ]
Yield
Reaction Conditions
Operation in experiment
37%
Stage #1: at -8 - 20℃; for 0.333333 h; Salt-ice bath Stage #2: With ammonia In water at 0 - 25℃;
Example 13(a) 4-Chloro-3-nitropyridin-2-amine(Aust. J. Chem. 1982, 35, 2025.)4-Chloro-2-aminopyridine (10 g, 77.5 mmol) was dissolved in concentrated sulfuric acid (10OmL) and using a salt-ice bath, was cooled to ca. -8 0C. Fuming nitric acid was slowly added whilst stirring and at such a rate that a temperature < 0 °C was maintained. The reaction mixture was then stirred for 20 minutes at ambient temperature and carefully poured onto ice. Ammonium hydroxide (32percent) was carefully added. Ice was used to maintain temperature < 25 0C until the solution reached pH 3. The solid product was filtered, washed with water and re-crystallised from 1:1 wateπEtOH. The solid was added in small portions to ice-cold concentrated sulfuric acid (200 mL) at a rate allowing a temperature of <4 °C to be maintained. Once addition was complete, the reaction mixture was allowed to reach ambient temperature. After 2.5 h at room temperature, 2 regioisomers (1:1), the 3 and 5-nitro compounds were observed (LCMS). The reaction mixture was poured onto ice and basifed with ammonium hydroxide (32percent). Filtration and subsequent washing with water provided the mixture of the 2 regioisomers. The products were dissolved in ethyl acetate to which was added heptane to effect trituration of the undesired regioisomer. Filtration of this isomer and evaporation of the ethyl acetate provided the desired product along with 15-20percent of the undesired isomer. These isomers could also be separated using silica flash chromatography (Combiflash.(R). system) with a suitable EtOAC/heptane gradient. (5 g, 37 percent). MS (ESI) m/z 172 (M-I), 174. RT (LCMS, 254nm) 2.2 min
32%
Stage #1: for 0.0833333 h; Cooling with ice Stage #2: at 0 - 55℃; for 1.16667 h;
To a 100 ml round-bottomed flask containing 2-amino-4-chloropyridine (0.480g, 3.75 mmol) cooled in an ice bath was added concentrated sulphuric acid (5.4 g). Thereaction mixture was stirred for 5 min and then nitric acid (70percent; 0.36 g) was addeddropwise. The reaction mixture was stirred at 0 °C for 10 min, then heated to 55 °C andstirred at this temperature for 1 h. It was cooled to room temperature and diluted with ice-1 0 water. The pH was carefully adjusted to ~ 7.5 with 10percent aqueous NaOH whereupon ayellow precipitate formed. This was filtered off, washed with water and dried in vacuoover P205. The product was purified by silica column chromatography (elution withdichloromethane) to provide in order of elution: 4-Chloro-3-nitropyridin-2-amine as ayellow solid (0.21 0 g, 32percent), 1 H-NMR (500 MHz, DMSO-d6) 6.87 (d, J = 5.2 Hz, 1 H,15 pyridine C-H), 7.21 (s, 2H, NH2), 8.11 (d, J = 5.2 Hz, 1 H, pyridine C-H). [00118] 4-chloro-5-nitropyridin-2-amine (0.080 g, 12percent): 1H-NMR (500 MHz, DMSO-d6)6.58 (s, 1 H, pyridine C-H) 7.58 (s, 2H, NH2), 8.79 (s, 1 H, pyridine C-H).
Reference：
[1] Tetrahedron Letters, 2012, vol. 53, # 42, p. 5597 - 5601
[2] Patent: WO2007/40438, 2007, A2, . Location in patent: Page/Page column 59
[3] Journal of Medicinal Chemistry, 2012, vol. 55, # 20, p. 8721 - 8734,14
[4] Journal of Medicinal Chemistry, 2012, vol. 55, # 20, p. 8721 - 8734
[5] Patent: WO2013/190320, 2013, A1, . Location in patent: Paragraph 00117; 00118
[6] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 8, p. 2512 - 2515
9
[ 24484-97-7 ]
[ 6980-08-1 ]
[ 24484-96-6 ]
Yield
Reaction Conditions
Operation in experiment
1.47 g
at 0 - 20℃; for 3 h;
The compounds were prepared as described in the literature with major modifications. To a solution of 4-chloropyridin-2-amine 9 (2.60 g, 0.02 mol) in sulfuric acid (96percent, 40 mL) was slowly added fuming nitric acid (20 mL) under intensively stirring at 0 C over a period of 6 h. The reaction mixture was allowed to stay at 0-5 C for 3 days and then poured into ice water (120 g).The mixture was adjusted to pH 3-5 with ammonium hydroxide (25percent, 160 mL) and the yellow precipitate filtered, washed with cooled water, and dried at room temperature to give 4-chloro-2-nitraminopyridine intermediate (3.46 g, 99percent) as yellow crystals; mp 204-205 C. The crude nitramine (2.73 g, 0.016 mol) was carefully dissolved in small portions into cooled sulfuric acid (96percent,54 mL) under constant stirring. The solution was allowed to warm to room temperature and stirred for further 3 h. After that, the reaction mixture was poured into ice water (60 g) and adjusted topH 6-7 with ammonium hydroxide (25percent, 150 mL) until a yellow crystalline precipitate was formed. The cooled product (mixture of 3- and 5-nitro isomers) was filtered under normal pressure, dried at room temperature over night, and washed several times with ethyl acetate (170 mL) until the color of the crystalline precipitate had turned to a slight yellow. The residue left after filtration was dissolved in ethanol (100 mL), boiled for 15 min, filtered to removethe insoluble precipitate, and recrystallized from dichloromethane/petroleum ether (50percent, 50 mL) to give the pure product 11 (Fraction 1). The combined ethyl acetate layers were evaporated to dryness and purified by repeated column chromatography on silica gel using 50percent dichloromethane/ethyl acetate as eluent. Chromatographically purified products were additionally recrystallized from dichloromethane/petroleum ether (50percent, each 50 mL), evaporated, and dried at 70 C to give pure product 10 (Fractions 2and 4) and 11 (Fraction 3, for details, see Supplementary data,Fig. S2).4.2.1. 4-Chloro-3-nitropyridin-2-amine (10). Slight yellow needles (1.47 g, 42percent over two steps); mp 176-177 C; Rf (50percent CH2Cl2/EtOAc) 0.69; 1H NMR (500 MHz, DMSO-d6) dH: 6.85 (1H, d,J5.36 Hz, H-5), 7.21 (2H, br s, NH2), 8.11 (1H, d, J5.36 Hz, H-6); 13CNMR (125 MHz, DMSO-d6) dC: 113.2 (C5), 129.5 (C3), 136.0 (C4),152.1 (C6), 152.8 (C2); LC/ESI-MS calcd for C5H4ClN3O2 m/z 173.0,found 171.9 [MH]e, 174.9 [MH].4.2.2. 4-Chloro-5-nitropyridin-2-amine (11).22b Yellow crystals(1.05 g, 30percent over two steps); mp 260-261 C; Rf (50percent CH2Cl2/EtOAc)0.48; 1H NMR (500 MHz, DMSO-d6) dH: 6.58 (1H, s, H-3), 7.59 (2H,br s, NH2), 8.79 (1H, s, H-6); 13C NMR (125 MHz, DMSO-d6) dC: 108.4(C3), 133.5 (C5), 137.1 (C4), 149.7 (C6), 162.7 (C2); LC/ESI-MS calcd for C5H4ClN3O2 m/z 173.0, found 171.9 [MH]
Reference：
[1] Australian Journal of Chemistry, 1982, vol. 35, # 10, p. 2025 - 2034
[2] Australian Journal of Chemistry, 1982, vol. 35, # 10, p. 2035 - 2040
[3] Tetrahedron, 2016, vol. 72, # 41, p. 6455 - 6466
10
[ 13091-23-1 ]
[ 1681-37-4 ]
[ 6980-08-1 ]
[ 40497-64-1 ]
[ 24484-96-6 ]
Reference：
[1] Liebigs Annalen der Chemie, 1991, # 9, p. 875 - 878
11
[ 6980-08-1 ]
[ 24484-98-8 ]
Yield
Reaction Conditions
Operation in experiment
97%
With iron; ammonium chloride In propan-1-ol; water at 70℃; for 2 h;
4-Chloropyridine-2,3-diamine In a 100-mL round bottom flask, 4-chloro-3-nitropyridin-2-amine (2 g, 11.52 mmol, 1.00 equiv) was dissolved in propanol (20 mL) and water (10 mL), to which was added Fe powder (3.23 g, 57.84 mmol, 5.02 equiv) and NH4Cl (3.06 g, 57.21 mmol, 4.96 equiv) in sequence at room temperature. The resulting mixture was stirred for 2 h at 70° C. After the reaction was done, the reaction mixture was cooled to room temperature and filtered through a Celite pad. The filtrate was concentrated under reduced pressure to afford 4-chloropyridine-2,3-diamine (1.6 g, 97percent) as black solid.
96%
With iron; ammonium chloride In water; isopropyl alcohol at 70℃; for 2 h;
a) 4-Chloropyridine-2,3-diamine (A 15) Iron powder (1.126 g, 20.17 mmol) followed by NH4CI (1.079 g, 20.17 mmol) were added to a stirred suspension of 2-amino-4-chloro-3-nitropyridine A14 (0.700 g, 4.03 mmol) in /-PrOH (30 ml_) and water (15 ml_) at room temperature. The reaction was heated to 70 °C and stirred at this temperature for 2 hours. The reaction was cooled and filtered through a plug of celite which was washed with EtOAc (150 ml_). The filtrate was washed with saturated aqueous NaHC03 (100 ml_), brine (100 ml_), dried (Na2S04), filtered and concentrated in vacuo to give the title compound (0.555 g, 96percent) as a brown solid. LCMS-A rt 1.34 min, m/z (positive ion) 144.1 , 146.2 [M+H]+.
Reference：
[1] Patent: US2016/96834, 2016, A1, . Location in patent: Paragraph 0322
[2] Patent: WO2014/128465, 2014, A1, . Location in patent: Page/Page column 54; 55
[3] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 23, p. 6567 - 6571
[4] Patent: US5298518, 1994, A,
[5] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 15, p. 4344 - 4353
[6] Patent: WO2008/144253, 2008, A1, . Location in patent: Page/Page column 60-61
12
[ 6980-08-1 ]
[ 1086423-62-2 ]
Reference：
[1] Patent: WO2008/144253, 2008, A1,
13
[ 6980-08-1 ]
[ 942947-95-7 ]
Yield
Reaction Conditions
Operation in experiment
99%
With N-Bromosuccinimide In acetonitrile at 80℃;
A solution of 4-chloro-3-nitropyridin-2-amine (2 g, 11.5 mmol) and N-bromosuccinimide (2.5 g, 13.8 mmol) in ACN (125 mL) was heated at 80 °C. After 1h, the reaction mixture was cooled was cooled to room temperature and volatiles were removed under reduced pressure. Purification (FCC, SiO2, 0-5percent EtOAc in DCM), afforded the title compound (2.9 g, 99percent). MS (ESI): mass calcd. for C5H3BrClN3O2, 250.9; m/z found, 251.8 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H), 7.37 (br s, 2H).
85%
With N-Bromosuccinimide In acetonitrile at 80℃; for 1 h;
4-Chloro-3-nitropyridin-2-amine (0.1 0 g, 0.58 mmol) was dissolved in dryacetonitrile (20 ml). To the stirred solution was then added N-bromosuccinimide (0.124g, 0.70 mmol), and the reaction mixture was heated at 80 °C for 1 h. Volatiles wereremoved in vacuo and the residue purified by silica column chromatography (elution with25 dichloromethane) to provide the title compound as a pale brown powder (0.125 g, 85percent).1 H-NMR (500 MHz, DMSO-d6) 7.35 (s, 2H, NH2), 8.41 (s, 1 H, 6-H).
Reference：
[1] Patent: WO2018/67786, 2018, A1, . Location in patent: Page/Page column 111
[2] Journal of Medicinal Chemistry, 2012, vol. 55, # 20, p. 8721 - 8734,14
[3] Journal of Medicinal Chemistry, 2012, vol. 55, # 20, p. 8721 - 8734
[4] Patent: WO2013/190320, 2013, A1, . Location in patent: Paragraph 00119
The compounds were prepared as described in the literature with major modifications. To a solution of 4-chloropyridin-2-amine 9 (2.60 g, 0.02 mol) in sulfuric acid (96percent, 40 mL) was slowly added fuming nitric acid (20 mL) under intensively stirring at 0 C over a period of 6 h. The reaction mixture was allowed to stay at 0-5 C for 3 days and then poured into ice water (120 g).The mixture was adjusted to pH 3-5 with ammonium hydroxide (25percent, 160 mL) and the yellow precipitate filtered, washed with cooled water, and dried at room temperature to give 4-chloro-2-nitraminopyridine intermediate (3.46 g, 99percent) as yellow crystals; mp 204-205 C. The crude nitramine (2.73 g, 0.016 mol) was carefully dissolved in small portions into cooled sulfuric acid (96percent,54 mL) under constant stirring. The solution was allowed to warm to room temperature and stirred for further 3 h. After that, the reaction mixture was poured into ice water (60 g) and adjusted topH 6-7 with ammonium hydroxide (25percent, 150 mL) until a yellow crystalline precipitate was formed. The cooled product (mixture of 3- and 5-nitro isomers) was filtered under normal pressure, dried at room temperature over night, and washed several times with ethyl acetate (170 mL) until the color of the crystalline precipitate had turned to a slight yellow. The residue left after filtration was dissolved in ethanol (100 mL), boiled for 15 min, filtered to removethe insoluble precipitate, and recrystallized from dichloromethane/petroleum ether (50percent, 50 mL) to give the pure product 11 (Fraction 1). The combined ethyl acetate layers were evaporated to dryness and purified by repeated column chromatography on silica gel using 50percent dichloromethane/ethyl acetate as eluent. Chromatographically purified products were additionally recrystallized from dichloromethane/petroleum ether (50percent, each 50 mL), evaporated, and dried at 70 C to give pure product 10 (Fractions 2and 4) and 11 (Fraction 3, for details, see Supplementary data,Fig. S2).4.2.1. 4-Chloro-3-nitropyridin-2-amine (10). Slight yellow needles (1.47 g, 42percent over two steps); mp 176-177 C; Rf (50percent CH2Cl2/EtOAc) 0.69; 1H NMR (500 MHz, DMSO-d6) dH: 6.85 (1H, d,J5.36 Hz, H-5), 7.21 (2H, br s, NH2), 8.11 (1H, d, J5.36 Hz, H-6); 13CNMR (125 MHz, DMSO-d6) dC: 113.2 (C5), 129.5 (C3), 136.0 (C4),152.1 (C6), 152.8 (C2); LC/ESI-MS calcd for C5H4ClN3O2 m/z 173.0,found 171.9 [MH]e, 174.9 [MH].4.2.2. 4-Chloro-5-nitropyridin-2-amine (11).22b Yellow crystals(1.05 g, 30percent over two steps); mp 260-261 C; Rf (50percent CH2Cl2/EtOAc)0.48; 1H NMR (500 MHz, DMSO-d6) dH: 6.58 (1H, s, H-3), 7.59 (2H,br s, NH2), 8.79 (1H, s, H-6); 13C NMR (125 MHz, DMSO-d6) dC: 108.4(C3), 133.5 (C5), 137.1 (C4), 149.7 (C6), 162.7 (C2); LC/ESI-MS calcd for C5H4ClN3O2 m/z 173.0, found 171.9 [MH]
bis-triphenylphosphine-palladium(II) chloride; In N,N-dimethyl-formamide; at 100℃; for 4h;
(1-1) Synthesis of 2-amino-3-nitro-4-(2-thienyl)pyridine To a solution of <strong>[6980-08-1]2-amino-3-nitro-4-chloropyridine</strong> (1.74 g, 10 mmol; which had been synthesised as described in) and dichlorobis(triphenylphosphine)palladium(II) (350 mg, 0.50 mmol) in DMF (50 ml), 2-(tributylstanyl)thiophene (3.82 ml, 12 mmol) was added under a nitrogen atmosphere and stirred at 100C for 4 hours. The solution was then poured into water (250 ml) and extracted three times with ethyl acetate (250 ml). The organic layers were dried over sodium sulfate and evaporated under reduced pressure to remove the solvent. The resulting residue was eluted by silica gel column chromatography with methylene chloride:ethyl acetate (100:0 to 49:1) to give 2-amlino-3-nitro-4-(2-thienyl)pyridine,(Rf 0.30/methylene chloride:ethyl acetate = 19:1) (2.07 g, yield 93%). 1H NMR (CDCl3); delta 8.17 (d, J = 5.1 Hz, 1H), 7.45 (dd, J = 5.0 and 1.1 Hz, 1H), 7.12 (dd, J = 3.6 and 1.1 Hz, 1H), 7.07 (dd, J = 5.0 and 3.6 Hz, 1H), 6.77 (d, J = 5.1 Hz, 1H), 5.66 (bs, 2H).
Synthesis 1; 4-(3-aminophenoxy)-3-nitropyridin-2-amine; Method A. 3-Hydroxyaniline (2.07 g, 19.0 mmol) was dissolved in dry DMF (65 mL) and the solution was degassed by argon bubbling for 10 minutes. Potassium ferf-butoxide (2.13 g, 19.0 mmol) was added and the stirring was continued for 1 hour at room temperature. 4-Chloro-3-nitropyridin-2-amine (3.0 g, 17.3 mmol) was added as a solid in one portion and the reaction mixture was subsequently heated at 800C for 20 hours. The solvent was evaporated in vacuo and the brown oily residue was taken up in 1 M HCI (aq) (50 mL). This layer was washed with EtOAc (3 x 50 mL) and subsequently basified to pH ~ 10 with 1M NaOH (aq). The brown precipitate was collected, washed with H2O (3 x 25 mL) and dried in vacuo, to afford 4-(3-aminophenoxy)-3-nitropyridin-2-amine (3.50 g, 80%). 1H-NMR (delta, ppm, DMSO-d6): 5.39 (s, 2H1 NH2), 6.02 (d, 1H, HPy,5, J = 5.7 Hz), 6.23 - 6.30 (m, 2H, Harom,Ph.), 6.47 (d, 1H, Haram,Ph', J=8.0 Hz), 7.04 - 7.24 (m, 3H, NH2 + Harom,PhO, 7.48 (m, 2H, Harom), 7.98 (d, 1 H, HPy,5); LC-MS (m/z): 247 (M + H, 100).
The compound 4-chloro-2-aminopyridine (6.4 g, 50 mmol) was slowly added to fuming nitric acid (50 mL) under ice-cooling. The reaction system was gradually warmed to room temperature and poured into water containing crushed ice. The residue was filtered and separated by flash column chromatography (dichloromethane: methanol = 100: 1) to give the title compound as a white solid. L: 4-chloro-3-nitro Yl-2-aminopyridine (7.4 g, yield 85%).
70%
With sulfuric acid; nitric acid; at 0 - 70℃; for 21h;
4-chloropyridin-2-amine (100 g, 0.77 mol) dissolved in 1.0 L H2SO4 and cooled to 0 degree and H2SO4(30mL) and HNO3(58.2g) was added dropwise a mixed solution slowly for 15 minutes. Raise the reaction solution to room temperature and stir for 20 hours. The temperature was increased to 50 ~ 70 and then was stirred for one hour. When the reaction was completed, the reaction mixture cooled to room temperature, ice-water and 10% NaOH was slowly added dropwise to adjust the pH to 7.5 and filtered to result in yellow solid product. the resultant yellow solid product was purified by silica gel column chromatography to give the desired compound 4-chloro-3-nitropyridin-2-amine (80g, yield:70%)
36%
To a solution of 2-amino-4-chloropyridine (5.00 g, 0.0389 mol) in sulfuric acid (40.8 mL) with stirring at 0 C. was added a solution of nitric acid (2.72 g, 0.0389 mol) and sulfuric acid (3.89 g, 0.0389 mol). The mixture was stirred (1 hr) then poured into 200 g ice and 100 ml water. The solid was filtered and collected. The solution was neutralized with 28% NH3 in water to pH 5. The solution was extracted with EtOAc (3×300 ml). The solid also was dissolved in EtOAc and neutralized with 28% NH3 in H2O. The organic layers were combined, concentrated with 30 g silica gel, and purified by flash chromatography (20 to 60% EtOAc/hexanes) to afford the title compound (2.40 g, 36%) as a yellow solid.
35%
With sulfuric acid; nitric acid; at 0℃; for 16h;
4-chloro-3-nitropyridin-2-amine A nitrating mixture (HNO3:H2SO4, 5 mL) was added to 4-chloropyridin-2-amine (2.56 g, 20 mmol) at 0 C. and stirred for 16 h. After completion of the reaction, the mixture was diluted with water and ethyl acetate, extracted with ethyl acetate, washed with water, brine, dried over anhydrous Na2SO4, and then concentrated under reduced pressure. The resulting crude product was purified by flash chromatography to afford 4-chloro-3-nitropyridin-2-amine as a yellow solid (1.211 g, 35% yield). HPLC: 97.2% purity. MS: 74.0 [M+H]+. 1H NMR: 400 MHz, DMSO-d6: delta 8.11 (d, J=5.24 Hz, 1H), 7.23 (s, 2H), 6.85 (d, -=5.24 Hz, 1H).
33%
With sulfuric acid; nitric acid; at 0 - 20℃; for 1h;
To a stirred solution of 2-amino-4-chloropyridine (5.00 g, 0.0389 mol) in concentrated sulfuric acid (40.8 mL) was added dropwise concentrated nitric acid (5.00 g, 0.0389 mol) and concentrated sulfuric acid (3.89 g) at 0C. 0.0389 mol). After addition, the mixture was allowed to warm to room temperature and stirred for 1 h. The reaction was then poured into a mixture of 200 g of ice and 100 mL of water. A large amount of a yellow solid precipitated and the solids were collected by filtration. The filtrate was neutralized with 28% ammonia to a pH of 9, and extracted three times with ethyl acetate and the organic phase was collected. The solid obtained by filtration was also dissolved in ethyl acetate, and the pH was adjusted to 9 with aqueous ammonia. The separated organic phase was combined with the foregoing organic phase, dried over anhydrous sodium sulfate, concentrated, and the residue was subjected to column chromatography to give the title compound (2.233 g, Yield 33%) is a yellow solid.
32%
[00116] To a 100 ml. round-bottomed flask containing 2-amino-4-chloropyridine (0.480 g, 3.75 mmol) cooled in an ice bath was added concentrated sulphuric acid (5.4 g). The reaction mixture was stirred for 5 min and then nitric acid (70%; 0.36 g) was added dropwise. The reaction mixture was stirred at 0 C for 10 min, then heated to 55 C and stirred at this temperature for 1 h. It was cooled to room temperature and diluted with ice- water. The pH was carefully adjusted to ~ 7.5 with 10% aqueous NaOH whereupon a yellow precipitate formed. This was filtered off, washed with water and dried in vacuo over P205. The product was purified by silica column chromatography (elution with dichloromethane) to provide in order of elution: 4-Chloro-3-nitropyridin-2-amine as a yellow solid (0.210 g, 32%), 1 H-NMR (500 MHz, DMSO-d6) 6.87 (d, J = 5.2 Hz, 1 H, pyridine C-H), 7.21 (s, 2H, NH2), 8.1 1 (d, J = 5.2 Hz, 1 H, pyridine C-H).
With sulfuric acid; nitric acid; at 0 - 5℃; for 48h;
Example 4 4-(2-Amino-3-nitro-pyridin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (5). Following the procedure of Recl. Trav. Chim. Pays-Bas 88(11): 1263 (1969), 4-Chloro-pyridin-2-ylamine (A) (6.8 g, 67 mmol) was carefully dissolved in H2SO4 (45.2 ml) at 0 C. Nitric acid (2.3 ml) was added, maintaining the temperature at 0 C. The solution was stirred at 5 C. for 2 days. After it was judged complete by TLC (40% ethyl acetate/hexane), the mixture was carefully made basic with the addition of solid Na2CO3. The mixture was then extracted with ethyl acetate several times. The ethyl acetate was dried over magnesium sulfate and the solvents were removed under vacuum. The resulting crude was dissolved in DMSO (25 ml) with t-butyl-1-piperazine carboxylate (14.3 g, 75 mmol) and DIEA (10.3 g, 80 mmol). This mixture was heated to 50 C. for 3 hours before it was judged complete by MS. The mixture was purified by HPLC Method E to yield the title product 5 (2.8 g (13%), 8.6 mmol). 1H NMR (DMSO-d6): delta 7.82 (d, J=5.8 Hz, 1H), 6.98 (bs, 2H), 6.31 (d, J=5.8 Hz, 1H), 3.41 (m, 4H), 3.13 (m, 4H), 1.41 (s, 9H). MS (ESI-POS): [M+H]+=324.
Step - III: Preparation of 4 -Chloro- 2-Amino - 3 - Nitropyridine; Dissolved 4-chloro 2-amino pyridine (28 gm) in cone, sulphuric acid (224 ml) under stirring. Added nitrating mixture [8.4ml fuming Nitric acid +17ml cone. H2SO4] slowly to the above solution and stirred for 1 hr at 25 - 300C. The reaction progress was monitored by TLC. After completion of the reaction the reaction solution was quenched on ice (1120 gm) and stirred for 15 minutes. The reaction mixture was extracted with dichloromethane (420 ml). The pH of the reaction mass was adjusted to pH 6 by 30% sodium carbonate solution.The above mass was then extracted with 4 x 420 ml ethyl acetate. The layers were separated and the organic layer neutralized with 200ml saturated sodium bicarbonate solution. The layers were again separated. It was then dried over anhydrous sodium sulphate and distilled under reduced pressure to get crude 4 - chloro - 2 - amino - 3 - nitropyridine.The crude compound was stirred in 210 ml MDC for lhr at RT. and filtered. The insoluble impurity was again washed with 2 x 105 ml MDC. Both the MDC layers were collected and distilled completely to yield a yellow solid. To this solid, 105 ml Methanol was added and heated for 500C forl hr. This mixture was then cooled to 0 to -5c and stirred for half hour at this temperature. The solid precipitated was filtered and dried to yield pure stage III having HPLC purity >; 95%. Dry weight- 8.4 gm.
1.2 g
To a solution of 4- chloro-pyridin-2-ylamine (5 g) in 96% aq H2SO4 (20 mL) at 0 C was added a mixture solution of 70% aq HN03 (2.5 mL) and 96% aq H2S04 (10 mL) drop-wise. After the addition was completed, the mixture was stirred at room temperature for 2h. The solution was poured onto ice/water and 6M aq. NaOH was added drop-wise to adjust pH to 9. Then the solid was filtered off, washed with water, and dried before it was purified by chromatography on alumina (eluent: pentane:EtOAc 2:1) to afford 4-chloro-3-nitro-pyridin-2-ylamine (1.2 g). 200 mg of this material was dissolved methanol (3mL) and NaOMe (125 mg) was added before the mixture was stirred at 60 C for 16h. 37%> aq HC1 was added drop-wise to adjust pH to 6. The mixture was cooled to 0 C, and the precipitated solid was filtered off, washed with water, and dried to afford 4-methoxy-3-nitro-pyridin-2-ylamine (180 mg). This material was dissolved in methanol (20 mL) and treated with hydrogen gas (1 bar) in the presence of 10%> palladium on charcoal at room temperature for 2h. The mixture was filtered and the filtrate was concentrated in vacuo to afford 4-methoxy-pyridine-2,3-diamine (50 mg). This procedure was repeated to produce more material. In the next step, 4-methoxy-pyridine-2,3-diamine (6.8 g) was dissolved in ethanol (200 mL). To this solution was slowly added methyl pyruvate (4.9 mL) at room temperature, and the mixture was stirred at ambient temperature for 3h before the volatiles were removed in vacuo. The residue was purified by chromatography on silica gel (eluent: pentane:EtOAc 5: 1 to 0: 1) to give afford 8-methoxy-2-methyl-4H-pyrido[2,3- b]pyrazin-3-one (6.1 g). To a suspension of 3 g of this material in DMF (12 mL) was added PyBroP (7.65 g) followed by DBU (3.58 g). The mixture was stirred overnight before the precipitated solid was filtered off, washed with ethanol, and dried to afford 3-(benzotriazol-l- yloxy)-8-methoxy-2-methyl-pyrido[2,3-b]pyrazine (3.5 g). 1.5 g of this material was dissolved in a mixture of ethanol (lOmL) and DCM (60mL). Hydrazine monohydrate (3.6g) was added, and the mixture was stirred overnight at ambient temperature before the volatiles were removed in vacuo. The residual solid was triturated from ethanol, filtered off, washed with ethanol, and dried to afford (8-methoxy-2-methyl-pyrido[2,3-b]pyrazin-3-yl)- hydrazine He (0.9 g).
With iron; ammonium chloride; In propan-1-ol; water; at 70℃; for 2.0h;
4-Chloropyridine-2,3-diamine In a 100-mL round bottom flask, 4-chloro-3-nitropyridin-2-amine (2 g, 11.52 mmol, 1.00 equiv) was dissolved in propanol (20 mL) and water (10 mL), to which was added Fe powder (3.23 g, 57.84 mmol, 5.02 equiv) and NH4Cl (3.06 g, 57.21 mmol, 4.96 equiv) in sequence at room temperature. The resulting mixture was stirred for 2 h at 70 C. After the reaction was done, the reaction mixture was cooled to room temperature and filtered through a Celite pad. The filtrate was concentrated under reduced pressure to afford 4-chloropyridine-2,3-diamine (1.6 g, 97%) as black solid.
96%
With iron; ammonium chloride; In water; isopropyl alcohol; at 70℃; for 2.0h;
a) 4-Chloropyridine-2,3-diamine (A 15) Iron powder (1.126 g, 20.17 mmol) followed by NH4CI (1.079 g, 20.17 mmol) were added to a stirred suspension of 2-amino-4-chloro-3-nitropyridine A14 (0.700 g, 4.03 mmol) in /-PrOH (30 ml_) and water (15 ml_) at room temperature. The reaction was heated to 70 C and stirred at this temperature for 2 hours. The reaction was cooled and filtered through a plug of celite which was washed with EtOAc (150 ml_). The filtrate was washed with saturated aqueous NaHC03 (100 ml_), brine (100 ml_), dried (Na2S04), filtered and concentrated in vacuo to give the title compound (0.555 g, 96%) as a brown solid. LCMS-A rt 1.34 min, m/z (positive ion) 144.1 , 146.2 [M+H]+.
With hydrogenchloride; iron; In methanol;
(1) 4-Chloro-2,3-diaminopyridine STR116 3.6 g of 2-amino-4-chloro-3-nitropyridine was added to 21 ml of methanol and 24 ml of concentrated hydrochloric acid, and the mixture was vigorously stirred. Powdery iron was added in small portions to the mixture. 10 min after the completion of the addition, the mixture was poured into an iced concentrated aqueous ammonia and extracted with ethyl acetate. The extract was dried over magnesium sulfate, and the solvent was distilled off in vacuo. The residue was purified by silica gel chromatography (CH2 Cl2:MeOH=20:1?10:1) to prepare 2.6 g of 4-chloro-2,3-diaminopyridine as a purplish white crystal. NMR(90 MHz, CDCl3, delta value): 7.20(d,1H,J=5 Hz),6.48(d,1H,J=5 Hz),5.74 (bs,2H),4.87(bs,2H).
With hydrogenchloride; tin(ll) chloride; In ethanol; water; at 75℃;
Intermediate 7 (2.31 g, 13.31 mmol) is suspended in EtOH (20.OmL), to which is added a solution of SnCl2 (6.31 g, 33.27 mmol) in HCl (con. 6.0 mL), and the reaction mixture is heated at 75C for half h. The solution is diluted with ethyl acetate (250 mL), washed with K2CO3 solution and brine, dried and evaporated to give crude 4-chloropyridine-2,3-diamine (8), which is <n="62"/>P A T E N TGNF Docket No.: P1267PC10 used without purification. 1H NMR 400 MHz (CDCl3) delta 7.26 (d, J= 5.4 Hz, IH), 6.55 (d, J= 5.4 Hz, IH), 5.86 (s, 2H), 4.97 (s, 2H); MS m/z 144.00 (M + 1).
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 50℃; for 3h;
Example 4 4-(2-Amino-3-nitro-pyridin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (5). Following the procedure of Recl. Trav. Chim. Pays-Bas 88(11): 1263 (1969), 4-Chloro-pyridin-2-ylamine (A) (6.8 g, 67 mmol) was carefully dissolved in H2SO4 (45.2 ml) at 0 C. Nitric acid (2.3 ml) was added, maintaining the temperature at 0 C. The solution was stirred at 5 C. for 2 days. After it was judged complete by TLC (40% ethyl acetate/hexane), the mixture was carefully made basic with the addition of solid Na2CO3. The mixture was then extracted with ethyl acetate several times. The ethyl acetate was dried over magnesium sulfate and the solvents were removed under vacuum. The resulting crude was dissolved in DMSO (25 ml) with t-butyl-1-piperazine carboxylate (14.3 g, 75 mmol) and DIEA (10.3 g, 80 mmol). This mixture was heated to 50 C. for 3 hours before it was judged complete by MS. The mixture was purified by HPLC Method E to yield the title product 5 (2.8 g (13%), 8.6 mmol). 1H NMR (DMSO-d6): delta 7.82 (d, J=5.8 Hz, 1H), 6.98 (bs, 2H), 6.31 (d, J=5.8 Hz, 1H), 3.41 (m, 4H), 3.13 (m, 4H), 1.41 (s, 9H). MS (ESI-POS): [M+H]+=324.
With sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 2h;
Synthesis 156; 4-Chloro-N-methyl-3-nitropyridin-2-amine; 2-Amino-4-chloro-3-nitropyridine (590 mg, 4 mmol) was dissolved in dry THF (15 mL), the solution was cooled to 00C and NaH (240 mg, 6 mmol) was added. The reaction mixture was stirred for 2 hours, and allowed to warm at room temperature. The solvent was evaporated and the residue extracted between AcOEt and water. The organic layer was dried (MgSO4) and evaporated. The crude mixture was purified by column chromatography (eluent DCM) to afford the title compound (190 mg, 25%). 1H-NMR (delta, ppm, DMSO-d6): 2.88 (d, 3H, Me, J=4.55 Hz), 6.86 (d, 1H, HPy,5, J=5.31 Hz), 7.44 (broad s, 1H, NH), 8.21 (d, 1 H, HPy,6, J=5.30 Hz).
(I) Coupling of <strong>[6980-08-1]2-amino-3-nitro-4-chloropyridine</strong> with phenolates; Synthesis 1; 4-(4-Aminophenoxy)-3-nitropyridin-2-amine (2); Method A. 4-Hydroxyaniline (0.7 g, 6.5 mmol) was dissolved in dry DMF (10 mL) and the solution was degassed with bubbling argon for 10 minutes. Potassium terf-butoxide (0.73 g, 6.5 mmol) was added, and the stirring and argon bubbling continued for 1 hour. 4- Chloro-3-nitropyridin-2-amine (1.0 g, 5.8 mmol) was dissolved in 5 mL dry DMF and added to the reaction mixture. The reaction mixture was heated and stirred at 7O0C for 20 hours, under argon. The solvent was evaporated and the residue was extracted between DCM and aqueous Na2CO3 containing 5% KOH. The extraction was repeated twice, the organic layer was dried over MgSO4, and evaporated to afford the title compound (1.4 g, 98%). 1H-NMR (delta, ppm, DMSO-d6): 5.18 (s, 2H, NH2,Ph), 5.90 (d, 1 H, HPy,5, J= 5.0Hz), EPO <DP n="119"/>6.65 (d, 2H1 Harom,Ph,3+5, J=10.0 Hz), 6.85 (d, 2H, Harom,Ph,2+6), 7.07 (s, 2H, NH2,Py), 7.95 (d, 1H, Hpy,6); LC-MS (m/z): 247 (M+H, 100).
Example 13(a) 4-Chloro-3-nitropyridin-2-amine(Aust. J. Chem. 1982, 35, 2025.)4-Chloro-2-aminopyridine (10 g, 77.5 mmol) was dissolved in concentrated sulfuric acid (10OmL) and using a salt-ice bath, was cooled to ca. -8 0C. Fuming nitric acid was slowly added whilst stirring and at such a rate that a temperature < 0 C was maintained. The reaction mixture was then stirred for 20 minutes at ambient temperature and carefully poured onto ice. Ammonium hydroxide (32%) was carefully added. Ice was used to maintain temperature < 25 0C until the solution reached pH 3. The solid product was filtered, washed with water and re-crystallised from 1:1 wate?EtOH. The solid was added in small portions to ice-cold concentrated sulfuric acid (200 mL) at a rate allowing a temperature of <4 C to be maintained. Once addition was complete, the reaction mixture was allowed to reach ambient temperature. After 2.5 h at room temperature, 2 regioisomers (1:1), the 3 and 5-nitro compounds were observed (LCMS). The reaction mixture was poured onto ice and basifed with ammonium hydroxide (32%). Filtration and subsequent washing with water provided the mixture of the 2 regioisomers. The products were dissolved in ethyl acetate to which was added heptane to effect trituration of the undesired regioisomer. Filtration of this isomer and evaporation of the ethyl acetate provided the desired product along with 15-20% of the undesired isomer. These isomers could also be separated using silica flash chromatography (Combiflash system) with a suitable EtOAC/heptane gradient. (5 g, 37 %). MS (ESI) m/z 172 (M-I), 174. RT (LCMS, 254nm) 2.2 min
32%; 12%
To a 100 ml round-bottomed flask containing 2-amino-4-chloropyridine (0.480g, 3.75 mmol) cooled in an ice bath was added concentrated sulphuric acid (5.4 g). Thereaction mixture was stirred for 5 min and then nitric acid (70%; 0.36 g) was addeddropwise. The reaction mixture was stirred at 0 C for 10 min, then heated to 55 C andstirred at this temperature for 1 h. It was cooled to room temperature and diluted with ice-1 0 water. The pH was carefully adjusted to ~ 7.5 with 10% aqueous NaOH whereupon ayellow precipitate formed. This was filtered off, washed with water and dried in vacuoover P205. The product was purified by silica column chromatography (elution withdichloromethane) to provide in order of elution: 4-Chloro-3-nitropyridin-2-amine as ayellow solid (0.21 0 g, 32%), 1 H-NMR (500 MHz, DMSO-d6) 6.87 (d, J = 5.2 Hz, 1 H,15 pyridine C-H), 7.21 (s, 2H, NH2), 8.11 (d, J = 5.2 Hz, 1 H, pyridine C-H). [00118] 4-chloro-5-nitropyridin-2-amine (0.080 g, 12%): 1H-NMR (500 MHz, DMSO-d6)6.58 (s, 1 H, pyridine C-H) 7.58 (s, 2H, NH2), 8.79 (s, 1 H, pyridine C-H).
With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 135℃; for 2.0h;Microwave reactor;
Preparation 5 In a microwave reaction vessel 4-chloro-3-nitro-2-pyridinamine (125 mg) and (3R, 4R) -1-benzyl-N, 4-dimethyl-3-piperidinamine (314 mg) were suspended in 2-propanol (6.25 mL) . To the mixture was addedN,N-diisopropylethylamine (0.63 mL) . The vessel was sealed and reacted in the microwave reactor at 135C for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with chloroform and methanol (100:0 to 90:10) to give N4- [ (3R, 4R) -l-benzyl-4-methyl-3- piperidinyl]-N4-methyl-3-nitro-2,4-pyridinediamine (230 mg) as a yellow amorphous . 1H-NMR (DMSO-d6) delta : 0.92 (3H, d, J=6.9Hz) , 1.21-1.66 (2H,m) , 1.96-2.17 (2H,m) ,2.46-2.51 (IH,m) ,2.57-2.71 (IH,m) ,2.83-2.85 (IH,m) ,3.48 (3H,s) ,3.86 (2H,s) ,3.86-3.88 (IH,m) , 6.33 (2H,d, J=6.2Hz) , 6.81 (2H,br) ,7.20-7.36 (5H,m) , 7.67 (2H,d, J=6.2Hz) .MS(ESI) :m/z 356(M+H)+
With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In tetrahydrofuran; water; at 140℃; for 0.166667h;Microwave irradiation;
Example 13 (b) 4-[3-(Morpholin-4-ylcarbonyl)phenyl]-3-nitropyridin-2-amineThe title compound was prepared using general method C except purification of the title compound was achieved using silica flash chromatography (40-80% EtOAc:heptane) from <strong>[6980-08-1]4-chloro-3-nitropyridin-2-amine</strong> (200 mg, 1.17 mmol), PdCl2(drhorhof)*DCM (40 mg) potassium carbonate (800 mg, 5.75 mmol) and 3-(morpholin-4-ylcarbonyl)boronic acid (540 mg, 2.3 mmol) dissolved in THF:water (9:1) (6 mL). (140 mg, 37 %); MS (ESI) m/z 329 (M+l) 327 (M-I), RT (LCMS, 254nm) 2.25 min.
2-(morpholin-2-ylmethyl)isoindoline-1,3-dione[ No CAS ]
[ 1034770-02-9 ]
Yield
Reaction Conditions
Operation in experiment
62%
With triethylamine; In ethanol; at 140℃; for 0.5h;Microwave irradiation;
Synthesis 22-1 -A; 2-((4-(2-Amino-3-nitropyridin-4-yl)morpholin-2-yl)methyl)isoindoline-1 ,3-dione; A solution of 2-(morpholin-2-ylmethyl)isoindoline-1 ,3-dione (20.5 mg, 0.083 mmol), <strong>[6980-08-1]4-chloro-3-nitropyridin-2-amine</strong> (14.5 mg, 0.084 mmol) and triethylamine (25 mul_, 0.25 mmol) in EtOH (0.8 mL) was heated at 1400C in a microwave reactor for 30 minutes. The solids were collected by filtration, washed with EtOH and dried to give the title compound as a bright yellow powder (20 mg, 62%).1H NMR (500 MHz, d6-DMSO) delta 2.82-2.92 (1H, m), 2.96-3.08 (1H, m), 3.08-3.15 (1H, m), 3.30-3.38 (1 H, m), 3.48-3.56 (1 H, m), 3.60-3.67 (1 H, m), 3.70-3.79 (1 H, m), 3.79-3.88(1H, m), 4.00-4.10 (1H, m), 6.32 (1H, d, J = 6.8 Hz), 6.89 (2H, s), 7.80-7.93 (4H+1H, m); LC-MS (2) Rt 2.42 min; m/z (ESI) 384 [MH+].
Synthesis 3 4-(4-amino-3-(methylthio)phenoxy)-3-nitropyridin-2-amineMethod A2 Sodium hydride (148mg) was added to dry DMSO (5.5mL) and the mixture was stirred at RT for 20 minutes under Ar atmosphere. 4-amino-3-(methylthio)phenol (573 mg, 3.7 mmol) was added thereto, and the mixture stirred for 10 more minutes. Next, 4-Chloro-3-nitropyridin-2-amine (3.7 mmol) was added, and the mixture was heated to 100C and stirred for 3 hours. After cooling down, water was added, and the mixture extracted three times with EtOAc. The combined organic layers were washed first with a saturated aqueous sodium hydrogen carbonate solution then water, dried over MgSO4 and evaporated to afford the title compound (657 mg, 61%) was obtained after purification by chromatography on silica gel (EtOAc-DCM, 1 :1) as a red brown solid (Rf 0.56, EtOAc-DCM, 1 :1).1H-NMR (DMSO-d6), delta (ppm), J (Hz): 2.36 (s, 3H, CH3); 5.18 (s, 2H, NH2, Ph), 5.92 (d, 1H, Hpy J=5.8 Hz), 6.75 (dd, 1 H, HPh J= 8.6 Hz and J=2.1 Hz), 6.81 (dd, 1H, HPh J= 8.7 and J=2.6 Hz), 6.98 (d, 1H, HPh J=2.6 Hz), 7.07 (bs, 2H, NH2, Py), 7.95 (d, 1H, HPy J=5.7 Hz). 13C-NMR (DMSO-d6), delta (ppm), J (Hz): 15.6, 99.8, 114.7, 119.7, 120.7, 121.4, 121.5, 143.2, 145.1, 152.8, 153.6, 159.9. LC-MS {m/z): 293 (M+H, 100), rt=5.87min.
Method A1 : Tert-butyl 4-hydroxyphenylcarbamate (3.63 g, 17.4 mmol) was dissolved in dry DMF (150 ml_). Potassium te/f-butoxide (2.62 g, 23.4 mmol) was added and the stirring was continued for 30 minutes at room temperature. 4-Chloro-3-nitropyridin-2- amine (3.0 g, 17.3 mmol) was added as a solid in one portion and the reaction mixture was subsequently heated at 85C for 4 hours. The reaction mixture was cooled, diluted with ethyl acetate (800 ml) and washed with water (1x 800 ml) and brine (2 x 800 ml). The organic layer was dried with magnesium sulphate and evaporated. The crude was chromatographed over silica (eluant ethyl acetate: cyclohexane 1 :2) to yield 4.0 g (63 % yield) of tert-butyl 4-(2-amino-3-nitropyridin-4-yloxy)phenylcarbamate.1H-NMR (CDCI3), delta (ppm), J (Hz): 1H-NMR, delta (ppm), J (Hz): 1.54 (9H), 6.04 (d, 1 H, J=7.4 Hz), 6.15 (bs, 2H), 7.06 (d, 2H, J=8.3 Hz)1 7.44 (d, 2H, J=8.3 Hz), 7.96 (d, 1H, J=7.4 Hz). LC-MS (m/z): 347 (M+H, 100).
Synthesis 13 Tert-butyl 4-(2-amino-3-nitropyridin-4-ylthio)phenylcarbamateMethod A3: Dry DMSO (15 mL) was added to NaH (1.24 g of a 60% dispersion in mineral oil, 25.7 mmol) in a round bottom flask under Ar. After 5 min, solid terf-butyl 4- <n="100"/>mercaptophenylcarbamate (6.98 g, 31.0 mmol) was added in three portions, which led to the formation of a yellow solution while effervescence occurred. After 15 min of stirring at RT, <strong>[6980-08-1]4-chloro-3-nitropyridin-2-amine</strong> (5.38 g, 31.0 mmol) at once. The yellow/brown solution was stirred for 30 min and EtOAc (150 mL) and H2O (400 mL) were subsequently added. The aqueous layer was extracted with EtOAc (3 x 100 mL) and the combined organic layers were washed once with saturated NaHCO3 (150 mL), dried (MgSO4), filtered, and concentrated to dryness to give the title compound as a bright yellow solid. Yield: 11.2 g (quantitative).1H-NMR (DMSO-d6), delta (ppm), J (Hz): 1.49 (s, 9H, tbetart- Bu), 5.83 (d, J=5.4, 1H, HPy), 7.47 (d, J=8.7, 2H1 Harom), 7.64 (d, J=8.7, 2H, Harom), 7.87-7.89 (m, 3H), 9.69 (s, 1H, NHBoc); 13C-NMR (DMSO-d6), delta (ppm), J (Hz): 28.0, 79.6, 110.3, 119.4, 121.5, 124.8, 136.4, 141.4, 152.3, 152.5, 153.6, 156.2; LC-MS: 364.0 (M+H, 100); HRMS: m/z calcd. for C16H19N4O4S [M+H+]: 363.11215; found: 363.11261.
To 400 mg (2.32 mmol) of 5-N-BOC-amino-8-hydroxy-quinoline dissolved in 30 mL DMF (dry), were added under stirring and argon atmosphere, 360 mg (3.20 mmol) tert-BuOK. After 30 minutes, 400 mg (2.32 mmol) <strong>[6980-08-1]2-amino-3-nitro-4-chloropyridine</strong> were added at once and the reaction mixture heated at 850C (bath) for 5 hours. After cooling, 200 mL AcOEt were added <n="93"/>and the solution extracted with 2 x 200 mL brine. The solution was dried (MgSO4) and evaporated under vacuum. The residue was purified on an lsolute column (Flash Si II; 50 g, 170 mL) eluted with AcOEt. The title compound was obtained as a yellow solid: 0.534 g. Yield: 58%. 1H NMR (500 MHz, DMSO-d6) delta: 1.51 (s, 9H, C(CH3J3), 5.65 (d, 1 H, HPyr, J=5.6 Hz), 7.14 (S, 2H1 NH2), 7.58-7.61 (m, 1 H1 HArom), 7.64 (d, 1 H, HArom, J= 8.3 Hz), 7.74 (d, 1 H, HArom, J= 8.3 Hz), 7.82 (d, 1 H, HPyr), 8.53-8.55 (m, 1H, Harom), 8.84-8.86 (m, 1H, Harom), 9.51 (S, 1 H, NH); LC-MS, tR = 6.51 min, m/z: 397.1 (M)+, calcd for C19H19N5O5.
NaH (60% in oil) (12.7 g, 317 mmol) was added to a solution of <strong>[6980-08-1]4-chloro-3-nitropyridin-2-amine</strong> (44) (25.0 g, 144 mmol) in THF (360 ml) under N2 at 0 C. The mixture was stirred at 0 C for 30 min. A solution of di-tert-butyl dicarbonate (34.7 mL, 151 mmol) in THF (120 ml) was added dropwise to the reaction mixture at 0 C for 20 min. The mixture was stirred at 0 C for 1 h. The mixture was quenched with saturated NH4Cl aqueous solution. The mixture was concentrated in vacuo until removing half amount of THF. The residue was diluted with EtOAc, washed with water containing acetic acid (20 mL), water and brine, dried over Na2SO4 and filtered onto SiO2-pad. The filtrate was concentrated in vacuo. The residue was collected by filtration and washed with IPE to give tert-butyl (4-chloro-3-nitropyridin-2-yl)carbamate (45) (37.7 g, 138 mmol, 96 %) as a light brown solid. 1H NMR (CDCl3) delta 1.52 (s, 9 H), 7.23 (d, J = 5.3 Hz, 1H), 7.71 (brs, 1H), 8.41 (d, J = 5.7 Hz, 1H).
36.4 g
With sodium hydride; for 1.5h;Cooling with ice;
To a solution of <strong>[6980-08-1]4-chloro-3-nitropyridin-2-amine</strong> (25.05 g) in THF (361 mL) was added 60% sodium hydride (13.85 g) under ice-cooling, and the mixture was stirred for 1 hr. Di-tert-butyl dicarbonate (33.5 mL) was added dropwise, and the mixture was stirred for 1.5 hr. A half amount of solvent was removed by concentration under reduced pressure, ethyl acetate was added, and the mixture was washed with water containing acetic acid (19.83 mL), water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was washed with IPE to give the title compound (36.4 g). 1H NMR (300 MHz, CDCl3) delta 1.49-1.54 (9H, m), 7.21-7.28 (1H, m), 7.72 (1H, brs), 8.41 (1H, dd, J = 5.3, 2.3 Hz).
Dry DMSO (20 mL) was added to NaH (1.029 g of a 60% dispersion in mineral oil, 25.7 mmol) in a round bottom flask under argon. After 5 minutes, solid fert-butyl 2-fluoro-4- hydroxyphenylcarbamate (5.59 g, 24.6 mmol) was added in three portions, giving a dark solution, which, after 15 minutes of stirring at room temperature, was treated with <strong>[6980-08-1]4-chloro-3-nitropyridin-2-amine</strong> (4.23 g, 24.4 mmol) at once. The dark red solution was heated to 0C for 1 hour and allowed to cool down to room temperature. EtOAc (150 mL) and H20 (200 mL) were subsequently added to the solution and the organic layer was isolated. The aqueous layer was extracted with EtOAc (3 x 100 mL) and the combined organic layers were washed once with saturated NaHC03 (150 mL), dried (MgS04), filtered, and concentrated to dryness to give a bright yellow solid. This material was used in the next step without further purification.Yield: 8.68 g (98%). 1H-NMR (DMSO-d6), delta (ppm), J (Hz): 1.46 (s, 9H, C(CH3)3), 6.08 (d, 1 H, PyrH), 7.01 (m, 1 H, ArH), 7.18 (br s, 2H, NH2), 7.22 (m, 1 H, ArH), 7.67 (m, 1 H, ArH), 8.04 (d, 1 H, PyrH), 9.03 (s, 1 H, NHBoc); 19F-NMR (DMSO-d6), delta (ppm): -120.7; LC-MS (4.72 min): m/z calcd. for C,6H17FN405 [M+H+]: 365.0; found:
97%
With potassium carbonate; In N,N-dimethyl-formamide; at 60 - 65℃; for 5h;Large scale;
To a 50 L flange flask was charged tert-butyl (2-fluoro-4-hydroxyphenyl)carbamate(2840 g active, 12.50 mol) and dimethylformamide (DMF) (18.5 L) followed by <strong>[6980-08-1]2-amino-3-nitro-4-chloropyridine</strong> (2083 g, 12.00 mol) and K2C03 (2420 g, 17.51 mol). DMF (3.5 L)was used for washings. The mixture was heated at 60-65C for 5 hours (HPLC showed95% by H PLC, >95% by NMR, 90% yield).
With potassium tert-butylate; In N,N-dimethyl-formamide; at 80℃; for 1h;Inert atmosphere;
4-Chloro-3-nitropyridin-2-amine (500 mg, 2.89 mmol) and 4-amino-2-fluorophenol (403.8 mg, 3.18 mmol) were mixed in dry DMF (10 mL), and t-BuOK (356.1 mg, 3.18 mmol) was added. This mixture was heated to 80 C under N2 for 1 h, then cooled to room temperature. Water (50 mL) was added to quench the reaction, and the mixture was extracted with EA (3 × 50 mL). The organic phase was washed with brine, dried over anhydrous Na2SO4, concentrated in vacuum, and purified by column chromatography to yield the corresponding ether 20b (618.0 mg, 81%). 1H NMR (300 MHz, DMSO) delta 7.95 (dd, J = 5.8, 0.7 Hz, 1H), 6.96 (t, J = 8.7 Hz, 1H), 6.54 - 6.40 (m, 2H), 6.15 (s, 2H), 6.03 (dd, J = 5.7, 1.3 Hz, 1H), 3.80 (s, 2H). EI-MS m/z: 264 (M)+.
45%
With potassium tert-butylate; In N,N-dimethyl-formamide; at 0℃; for 2h;
<strong>[6980-08-1]2-amino-3-nitro-4-chloropyridine</strong> (346 mg, 2 mmol)2-fluoro-4-chlorophenol (508 mg, 4 mmol)After dissolving in 1 ml of DMF,The mixture was thoroughly stirred under ice bath and potassium tert-butoxide (448 mg, 4 mmol)At 0 CReaction 2h,After completion of the reaction, dry DMF, dissolved in ethyl acetate and water,Saturated aqueous ammonium chloride solution.After drying the solvent to give a black oil, the brown powder 2-9a (310 mg, 45%) was obtained by column chromatography (methanol: dichloromethane = 1: 50).
Stage #1: 4-Amino-3-methoxyphenol With sodium hydride; dimethyl sulfoxide In mineral oil at 20℃; for 0.166667h; Inert atmosphere;
Stage #2: 4-chloro-3-nitro-2-pyridinamine In dimethyl sulfoxide; mineral oil at 20 - 100℃; Inert atmosphere;
Normal-butyllithium (1.57 M solution in hexane: 3.2 mL, 5.0 mmol) was added to a solution of 2,2'-bithiophene (830 mg, 5.0 mmol) in THF (50 mL) at -78C. This solution was stirred at -78C for 30 min, and then tributylstannyl chloride (1.5 mL) was added thereto. The reaction solution was stirred at room temperature for 30 min and was then separated between water and ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The organic layer was concentrated and was then added to a solution of <strong>[6980-08-1]2-amino-3-nitro-4-chloropyridine</strong> (519 mg, 3.0 mmol) and dichlorobis(triphenylphosphine)palladium (105 mg, 0.15 mmol) in DMF (18 mL). This solution was stirred at 100C for 5 hr and was then separated between ethyl acetate and water. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 4-(2,2'-Bithien-5-yl)-3-nitropyridine-2-amine (809 mg, 89%) was obtained through purification by silica gel column chromatography (elution with a solution of 2% ethyl acetate in methylene chloride). 4-(2,2',5',2"-Terthiophen-5-yl)-3-nitropyridine-2-amine (250 mg, yield: 22%) was synthesized using 2,2',5',2"-terthiophene (1.24 g, 5.0 mmol) by the same reaction. 4-(2,2'-Bithien-5-yl)-3-nitropyridine-2-amine: 1H NMR (300 MHz, DMSO-d6) delta 8.19 (d, 1H, J = 5.1 Hz), 7.60 (dd, 1H, J = 1.1, 5.1 Hz), 7.41 (dd, 1H, J = 1.2, 3.6 Hz), 7.35 (d, 1H, J = 3.8 Hz), 7.20 (d, 1H, J = 3.9 Hz), 7.14 (dd, 1H, J = 3.6, 5.1 Hz), 6.97 (bs, 1H), 6.80 (d, 1H, J = 5.1 Hz). HRMS (FAB, 3-NBA matrix) for C13H10N3O2S2, (M+H)+ calculated value: 304.0214, observed value: 304.0172. 4-(2,2',5',2"-Terthien-5-yl)-3-nitropyridine-2-amine: 1H NMR (300 MHz, DMSO-d6) delta 8.19 (d, 1H, J = 5.0 Hz), 7.57 (dd, 1H, J = 1.1, 5.1 Hz), 7.40 (m, 3H), 7.32 (d, 1H, J = 3.8 Hz), 7.22 (d, 1H, J = 3.9 Hz), 7.13 (dd, 1H, J = 3.7, 5.1 Hz), 6.99 (bs, 2H), 6.80 (d, 1H, J = 5.0 Hz).
Stage #1: 4,6-dichloro-1-hydroxy-3-aminobenzene With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 20℃; for 1h; Inert atmosphere;
Stage #2: 4-chloro-3-nitro-2-pyridinamine In N,N-dimethyl-formamide at 80℃; for 20h; Inert atmosphere; Further stages;
With hydrogenchloride; water; sodium nitrite; at 0 - 70℃;
Example - 2: Synthesis of 2-ChIoro-3-nitropyridin-4-ol; Step-I: Preparation of 4-chIoro-3-nitropyridin-2-oI; Charged 2-amino-4-chloro-3-nitropyridine (50.0 gm) in D.M. water (1.0 lit) under stirring at 25 - 300C. Charged cone, hydrochloric acid (450 ml) in one lot. Cooled the reaction mass to 0 to 5C and started the addition of sodium nitrite solution (23 gm in 500 ml D. M. water) maintaining temperature at 0 to 5C. Stirred the reaction mixture at 0 to 50C for 30 min. slowly raised the temperature of the reaction mass to 25 - 300C and then to 60 to 70C, maintained for 2 hrs. After 2 hrs cooled the reaction to 25 - 300C and extracted reaction mass with dichloromethane (4x250 ml). Collected all the organic layers and dried over anhydrous sodium sulphate, concentrated the solvent under vacuum to get desired product. Dry wt = 30 gm (60%)
Intermediate G1 : 4-(4-Amino-2,3-dichlorophenoxy)pyridine-2,3-diamine.Intermediate G1To a stirred solution of <strong>[39183-17-0]4-amino-2,3-dichlorophenol</strong> (1 .00 g, 5.62 mmol) in dry DMF (20 mL) under N2 was added K2C03 (854 mg, 6.18 mmol) and the mixture kept at RT for 10 min and then treated with a solution of 4-chloro-3-nitropyridin-2-amine (1 .024 g, 5.90 mmol) in dry DMF (5.0 mL) in a single portion. The reaction mixture was maintained at RT for 19 hr and was then partitioned between EtOAc (100 mL) and water (100 m L). The aq layer was separated and was extracted with EtOAc (4 x 70 mL) and the combined organic extracts were dried and evaporated in vacuo. The residue was purified by flash column chromatography (Si02, 80 g, EtOAc in isohexane, 0-70percent, gradient elution) to afford 4-(4- amino-2,3-dichlorophenoxy)-3-nitropyridin-2-amine as a dark solid (1 .28 g, 70percent); R' 1 .85 min (Method 2); m/z 315 (M+H)+ (ES+).
70%
Intermediate G1: 4-(4-Amino-2,3-dichlorophenoxy)pyridine-2,3-diamine To a stirred solution of <strong>[39183-17-0]4-amino-2,3-dichlorophenol</strong> (1.00 g, 5.62 mmol) in dry DMF (20 mL) under N2 was added K2CO3 (854 mg, 6.18 mmol) and the mixture kept at RT for 10 min and then treated with a solution of 4-chloro-3-nitropyridin-2-amine (1.024 g, 5.90 mmol) in dry DMF (5.0 mL) in a single portion. The reaction mixture was maintained at RT for 19 hr and was then partitioned between EtOAc (100 mL) and water (100 mL). The aq layer was separated and was extracted with EtOAc (4*70 mL) and the combined organic extracts were dried and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 80 g, EtOAc in isohexane, 0-70percent, gradient elution) to afford 4-(4-amino-2,3-dichlorophenoxy)-3-nitropyridin-2-amine as a dark solid (1.28 g, 70percent); Rt 1.85 min (Method 2); m/z 315 (M+H)+ (ES+).
Intermediate H1 : 8-((2-Amino-3-nitropyridin-4-yl)oxy)quinolin-5-amine.Intermediate H1To a stirred solution of 5-aminoquinolin-8-ol dihydrochloride (2.00 g, 8.60 mmol) in DMSO (30 mL) under N2 was added K2C03 (3.79 g, 27.5 mmol) and after 1 hr at RT the mixture was treated with <strong>[6980-08-1]4-chloro-3-nitropyridin-2-amine</strong> (1 .34 g, 7.72 mmol) in a single portion. The reaction mixture was heated to 70C for 2 hr and was then cooled to RT and diluted with water (500 mL). A precipitate formed which was isolated by filtration, washed with water (2 x 20 mL) and then dried in vacuo at 40C to afford the title compound, Intermediate H1 as a dark brown solid (1 .50 g, 53%); R' O.99 min (Method 2); m/z 298 (M+H)+ (ES+).
53%
With potassium carbonate; In dimethyl sulfoxide; at 20 - 70℃; for 2h;Inert atmosphere;
Intermediate H1: 8-((2-Amino-3-nitropyridin-4-yl)oxy)quinolin-5-amine To a stirred solution of 5-aminoquinolin-8-ol dihydrochloride (2.00 g, 8.60 mmol) in DMSO (30 mL) under N2 was added K2CO3 (3.79 g, 27.5 mmol) and after 1 hr at RT the mixture was treated with <strong>[6980-08-1]4-chloro-3-nitropyridin-2-amine</strong> (1.34 g, 7.72 mmol) in a single portion. The reaction mixture was heated to 70 C. for 2 hr and was then cooled to RT and diluted with water (500 mL). A precipitate formed which was isolated by filtration, washed with water (2*20 mL) and then dried in vacuo at 40 C. to afford the title compound, Intermediate H1 as a dark brown solid (1.50 g, 53%); Rt 0.99 min (Method 2); m/z 298 (M+H)+ (ES+).
a) Diethyl 2-(2-amino-3-nitropyridin-4-yl)malonate (A 132) NaH (60% dispersion in mineral oil, 0.830 g, 20.7 mmol) was added to a solution of diethyl malonate (3.16 ml_, 20.7 mmol) in NMP (50 ml_) and the resulting solution was stirred at room temperature for 10 minutes. 4-Chloro-3-nitropyridin-2-amine A14 (1.00 g, 5.76 mmol) was then added and the mixture heated at 50 C for 2 hours. The mixture was cooled to room temperature and diluted with EtOAc (250 ml_) and water (100 ml_). The organic layer was separated and washed with water (100 ml_) followed by brine (100 ml_). This process was repeated three times before the organic layer was dried (Na2S04), filtered and the filtrate concentrated under reduced pressure to give a yellow oil which was purified by silica gel column chromatography (40 g Si02 cartridge, 0-100% EtOAc in petroleum benzine 40-60 C) to give the title compound as a yellow solid (1.69 g, 99%). H NMR (400 MHz, ck-DMSO) delta 8.28 (d, J = 4.9 Hz, 1 H), 7.53 (s, 2H), 6.58 (d, J = 5.0 Hz, 1 H), 5.20 (s, 1 H), 4.18 (qd, J = 7.1 , 0.9 Hz, 4H), 1.18 (t, J = 7.1 Hz, 6H). LCMS-B: rt 3.20 min, m/z (positive ion) 298 [M+H]+.
87%
The compounds were prepared in analogy to a published procedure. A suspension of sodium hydride (60%, 1.5 mmol) in mineral oil was washed with n-hexane (310 mL), the solvent was pipetted out and traces were removed under reduced pressure, and the remaining material was suspended in dry DMF (5 mL) under argon atmosphere. The mixture was cooled to 0-5 C and a solution of malonic acid dialkyl ester (1.0 mmol) in dry DMF (0.5 mL) was added dropwise. During malonate addition the temperature was not allowed to rise about 40 C. When the hydrogen evolution ceased (about 5-10 min) the reaction was allowed to warm to 50 C and stirred for further 30 min at the same temperature, after which a solution of the corresponding 4-chloro-nitropyridine-2-amine (10 or 11, 0.5 mmol) in DMF (1 mL) was added dropwise while the temperature kept below 50-55 C. The mixture was stirred for specified time at this temperature. After the starting material was consumed as monitored by TLC control (90% dichloromethane/methanol), the reaction mixture was evaporated under reduced pressure, the residue diluted with ice water (5 mL), and neutralized carefully with hydrochloric acid (2.0 N, 2 mL). The formed precipitate was filtered and washed with ice water (35 mL). The crude product was purified by column chromatography on silica gel using 50% dichloromethane/ethyl acetate as eluent to afford the corresponding condensed product 18 or 19. 4.4.1. Diethyl 2-(2-amino-3-nitropyridin-4-yl)malonate (18).18 Yellowcrystals (240.3 mg, 87%); mp 117e118 C; Rf (50% CH2Cl2/EtOAc) 0.77; 1H NMR (500 MHz, DMSO-d6) dH: 1.17 (6H, t, J7.25 Hz, 2OCH2CH3),4.17 (4H, dq, J1.58, 7.25 Hz, 2OCH2CH3), 5.20 (1H, s, CH), 6.58 (1H,d, J5.36 Hz, H-5), 7.50 (2H, s, NH2), 8.27 (1H, d, J4.73 Hz, H-6); 13CNMR (125 MHz, DMSO-d6) dC: 13.9 (2OCH2CH3), 55.1 (CH), 66.9(2OCH2CH3), 114.3, 128.2, 139.4, 153.8, 153.9, 166.3; LC/ESI-MS calcdfor C12H15N3O6 m/z 297.3, found 296.0 [MH]e, 298.3 [MH].
82%
General procedure: The compounds were synthesized in analogy to a published procedure.S1 A solution of malonic acid diethyl ester (1.0 mmol) in dry DMF (0.3 mL) was added slowly under an argon atmosphere to a suspension of sodium hydride (60% in paraffin, 1.0 mmol) in dry DMF (3 mL). During malonate addition the temperature was not allowed to rise about 50 C. When hydrogen evolution ceased (ca. 5 min) the mixture was allowed to stand for 30 min at the same temperature, after which a solution of the corresponding 2-amino-4-chloro-nitropyridine (8 or 9, 0.3 mmol) in DMF (1 mL) was slowly added while the temperature kept below 58 C. The mixture was strirred for the appropriate time at this temperature (TLC-control: dichloromethane/methanol, 9 : 1). The reaction mixture was evaporated under reduced pressure, the residue diluted with water (5 mL), and neutralized carefully with 2N hydrochloric acid (2 mL). The precipitate was filtered, washed with ice-water (3x5 mL) and dried at 70 C to yield the corresponding condensed product 10 or 11 as yellow solids.
A solution of 4-chloro-3-nitropyridin-2-amine (2 g, 11.5 mmol) and N-bromosuccinimide (2.5 g, 13.8 mmol) in ACN (125 mL) was heated at 80 C. After 1h, the reaction mixture was cooled was cooled to room temperature and volatiles were removed under reduced pressure. Purification (FCC, SiO2, 0-5% EtOAc in DCM), afforded the title compound (2.9 g, 99%). MS (ESI): mass calcd. for C5H3BrClN3O2, 250.9; m/z found, 251.8 [M+H]+.1H NMR (400 MHz, DMSO-d6) delta 8.42 (s, 1H), 7.37 (br s, 2H).
85%
With N-Bromosuccinimide; In acetonitrile; at 80℃; for 1h;
4-Chloro-3-nitropyridin-2-amine (0.1 0 g, 0.58 mmol) was dissolved in dryacetonitrile (20 ml). To the stirred solution was then added N-bromosuccinimide (0.124g, 0.70 mmol), and the reaction mixture was heated at 80 C for 1 h. Volatiles wereremoved in vacuo and the residue purified by silica column chromatography (elution with25 dichloromethane) to provide the title compound as a pale brown powder (0.125 g, 85%).1 H-NMR (500 MHz, DMSO-d6) 7.35 (s, 2H, NH2), 8.41 (s, 1 H, 6-H).
With N-chloro-succinimide; In acetonitrile; at 80℃; for 1h;
4-Chloro-3-nitropyridin-2-amine (0.1 0 g, 0.58 mmol) was dissolved in dryacetonitrile (20 ml). To the stirred solution was then added N-chlorosuccinimide (0.0945 g, 0.70 mmol), and the reaction mixture was heated at 80 C for 1 h. Volatiles wereremoved in vacuo and the residue purified by silica column chromatography (elution withdichloromethane) to provide the product as a pale brown powder (0.125 g, 85%). 1 HNMR(500 MHz, DMSO-d6) 7.35 (s, 2H, NH2), 8.36 (s, 1 H, 6-H).
85%
With N-chloro-succinimide; In acetonitrile; at 80℃; for 1h;
[00118] 4-Chloro-3-nitropyridin-2-amine (0.10 g, 0.58 mmol) was dissolved in dry acetonitrile (20 mL). To the stirred solution was then added A/-chlorosuccinimide (0.094 g, 0.70 mmol), and the reaction mixture was heated at 80 C for 1 h. Volatiles were removed in vacuo and the residue purified by silica column chromatography (elution with dichloromethane) to provide the title compound as a pale brown powder (0.125 g, 85%). 1 H-NMR (500 MHz, DMSO-d6) 7.35 (s, 2H, NH2), 8.36 (s, 1 H, 6-H).
71%
With N-chloro-succinimide; In acetonitrile; at 80℃;
4-Chloro-3-nitro-pyridin-2-amine (5.00 g, 28.85 mmol) in acetonitrile (150 mL)To the suspension was added 1-chloropyrrolidine-2,5-dione (5.39 g, 40.36 mmol).The reaction mixture was stirred at 80 C overnight.It was then concentrated under reduced pressure.The residue obtained was purified by silica gel column chromatography (EtOAc)The crude product was subjected to silica gel column chromatography.(EA/PE (v/v) = 1/5 to 1/3) purified to give the title compound as a yellow solid(4.26 g, yield 71%).
71%
With N-chloro-succinimide; In acetonitrile; at 80℃;
To a suspension of 4-chloro-3-nitro-pyridin-2-amine (5.00g, 28.85 mmol) in acetonitrile (150 mL) was added l-chloropyrrolidine-2,5-dione (5.39 g, 40.36 mmol). The mixture was heated at 80 C overnight. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting with DCM). The crude product was once again purified by silica gel column chromatography (EA/PE (v/v) = 1/5 to 1/3) to afford the title compound as a yellow solid (4.26g, yield 71%).MS (ESI, pos. ion) m/z: 207.9 [M+H]+; NMR (400 MHz, CDCh) delta (ppm): 8.27 (s, 1H), 5.81 (s, 2H).
Multi-step reaction with 3 steps
1: N-chloro-succinimide / acetonitrile / 1 h / 80 °C
2: N-ethyl-N,N-diisopropylamine / isopropyl alcohol / 18 h / 45 °C
3: sodium dithionite / ethanol / 24 h / 80 °C
Multi-step reaction with 3 steps
1: N-chloro-succinimide / acetonitrile / 1 h / 80 °C
2: N-ethyl-N,N-diisopropylamine / isopropyl alcohol / 18 h / 45 °C
3: sodium dithionite / ethanol; water / 24 h / 80 °C
Stage #1: methanol; sodium methylate; 4-chloro-3-nitro-2-pyridinamine at 60℃; for 16h;
Stage #2: With hydrogenchloride In water
(8-Methoxy-2-methyl-pyrido[2,3-b]pyrazin-3-yl)-hydrazine (He).
To a solution of 4- chloro-pyridin-2-ylamine (5 g) in 96% aq H2SO4 (20 mL) at 0 °C was added a mixture solution of 70% aq HN03 (2.5 mL) and 96% aq H2S04 (10 mL) drop-wise. After the addition was completed, the mixture was stirred at room temperature for 2h. The solution was poured onto ice/water and 6M aq. NaOH was added drop-wise to adjust pH to 9. Then the solid was filtered off, washed with water, and dried before it was purified by chromatography on alumina (eluent: pentane:EtOAc 2:1) to afford 4-chloro-3-nitro-pyridin-2-ylamine (1.2 g). 200 mg of this material was dissolved methanol (3mL) and NaOMe (125 mg) was added before the mixture was stirred at 60 °C for 16h. 37%> aq HC1 was added drop-wise to adjust pH to 6. The mixture was cooled to 0 °C, and the precipitated solid was filtered off, washed with water, and dried to afford 4-methoxy-3-nitro-pyridin-2-ylamine (180 mg). This material was dissolved in methanol (20 mL) and treated with hydrogen gas (1 bar) in the presence of 10%> palladium on charcoal at room temperature for 2h. The mixture was filtered and the filtrate was concentrated in vacuo to afford 4-methoxy-pyridine-2,3-diamine (50 mg). This procedure was repeated to produce more material. In the next step, 4-methoxy-pyridine-2,3-diamine (6.8 g) was dissolved in ethanol (200 mL). To this solution was slowly added methyl pyruvate (4.9 mL) at room temperature, and the mixture was stirred at ambient temperature for 3h before the volatiles were removed in vacuo. The residue was purified by chromatography on silica gel (eluent: pentane:EtOAc 5: 1 to 0: 1) to give afford 8-methoxy-2-methyl-4H-pyrido[2,3- b]pyrazin-3-one (6.1 g). To a suspension of 3 g of this material in DMF (12 mL) was added PyBroP (7.65 g) followed by DBU (3.58 g). The mixture was stirred overnight before the precipitated solid was filtered off, washed with ethanol, and dried to afford 3-(benzotriazol-l- yloxy)-8-methoxy-2-methyl-pyrido[2,3-b]pyrazine (3.5 g). 1.5 g of this material was dissolved in a mixture of ethanol (lOmL) and DCM (60mL). Hydrazine monohydrate (3.6g) was added, and the mixture was stirred overnight at ambient temperature before the volatiles were removed in vacuo. The residual solid was triturated from ethanol, filtered off, washed with ethanol, and dried to afford (8-methoxy-2-methyl-pyrido[2,3-b]pyrazin-3-yl)- hydrazine He (0.9 g).
To a solution of <strong>[6980-08-1]2-amino-3-nitro-4-chloropyridine</strong> (300 mg, 1.73 mmol, an intermediate in preparation of compound 16) in 5 mL anhydrous DMF was added sodium methoxide (187mg, 3.46 mmol). This mixture was stirred at room temperature for 3 h then poured onto 20 g crushed ice and extracted with ethyl acetate. The extracts were dried, evaporated and purified by column chromatography on silica gel (DCM/MeOH=40:1) to give 2-amino-3-nitro-4-methoxylpyridine (255mg, 87.3%) as yellow solid. The next steps followed the general procedure and gave the title compound as white solid (166 mg, 57.1% over 2 steps). IR (KBr) nu 3028, 2870, 2750, 1714, 1688, 1621, 1506, 1378, 1140, 981cm-1; 1H NMR (400MHz, DMSO-d6) delta 3.93 (3H, s, CH3), 6.91 (1H, d, J=6.0Hz, H-7), 8.00 (1H, d, J=6.0Hz, H-6), 11.50 (1H, s, NH-1), 12.23 (1H, s, NH-4); 13C NMR (100MHz, DMSO-d6) delta 56.33, 102.87, 110.64, 139.22, 143.62, 152.30, 154.66, 155.97; HRMS-EI C8H7N3O3 calcd [M+Na]+ 216.0385, found 216.0384.
78%
In methanol; for 18h;Reflux;
a) 4-Methoxy-3-nitropyridin-2-amine (A23) 4-Chloro-3-nitropyridin-2-amine A14 (0.600 g, 3.46 mmol) was dissolved in dry MeOH (40 mL) under an atmosphere of nitrogen and NaOMe (0.467 g, 8.64 mmol) was added. The reaction was heated at reflux for 18 hours, cooled and quenched with water (5 mL) and then concentrated in vacuo. The resulting residue was diluted with EtOAc (150 mL) and saturated aqueous NaHC03 (100 mL), the layers were separated and the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organics were washed with brine (100 mL), dried (Na2S04), filtered and concentrated in vacuo to give the crude product which was purified by silica gel chromatography (40 g silica cartridge, 0-100% EtOAc in cyclohexane) to give the title compound (0.457 g, 78%) as a yellow solid. H NMR (400 MHz, cf DMSO) delta 8.04 (d, J = 5.8 Hz, 1 H), 6.90 (s, 2H), 6.51 (d, J = 5.8 Hz, 1 H), 3.87 (s, 3H). LCMS-B rt 1.82 min, m/z (positive ion) 170.1 [M+H]+.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate In 1,2-dimethoxyethane; water at 150℃; for 0.25h; Microwave irradiation;
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 75℃; for 15h;Inert atmosphere;
Step 1 To a solution of <strong>[6980-08-1]4-chloro-3-nitropyridin-2-amine</strong> (LXXXI) (5.00 g, 28.9 mmol, 1.00 eq) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (LXXXII) (7.1 g, 34.6 mmol, 1.20 eq) in a mixture of toluene (30 mL), H2O (18 mL) and EtOH (6 mL) was added Pd(PPh3)4(1.0 g, 0.87 mmol, 0.03 eq) and Na2CO3 (6.1 g, 57.6 mmol, 2 eq). The mixture was stirred at 75 C. for 15 h under a nitrogen atmosphere. The reaction mixture was then poured into brine (100 mL) and extracted with EtOAc (30 mL*3), the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resultant residue was purified by chromatography on silica gel (PE:EtOAc=5:1-1:1) to afford 3-nitro-[4,4'-bipyridin]-2-amine (LXXXIII) (1.80 g, 8.33 mmol, 28.8% yield) as a yellow solid. ESIMS found C10H8N4O2 m/z 217.1 (M+H).
28.8%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 75℃; for 15h;Inert atmosphere;
To a solution of <strong>[6980-08-1]4-chloro-3-nitropyridin-2-amine</strong> (LXXXII) (5.00 g, 28.9 mmol, 1.00 eq) and 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (LXXXIII) (7.1 g, 34.6 mmol, 1.20 eq) in a mixture of toluene (30 mL), H2O (18 mL) and EtOH (6 mL) was added Pd(PPh3)4 (1.0 g, 0.87 mmol, 0.03 eq) and Na2C03 (6.1 g, 57.6 mmol, 2 eq). The mixture was stirred at 75C for 15 h under a nitrogen atmosphere. The reaction mixture was then poured into brine (100 mL) and extracted with EtOAc (30 mL x 3), the combined organic layers were dried over anhydrous Na2S04, filtered and concentrated in vacuo. The resultant residue was purified by chromatography on silica gel (PE:EtOAc = 5: 1?1: 1) to afford 3-nitro-[4,4'-bipyridin]-2-amine (LXXXIV) (1.80 g, 8.33 mmol, 28.8% yield) as a yellow solid. ESIMS found CioH8N402 m/z 217.1 (M+H).
28.8%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 75℃; for 15h;Inert atmosphere;
Preparation of intermediate 3-nitro-[4,4?-bipyridin]-2-amine (LXXXIII) is depicted below in Scheme 15. Step 1 (0866) To a solution of <strong>[6980-08-1]4-chloro-3-nitropyridin-2-amine</strong> (LXXX) (5.00 g, 28.9 mmol, 1.00 eq) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (LXXXI) (7.1 g, 34.6 mmol, 1.20 eq) in a mixture of toluene (30 mL), H2O (18 mL) and EtOH (6 mL) was added Pd(PPh3)4 (1.0 g, 0.87 mmol, 0.03 eq) and Na2CO3 (6.1 g, 57.6 mmol, 2 eq). The mixture was stirred at 75 C. for 15 h under a nitrogen atmosphere. The reaction mixture was then poured into brine (100 mL) and extracted with EtOAc (30 mL×3), the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resultant residue was purified by chromatography on silica gel (PE:EtOAc=5:1?1:1) to afford 3-nitro-[4,4?-bipyridin]-2-amine (LXXXII) (1.80 g, 8.33 mmol, 28.8% yield) as a yellow solid. ESIMS found C10H8N4O2 m/z 217.1 (M+H).
28.8%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 75℃; for 15h;Inert atmosphere;
Step 1 (0890) To a solution of <strong>[6980-08-1]4-chloro-3-nitropyridin-2-amine</strong> (XCV) (5.00 g, 28.9 mmol, 1.00 eq) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (XCVI) (7.1 g, 34.6 mmol, 1.20 eq) in a mixture of toluene (30 mL), H2O (18 mL) and EtOH (6 mL) was added Pd(PPh3)4 (1.0 g, 0.87 mmol, 0.03 eq) and Na2CO3 (6.1 g, 57.6 mmol, 2 eq). The mixture was stirred at 75 C. for 15 h under a nitrogen atmosphere. The reaction mixture was then poured into brine (100 mL) and extracted with EtOAc (30 mL×3), the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resultant residue was purified by chromatography on silica gel (PE:EtOAc=5:1?1:1) to afford 3-nitro-[4,4?-bipyridin]-2-amine (XCVII) (1.80 g, 8.33 mmol, 28.8% yield) as a yellow solid. ESIMS found C10H8N4O2 m/z 217.1 (M+H).
With bis-triphenylphosphine-palladium(II) chloride; In water; toluene; at 75℃; for 16h;Inert atmosphere;
Step 1 A solution of <strong>[6980-08-1]4-chloro-3-nitropyridin-2-amine</strong> (LXXXI) (5.00 g, 28.9 mmol, 1.00 eq), 2-(tributylstannyl)pyridine (LXXXV) (15.9 g, 43.4 mmol, 1.50 eq), and Pd(PPh3)2Cl2 (1.05 g, 1.44 mmol, 0.05 eq) in a mixture of toluene (25 mL) and H2O (9 mL) was stirred at 75 C. for 16 h under a nitrogen atmosphere. The reaction mixture was then poured into brine (80 mL) and extracted with EtOAc (30 mL*3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resultant residue was purified by chromatography on silica gel (PE:EtOAc=5:1-1:1) to afford 3'-nitro-[2,4'-bipyridin]-2'-amine (LXXXVI) (1.6 g, 7.40 mmol, 25.6% yield) as a yellow solid. ESIMS found C10HsN4O2 m/z 217.1 (M+H).
25.6%
With bis-triphenylphosphine-palladium(II) chloride; In water; toluene; at 75℃; for 16h;Inert atmosphere;
A solution of 4-chloro-3-nitropyridin-2 -amine (LXXXII) (5.00 g, 28.9 mmol, 1.00 eq), 2-(tributylstannyl)pyridine (LXXXVI) (15.9 g, 43.4 mmol, 1.50 eq), and Pd(PPh3)2Cl2 (1.05 g, 1.44 mmol, 0.05 eq) in a mixture of toluene (25 mL) and H2O (9 mL) was stirred at 75C for 16 h under a nitrogen atmosphere. The reaction mixture was then poured into brine (80 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over anhydrous Na2SC>4, filtered and concentrated in vacuo. The resultant residue was purified by chromatography on silica gel (PE:EtOAc = 5: 1?1 : 1) to afford 3'-nitro-[2,4'-bipyridin]-2'-amine (LXXXVII) (1.6 g, 7.40 mmol, 25.6% yield) as a yellow solid. ESIMS found CioH8N402 m/z 217.1 (M+H).
25.6%
With bis-triphenylphosphine-palladium(II) chloride; In water; toluene; at 75℃; for 16h;Inert atmosphere;
Preparation of intermediate 3-nitro-[4,4?-bipyridin]-2-amine (LXXXVI) is depicted below in Scheme 16. Step 1 (0869) A solution of <strong>[6980-08-1]4-chloro-3-nitropyridin-2-amine</strong> (LXXX) (5.00 g, 28.9 mmol, 1.00 eq), 2-(tributylstannyl)pyridine (LXXXIV) (15.9 g, 43.4 mmol, 1.50 eq), and Pd(PPh3)2Cl2 (1.05 g, 1.44 mmol, 0.05 eq) in a mixture of toluene (25 mL) and H2O (9 mL) was stirred at 75 C. for 16 h under a nitrogen atmosphere. The reaction mixture was then poured into brine (80 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resultant residue was purified by chromatography on silica gel (PE:EtOAc=5:1?1:1) to afford 3?-nitro-[2,4?-bipyridin]-2?-amine (LXXXV) (1.6 g, 7.40 mmol, 25.6% yield) as a yellow solid. ESIMS found C10H8N4O2 m/z 217.1 (M+H).
25.6%
With bis-triphenylphosphine-palladium(II) chloride; In water; toluene; at 75℃; for 16h;Inert atmosphere;
Step 1 (0893) A solution of <strong>[6980-08-1]4-chloro-3-nitropyridin-2-amine</strong> (XCV) (5.00 g, 28.9 mmol, 1.00 eq), 2-(tributylstannyl)pyridine (XCIX) (15.9 g, 43.4 mmol, 1.50 eq), and Pd(PPh3)2Cl2 (1.05 g, 1.44 mmol, 0.05 eq) in a mixture of toluene (25 mL) and H2O (9 mL) was stirred at 75 C. for 16 h under a nitrogen atmosphere. The reaction mixture was then poured into brine (80 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resultant residue was purified by chromatography on silica gel (PE:EtOAc=5:1?1:1) to afford 3?-nitro-[2,4?-bipyridin]-2?-amine (C) (1.6 g, 7.40 mmol, 25.6% yield) as a yellow solid. ESIMS found C10H8N4O2 m/z 217.1 (M+H).
N-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl) methanesulfonamide[ No CAS ]
[ 6980-08-1 ]
N-(3-(2-amino-3-nitropyridin-4-yl)-5-fluorobenzyl)methanesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
37.4%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 80℃;Inert atmosphere;
Step 4 A solution of N-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)methanesulfonamide (CVII) (6.83 g, 20.75 mmol, 1.2 eq), <strong>[6980-08-1]4-chloro-3-nitropyridin-2-amine</strong> (LXXXI) (3.0 g, 17.29 mmol, 1.0 eq), Na2CO3 (6.41 g, 60.52 mmol) and Pd(dppf)Cl2 (641.27 mg, 864.50 mumol) in dioxane (40 mL) and H2O (8 mL) was de-gassed and then heated to 80 C. overnight under N2. TLC (PE:EtOAc=1:1) showed the starting material was consumed completely. The reaction mixture was poured into H2O (300 mL). The mixture was extracted with EtOAc (3*250 mL). The organic phase was washed with saturated brine (300 mL), dried over anhydrous NaSO4, concentrated in vacuum to give a residue. The crude product was purified by silica gel chromatography (PE:EtOAc=10:1) to give N-(3-(2-amino-3-nitropyridin-4-yl)-5-fluorobenzyl) methanesulfonamide (CVIII) (2.2 g, 6.46 mmol, 37.4% yield) as brown solid. ESIMS found C13H13FN4O4S m/z 341.1 (M+H).
37.4%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 80℃;Inert atmosphere;
A solution of N-(3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) benzyl)methane sulfonamide (CXV) (6.83 g, 20.75 mmol, 1.2 eq), 4-chloro-3-nitropyridin-2 -amine (LXXXII) (3.0 g, 17.29 mmol, 1.0 eq), Na2C03 (6.41 g, 60.52 mmol) and Pd(dppf)Cl2 (641.27 mg, 864.50 mupiiotaomicron) in dioxane (40 mL) and H20 (8 mL) was de-gassed and then heated to 80C overnight under N2. TLC (PE:EtOAc = 1: 1) showed the starting material was consumed completely. The reaction mixture was poured into H20 (300 mL). The mixture was extracted with EtOAc (3 x 250 mL). The organic phase was washed with brine (300 mL), dried over anhydrous NaSOzt, concentrated in vacuum to give a residue. The crude product was purified by silica gel chromatography (PE:EtOAc = 10: 1) to give N-(3-(2-amino-3-nitropyridin-4-yl)-5-fluorobenzyl) methanesulfonamide (CXVI) (2.2 g, 6.46 mmol, 37.4% yield) as brown solid. ESIMS found Ci3Hi3FN404S mlz 341.1 (M+H).
37.4%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 80℃;Inert atmosphere;
Step 4 (0894) A solution of N-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)methanesulfonamide (CVI) (6.83 g, 20.75 mmol, 1.2 eq), <strong>[6980-08-1]4-chloro-3-nitropyridin-2-amine</strong> (LXXX) (3.0 g, 17.29 mmol, 1.0 eq), Na2CO3 (6.41 g, 60.52 mmol) and Pd(dppf)Cl2 (641.27 mg, 864.50 mumol) in dioxane (40 mL) and H2O (8 mL) was de-gassed and then heated to 80 C. overnight under N2. TLC (PE:EtOAc=1:1) showed the starting material was consumed completely. The reaction mixture was poured into H2O (300 mL). The mixture was extracted with EtOAc (3×250 mL). The organic phase was washed with saturated brine (300 mL), dried over anhydrous NaSO4, concentrated in vacuum to give a residue. The crude product was purified by silica gel chromatography (PE:EtOAc=10:1) to give N-(3-(2-amino-3-nitropyridin-4-yl)-5-fluorobenzyl) methanesulfonamide (CVII) (2.2 g, 6.46 mmol, 37.4% yield) as brown solid. ESIMS found C13H13FN4O4S m/z 341.1 (M+H).
2.2 g
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 80℃;Inert atmosphere;
Step 4 (0918) A solution of N-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)methanesulfonamide (CXXI) (6.83 g, 20.75 mmol, 1.2 eq), <strong>[6980-08-1]4-chloro-3-nitropyridin-2-amine</strong> (XCV) (3.0 g, 17.29 mmol, 1.0 eq), Na2CO3 (6.41 g, 60.52 mmol) and Pd(dppf)Cl2 (641.27 mg, 864.50 mumol) in dioxane (40 mL) and H2O (8 mL) was de-gassed and then heated to 80 C. overnight under N2. TLC (PE:EtOAc=1:1) showed the starting material was consumed completely. The reaction mixture was poured into H2O (300 mL). The mixture was extracted with EtOAc (3×250 mL). The organic phase was washed with saturated brine (300 mL), dried over anhydrous NaSO4, concentrated in vacuum to give a residue. The crude product was purified by silica gel chromatography (PE:EtOAc=10:1) to give N-(3-(2-amino-3-nitropyridin-4-yl)-5-fluorobenzyl) methanesulfonamide (CXXII) (2.2 g, 6.46 mmol, 37.4% yield) as brown solid. ESIMS found C13H13FN4O4S m/z 341.1 (M+H).
1-(2-[[(tert-butyldimethylsilyl)oxy]methyl]-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(4-methylphenyl)-2,3-dihydro-1H-imidazol-2-one[ No CAS ]
[ 6980-08-1 ]
1-[3-(2-amino-3-nitropyridin-4-yl)-2-[[(tert-butyldimethylsilyl)oxy]methyl]phenyl]-3-(4-methylphenyl)-2,3-dihydro-1H-imidazol-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
49%
With tetrakis(triphenylphosphine) palladium(0); potassium acetate; In 1,4-dioxane; dichloromethane; at 120℃; for 18h;Inert atmosphere;
1-[3-(2-Amino-3-nitropyridin-4-yl)-2-[[(tert-butyldimethylsilyl)oxy]methyl]phenyl]-3-(4-methylphenyl)-2,3-dihydro-1H-imidazol-2-one A 10-mL round bottom flask purged and maintained with an inert atmosphere of nitrogen, 1-(2-[[(tert-butyldimethylsilyl)oxy]methyl]-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(4-methylphenyl)-2,3-dihydro-1H-imidazol-2-one (100 mg, 0.19 mmol, 1.00 equiv), <strong>[6980-08-1]4-chloro-3-nitropyridin-2-amine</strong> (50 mg, 0.29 mmol, 1.50 equiv), Pd(PPh3)4(22 mg, 0.02 mmol, 0.10 equiv) and KOAc (37.7 mg, 0.38 mmol, 2.00 equiv) were mixed in dioxane (5 ml) at room temperature. The resulting mixture was then stirred for 18 h at 120 C. After the reaction was done, the reaction mixture was cooled to room temperature, diluted with 10 mL water and extracted with ethyl acetate (3*10 ml). The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified in a silica gel column eluting with methanol in dichloromethane (1% to 20% gradient) to afford 1-[3-(2-amino-3-nitropyridin-4-yl)-2-[[(tert-butyldimethylsilyl)oxy]methyl]phenyl]-3-(4-methyl phenyl)-2,3-dihydro-1H-imidazol-2-one (50 mg, 49%) as yellow solid. MS: m/z=532.4 [M+H]+.
4-(4-methylimidazol-1-yl)-3-nitro-pyridin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
31.6%
In N,N-dimethyl-formamide; at 130℃; for 0.5h;Sealed tube; Microwave irradiation;
Step 1 (1143) 4-Chloro-3-nitro-pyridin-2-amine (LXXXI) (3.00 g, 17.3 mmol, 1.0 eq) and 4-methyl-1H-imidazole (XCI) (2.84 g, 34.6 mmol, 2.0 eq) were taken up into a microwave tube in DMF (20 mL). The sealed tube was heated at 130 C. for 30 min under microwave. TLC showed the starting material was consumed, LC/MS showed the desired product was found. 10% NH4Cl (60 mL) were added. The aqueous layer was extracted with DCM (2×100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, concentrated in vacuum. The residue was purified by chromatography on silica gel (PE:THF=1:1) to give the product 4-(4-methylimidazol-1-yl)-3-nitro-pyridin-2-amine (XCII) (1.20 g, 5.47 mmol, 31.6% yield) as a yellow solid. 1H NMR (CDCl3, 400 MHz) delta ppm 2.30 (d, J=0.75 Hz, 3H), 5.96-6.26 (m, 2H), 6.68 (d, J=5.02 Hz, 1H), 6.72-6.75 (m, 1H), 7.57 (d, J=1.0 Hz, 1H), 8.32 (d, J=5.14 Hz, 1H); ESIMS found C9H9N5O2 m/z 219.1 (M+H).
31.6%
In N,N-dimethyl-formamide; at 130℃; for 0.5h;Sealed tube; Microwave irradiation;
4-Chloro-3-nitro-pyridin-2-amine (LXXXII) (3.00 g, 17.3 mmol, 1.0 eq) and 4-methyl-lH-imidazole (XCIII) (2.84 g, 34.6 mmol, 2.0 eq) were taken up into a microwave tube in DMF (20 mL). The sealed tube was heated at 130C for 30 min under microwave. TLC showed the starting material was consumed, LC/MS showed the desired product was found. 10% NH4CI (60 mL) were added. The aqueous layer was extracted with DCM (2 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SC>4, concentrated in vacuum. The residue was purified by chromatography on silica gel (PE:THF = 1 : 1) to give the product 4-(4- methylimidazol-l-yl)-3-nitro-pyridin-2 -amine (XCIV) (1.20 g, 5.47 mmol, 31.6% yield) as a yellow solid. NMR (CDC13, 400 MHz) delta ppm 2.30 (d, J=0.75Hz, 3H), 5.96-6.26 (m, 2H), 6.68 (d, J=5.02Hz, 1H), 6.72-6.75 (m, 1H), 7.57 (d, J=1.0Hz, 1H), 8.32 (d, J=5.14Hz, 1H); ESIMS found C9H9N502 m/z 219.1 (M+H).
31.6%
In N,N-dimethyl-formamide; at 130℃; for 0.5h;Microwave irradiation; Sealed tube;
Preparation of intermediate 4-(2-fluorophenyl)-3-nitropyridin-2-amine (XCII) is depicted below in Scheme 18. Step 1 (0877) 4-Chloro-3-nitro-pyridin-2-amine (LXXX) (3.00 g, 17.3 mmol, 1.0 eq) and 4-methyl-1H-imidazole (XC) (2.84 g, 34.6 mmol, 2.0 eq) were taken up into a microwave tube in DMF (20 mL). The sealed tube was heated at 130 C. for 30 min under microwave. TLC showed the starting material was consumed, LC/MS showed the desired product was found. 10% NH4Cl (60 mL) were added. The aqueous layer was extracted with DCM (2×100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, concentrated in vacuum. The residue was purified by chromatography on silica gel (PE:THF=1:1) to give the product 4-(4-methylimidazol-1-yl)-3-nitro-pyridin-2-amine (XCI) (1.20 g, 5.47 mmol, 31.6% yield) as a yellow solid. 1H NMR (CDCl3, 400 MHz) delta ppm 2.30 (d, J=0.75 Hz, 3H), 5.96-6.26 (m, 2H), 6.68 (d, J=5.02 Hz, 1H), 6.72-6.75 (m, 1H), 7.57 (d, J=1.0 Hz, 1H), 8.32 (d, J=5.14 Hz, 1H); ESIMS found C9H9N5O2 m/z 219.1 (M+H).
31.6%
In N,N-dimethyl-formamide; at 130℃; for 0.5h;Microwave irradiation; Sealed tube;
Step 1 (0901) 4-Chloro-3-nitro-pyridin-2-amine (XCV) (3.00 g, 17.3 mmol, 1.0 eq) and 4-methyl-1H-imidazole (CV) (2.84 g, 34.6 mmol, 2.0 eq) were taken up into a microwave tube in DMF (20 mL). The sealed tube was heated at 130 C. for 30 min under microwave. TLC showed the starting material was consumed, LC/MS showed the desired product was found. 10% NH4Cl (60 mL) were added. The aqueous layer was extracted with DCM (2×100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, concentrated in vacuum. The residue was purified by chromatography on silica gel (PE:THF=1:1) to give the product 4-(4-methylimidazol-1-yl)-3-nitro-pyridin-2-amine (CVI) (1.20 g, 5.47 mmol, 31.6% yield) as a yellow solid. 1H NMR (CDCl3, 400 MHz) delta ppm 2.30 (d, J=0.75 Hz, 3H), 5.96-6.26 (m, 2H), 6.68 (d, J=5.02 Hz, 1H), 6.72-6.75 (m, 1H), 7.57 (d, J=1.0 Hz, 1H), 8.32 (d, J=5.14 Hz, 1H); ESIMS found C9H9N5O2 m/z 219.1 (M+H).
2-(5-fluoro-thiophen-2-yl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane[ No CAS ]
[ 6980-08-1 ]
4-(5-fluorothiophen-2-yl)-3-nitropyridin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
38.7%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 100℃; for 3h;Inert atmosphere;
Step 1 A solution of 2-chloro-3-nitro-pyridin-4-amine (LXXXI) (1.5 g, 8.64 mmol), 2-(5-fluorothiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (XCIV) (2.96 g, 12.96 mmol), Pd(dppf)Cl2 (632 mg, 0.86 mmol) and Cs2CO3 (5.63 g, 17.29 mmol) in dioxane (30 mL) and H2O (5 mL) was de-gassed and then heated to 100 C. under N2 for 3 h. TLC (PE:EtOAc=1:1) showed the starting material was consumed completely. The mixture was concentrated in vacuum to give a residue, which was purified by column chromatography to afford 4-(5-fluorothiophen-2-yl)-3-nitropyridin-2-amine (XCV) (800 mg, 3.34 mmol, 38.7% yield). ESIMS found C9H6FN3O2S m/z 240.1 (M+H).
38.7%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 100℃; for 3h;Inert atmosphere;
A solution of 2-chloro-3-nitro-pyridin-4-amine (LXXXII) (1.5 g, 8.64 mmol), 2-(5-fluorothiophen-2-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (XCVI) (2.96 g, 12.96 mmol), Pd(dppf)Cl2 (632 mg, 0.86 mmol) and CS2CO3 (5.63 g, 17.29 mmol) in dioxane (30 mL) and H2O (5 mL) was de-gassed and then heated to 100C under N2 for 3 h. TLC (PE:EtOAc = 1 : 1) showed the starting material was consumed completely. The mixture was concentrated in vacuum to give a residue, which was purified by column chromatography to afford 4-(5-fluorothiophen-2-yl)-3- nitropyridin-2 -amine (XCVII) (800 mg, 3.34 mmol, 38.7% yield). ESIMS found C9H6FN302S m/z 240.1 (M+H).
38.7%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 100℃; for 3h;Inert atmosphere;
Preparation of intermediate 4-(5-fluorothiophen-2-yl)pyridine-2,3-diamine (XCV) is depicted below in Scheme 19. Step 1 (0880) A solution of 2-chloro-3-nitro-pyridin-4-amine (LXXX) (1.5 g, 8.64 mmol), 2-(5-fluorothiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (XCIII) (2.96 g, 12.96 mmol), Pd(dppf)Cl2 (632 mg, 0.86 mmol) and Cs2CO3 (5.63 g, 17.29 mmol) in dioxane (30 mL) and H2O (5 mL) was de-gassed and then heated to 100 C. under N2 for 3 h. TLC (PE:EtOAc=1:1) showed the starting material was consumed completely. The mixture was concentrated in vacuum to give a residue, which was purified by column chromatography to afford 4-(5-fluorothiophen-2-yl)-3-nitropyridin-2-amine (XCIV) (800 mg, 3.34 mmol, 38.7% yield). ESIMS found C9H6FN3O2S m/z 240.1 (M+H).
38.7%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 100℃; for 3h;Inert atmosphere;
Step 1 (0904) A solution of 2-chloro-3-nitro-pyridin-4-amine (XCV) (1.5 g, 8.64 mmol), 2-(5-fluorothiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CVIII) (2.96 g, 12.96 mmol), Pd(dppf)Cl2 (632 mg, 0.86 mmol) and Cs2CO3 (5.63 g, 17.29 mmol) in dioxane (30 mL) and H2O (5 mL) was de-gassed and then heated to 100 C. under N2 for 3 h. TLC (PE:EtOAc=1:1) showed the starting material was consumed completely. The mixture was concentrated in vacuum to give a residue, which was purified by column chromatography to afford 4-(5-fluorothiophen-2-yl)-3-nitropyridin-2-amine (CIX) (800 mg, 3.34 mmol, 38.7% yield). ESIMS found C9H6FN3O2S m/z 240.1 (M+H).
(E)-N'-(4-chloro-3-nitropyridin-2-yl)-N,N-dimethylformamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
In methanol; at 75℃; for 16h;
General procedure: The compounds were prepared as described in the literature with minor modifications. To a solution of the corresponding 4-chloro-nitropyridin-2-amine (10 or 11, 1.0 mmol) in methanol (10 mL per 1.0 mmol starting material) and dimethylformamide(1.0 mL) was added dimethylformamide dimethyl acetal (DMFDMA, 1.0 mL) and heated to 75 C. After a reaction time of 16-20 h,the solvent was evaporated and the residue was stirred under water-petroleum ether (50%, 10 mL) until full crystallization. The product was filtered under reduced pressure, washed with petroleum ether (310 mL), and dried at 70 C to afford amidine 16 or 17. 4.3.1. (E)-N0-(4-Chloro-3-nitropyridin-2-yl)-N,N-dimethylform-amide (16).24 Yellow crystals (194.9 mg, 87%); mp 121e123 C; 1HNMR (500 MHz, DMSO-d6) dH: 2.96 (3H, s, NMe2), 3.14 (3H, s,NMe2), 7.21 (1H, d, J5.36 Hz, H-5), 8.28 (1H, d, J5.67 Hz, H-6),8.61 (1H, s, NHNMe2); 13C NMR (125 MHz, DMSO-d6) dC: 34.5,40.7, 116.8, 133.6, 138.9, 150.1, 154.6, 156.9; LC/ESI-MS calcd forC8H9ClN4O2 m/z 228.1, found 228.9 [MH].
4-chloro-3-nitro-N-phenylpyridin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 6℃;Reflux;
To the, <strong>[6980-08-1]4-chloro-3-nitropyridin-2-amine</strong> (80g, 0.46mol) synthesized in preparation example 1, iodobenzene (51g, 0.55mol), Pd2(dba)3(50.5g, 0.046mol), Cs2CO3(374.6g, 1.15mol), Xantphos(5.32g, 0.0092mol) in toluene (1.5 L) solvent was added, and then heated, and the mixture was heated under reflux for 6 hours. After cooling to room temperature, the reaction was stopped by adding aqueous solution ammonium chloride 500 ml to the reaction liquid. After extracting the mixture with E.A 500 mL, it was washed with distilled water, to give an organic layer. the thus obtained organic layer is dried with anhydrous MgSO4, and evaporated under reduced pressure and then purified by silica gel column chromatography to give the objective compound 4-chloro-3-nitro-N-phenylpyridin-2-amine (57g, yield 50%).
ethyl 7-chloro-8-nitroimidazo[1,2-a]pyridine-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sulfuric acid; In water; acetonitrile; at 100℃; for 5h;
To a solution of <strong>[33142-21-1]ethyl 2-chloro-3-oxopropanoate</strong> (13.0 g, 86.3 mmol) in acetonitrile (100 mL) was added concentrated aqueous sulfuric acid solution (2.30 mL, 43.2 mmol) and 4-chloro- 3-nitropyridin-2-amine (5.00 g, 28.8 mmol). The resulting mixture was heated at 100C for 5 h, then cooled and concentrated. The residue was purified by silica gel column chromatography (PE/EtOAc = 5/1) to give the title compound. ?H NMR (400 MHz, CD3OD) oe 9.43 (d, J 7.4 Hz, 1H), 7.83 (s, 1H), 7.42 (d, J= 7.4 Hz, 1H), 4.45 (q, J= 7.2 Hz, 2H), 1.42 (t, J= 7.0 Hz, 3H).
4-(4-methylpiperazin-1-yl)-3-nitropyridin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 90℃; for 12h;
2-Amino-3-nitro-4-chloropyridine (967 mg, 5.59 mmol) was dissolved in isopropanol (20 mL) and DIPEA (1.85 mL, 11.18 mmol) was added followed by N-methylpiperazine (0.744) mL, 6.71 mmol). The mixture was reacted at 90 C. for 12 h. A large amount of gold solid was isolated by cooling and was filtered, washed with isopropyl alcohol and ether in that order, and dried in vacuo to give the title compound (1.21 g, yield 92%) as a golden yellow solid.
N'-(4-((2-amino-3-nitropyridin-4-yl)oxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With potassium tert-butylate; In N,N-dimethyl-formamide; at 80℃; for 1h;Inert atmosphere;
<strong>[6980-08-1]2-amino-3-nitro-4-chloropyridine</strong> (1 g, 5.8 mmol) was dissolved in anhydrous DMF and 1.1 eq of compound 26 was added therein followed by the addition of 1.1 eq of potassium tert-butoxide. The atmosphere was replaced with N2 three times. The mixture was allowed to react for 1 h with stirring at 80 C. and the reaction was monitored by TLC. After the reaction was completed, the resultant was diluted with EA, washed with saturated NH4Cl solution and saturated NaCl, dried over anhydrous Na2SO4 and concentrated under reduced pressure, and the residue was purified by column chromatography to give the title compound, yield 81%. 1H NMR (300 MHz, DMSO) delta 10.64 (s, 1H), 9.94 (s, 1H), 8.05 (d, J=5.7 Hz, 1H), 7.97 (t, J=8.6 Hz, 1H), 7.62 (dd, J=9.0, 5.0 Hz, 2H), 7.32 (d, J=11.2 Hz, 1H), 7.25 (s, 2H), 7.18 (t, J=8.9 Hz, 2H), 7.06 (d, J=8.4 Hz, 1H), 6.06 (d, J=5.6 Hz, 1H), 1.58 (t, J=10.6 Hz, 4H).
2-(piperazin-1-yl)-1H-benzimidazole-4-carboxylic acid methyl ester[ No CAS ]
[ 6980-08-1 ]
methyl 2-(4-(2-amino-3-nitropyridin-4-yl)piperazin-1-yl)-1H-benzimidazole-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
54%
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 8h;
4-Chloro-3-nitro-2-aminopyridine (102 mg, 0.59 mmol) was added to dimethylformamide (5 mL) dissolved in compound c (100 mg, 0.41 mmol).Diisopropylethylamine (95 mg, 0.74 mmol), reacted at room temperature for 8 hours, the solvent was removed under reduced pressure and the residue was purified by flash column chromatography(dichloromethane:methanol = 10:1) gave the white solid compound d:2-(4-(2-Amino-3-nitropyridin-4-yl)piperazin-1-yl)-1- Hydrogen-benzimidazole-4-carboxylic acid methyl ester (100 mg, yield 54%).
4-N-[3-chloro-4-(3-fluorobenzyloxy)phenyl]-3-nitropyridine-2,4-diamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With triethylamine; In ethanol; for 8h;Reflux;
General procedure: To a solution of the pyridine 3 (300 mg, 1.73 mmol) [51] in absolute ethanol (10 mL) were added triethylamine (0.5 mL, 3.58 mmol) and the aniline 6 (500 mg, 1.99 mmol) [45] and the mixture was heated at reflux for 8 h. The solvent was vacuum evaporated, water was added to the residue and the precipitate was filtered, washed with water, dried and purified using silica gel column chromatography (dichloromethane) to give pure 7 (440 mg, 65%).
With tris(dibenzylideneacetone)dipalladium(0) chloroform complex; 1,1'-bis-(diphenylphosphino)ferrocene; In N,N-dimethyl-formamide; at 120℃; for 2h;Inert atmosphere;
to a 50 mL flask was added <strong>[6980-08-1]4-chloro-3-nitropyridine-2-amine</strong> (1.0 equiv, 2.88 mmol, 500 mg), 1,1'- bis(diphenylphosphino)ferrocene (0.2 equiv, 0.58 mmol, 320 mg), Zn(CN)2(2.0 equiv, 5.76 mmol, 680 mg), Pd2(dba) CITCl (0.10 equiv, 0.29 mmol, 299 mg) and DMF (10 mL). The reaction system was purged with nitrogen and heated at 120 C for 2 h. The reaction solution was quenched with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The remaining residue was purified by silica gel chromatography eluting with ethyl acetate/petroleum ether (1 :3) to afford 200 mg (42.3%) of the desired product as an orange solid. MS (M+H)+= 165.1
With palladium diacetate; caesium carbonate; catacxium A In water; toluene at 100℃; for 12h;
B.7.7.1 4-Cyclopropyl-3-nitropyridin-2-amine
A mixture of 4-chloro-3-nitro-2-pyridinamine [6980-08-1] (95.0 g, 547 mmol), potassium cyclopropyltrifluoroborate [1065010-87-8] (162 g, 1.09 mol), palladium acetate (2.46 g, 11.0 mmol), cesium carbonate (535 g, 1.64 mol) and cataCXium A (5.89 g, 16.4 mmol) in H2O (250 mL) and toluene (2.5 L) was stirred at 100°C for 12 h. The reaction mixture was filtered through a pad of Celite and the filter-cake was washed with EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (3 x 500 mL). The combined organic extracts were concentrated in vacuo. The crude mixture was purified by column chromatography (SiO2, mobile phase gradient: petroleum ether / EtOAc from 20:1 to 3:1) to afford intermediate J1 (70 g, 71%) as a yellow solid.
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