* 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] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 22, p. 5941 - 5952
2
[ 2789-25-5 ]
[ 3243-24-1 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 22, p. 5941 - 5952
3
[ 14432-13-4 ]
[ 2604-39-9 ]
[ 2789-25-5 ]
Yield
Reaction Conditions
Operation in experiment
70%
Stage #1: at 20 - 100℃; for 1 h; Stage #2: With ammonia In water at 20℃;
2-ChloiO-4-nitroaminopyridine (10.0 g, mol) was carefully dissolved in 100 mL of concentrated sulfuric acid at room temperature and heated 100 0C for Ih. After the solution was cooled to room temperature, it was poured onto 250 g of crushed ice and treated with concentrated ammonium hydroxide until pH was reached at 3 while the temperature was kept below 200C with ice bath. The yellow solid was separated and extracted with ethyl acetate (200 ml x 3) from aqueous layer. The collected organic layer was concentrated and the residue was purified with silica gel column chromatography (hexane: EtOAc = 4: 1 to EtOAc v/v) to give 6.0 g of 4-Amino-2-chloro-3-nitropyridine in 70 percent yield and 2.0 g of 4-amino-2- Chloro-5-nitropyridine in 25 percent yield. 4-Amino-2-chloro-3-nitropyridine: mp 179-181 °C; UV (H2O) λmax 238.0 (ε 13586, pH 11), 1H-NMR (DMSO, 500 MHz) δ 7.91 (d, J= 6.0, IH), 7.37 (s, 2H), 6.83 (d, J = 6.0, IH); 13C-NMR (DMSO, 125 MHz) δ 149.54, 149.24, 142.69, 142.33, 122.45; 4-amino-2-chloro-5-nitropyridine: 1H-NMR (DMSO, 500 MHz) δ 8.85 (s, IH), 7.37 (s, 2H), 6.96 (s, IH).
Reference：
[1] Patent: WO2007/47793, 2007, A2, . Location in patent: Page/Page column 87
[2] Roczniki Chemii, 1956, vol. 30, p. 1139,1144[3] Chem.Abstr., 1957, p. 12089
[4] Nucleosides, nucleotides and nucleic acids, 2004, vol. 23, # 1-2, p. 67 - 76
[5] Organic and Biomolecular Chemistry, 2013, vol. 11, # 38, p. 6526 - 6545
4
[ 14432-12-3 ]
[ 2604-39-9 ]
[ 2789-25-5 ]
Reference：
[1] Patent: WO2006/84281, 2006, A1, . Location in patent: Page/Page column 187
[2] Organic and Biomolecular Chemistry, 2013, vol. 11, # 38, p. 6526 - 6545
[3] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 22, p. 5941 - 5952
[4] Patent: CN103819398, 2016, B, . Location in patent: Paragraph 0030-0038
[5] European Journal of Medicinal Chemistry, 2018, vol. 156, p. 240 - 251
5
[ 109-09-1 ]
[ 2604-39-9 ]
[ 2789-25-5 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 22, p. 5941 - 5952
6
[ 2402-95-1 ]
[ 2604-39-9 ]
[ 2789-25-5 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 22, p. 5941 - 5952
7
[ 14432-16-7 ]
[ 2604-39-9 ]
[ 2789-25-5 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 22, p. 5941 - 5952
8
[ 14432-13-4 ]
[ 7664-93-9 ]
[ 2604-39-9 ]
[ 2789-25-5 ]
Reference：
[1] Roczniki Chemii, 1956, vol. 30, p. 1139,1144[2] Chem.Abstr., 1957, p. 12089
9
[ 14432-13-4 ]
[ 2604-39-9 ]
[ 2789-25-5 ]
Yield
Reaction Conditions
Operation in experiment
70%
Stage #1: at 20 - 100℃; for 1 h; Stage #2: With ammonia In water at 20℃;
2-ChloiO-4-nitroaminopyridine (10.0 g, mol) was carefully dissolved in 100 mL of concentrated sulfuric acid at room temperature and heated 100 0C for Ih. After the solution was cooled to room temperature, it was poured onto 250 g of crushed ice and treated with concentrated ammonium hydroxide until pH was reached at 3 while the temperature was kept below 200C with ice bath. The yellow solid was separated and extracted with ethyl acetate (200 ml x 3) from aqueous layer. The collected organic layer was concentrated and the residue was purified with silica gel column chromatography (hexane: EtOAc = 4: 1 to EtOAc v/v) to give 6.0 g of 4-Amino-2-chloro-3-nitropyridine in 70 percent yield and 2.0 g of 4-amino-2- Chloro-5-nitropyridine in 25 percent yield. 4-Amino-2-chloro-3-nitropyridine: mp 179-181 °C; UV (H2O) λmax 238.0 (ε 13586, pH 11), 1H-NMR (DMSO, 500 MHz) δ 7.91 (d, J= 6.0, IH), 7.37 (s, 2H), 6.83 (d, J = 6.0, IH); 13C-NMR (DMSO, 125 MHz) δ 149.54, 149.24, 142.69, 142.33, 122.45; 4-amino-2-chloro-5-nitropyridine: 1H-NMR (DMSO, 500 MHz) δ 8.85 (s, IH), 7.37 (s, 2H), 6.96 (s, IH).
Reference：
[1] Patent: WO2007/47793, 2007, A2, . Location in patent: Page/Page column 87
[2] Roczniki Chemii, 1956, vol. 30, p. 1139,1144[3] Chem.Abstr., 1957, p. 12089
[4] Nucleosides, nucleotides and nucleic acids, 2004, vol. 23, # 1-2, p. 67 - 76
[5] Organic and Biomolecular Chemistry, 2013, vol. 11, # 38, p. 6526 - 6545
10
[ 5975-12-2 ]
[ 2789-25-5 ]
Yield
Reaction Conditions
Operation in experiment
71%
With ammonia In ethanol at 20℃; for 96 h;
3b) 4-amino-2-chloro-3-nitropyridine A solution of 28.0 g (0.193 mol) of 2,4-dichloro-3-nitropyridine in 300 ml of ammonia-saturated ethanol was stirred for four days at ambient temperature, then evaporated to dryness and the crude product thus obtained was purified by column chromatography (silica gel, eluant:dichloromethane with 0-5percent ethanol). Yield: 71percent of theory. C5H4ClN3O2 (173.56) Mass spectrum: (M+H)+=174/6
40%
With ammonia In ethanol at 20℃; for 7 h;
[1208] A solution of L-1 (20.00 g, 103.64 mmol, 1.00 eq) in ethanolic NH3 (600 ml of absolute ethanol saturated at 5°C with dry NH3) was stirred at rt for 7h. Then, the reaction solution was concentrated in vacuum to get a residue. The residue was triturated with boiling chloroform (120 ml). The resulting insoluble solid was filtered and dried in vacuum. Crystallization of this material from EA (200 ml) gave L-2 (7.20 g, 41.62 mmol, 40percent yield) as a brown solid.
Reference：
[1] Patent: WO2006/84281, 2006, A1, . Location in patent: Page/Page column 187
[2] Organic and Biomolecular Chemistry, 2013, vol. 11, # 38, p. 6526 - 6545
[3] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 22, p. 5941 - 5952
[4] Patent: CN103819398, 2016, B, . Location in patent: Paragraph 0030-0038
[5] European Journal of Medicinal Chemistry, 2018, vol. 156, p. 240 - 251
12
[ 14432-12-3 ]
[ 2789-25-5 ]
Yield
Reaction Conditions
Operation in experiment
44%
at 0℃; for 1 h;
Potassium nitrate (7.86 g, 0.0784 mol) was added portionwise to 2-chloro-4-aminopyridine (10.00 g, 0.078 mol) in concentrated sulfuric acid (80 mL) at 0 ° C, and the reaction was continued at 0 ° C for 1 hour. After completion, the reaction solution was poured into crushed ice, concentrated aqueous ammonia was added to adjust the pH to 3, stirred for 15 minutes, filtered, and a solid was collected. Add solid to concentrated sulfuric acid (80mL), heat to 80 ° C for 5 hours, cool, pour the reaction solution into crushed ice, add concentrated ammonia to adjust the pH to 3, stir for 15 minutes, filter, collect solids, through silica gel column Chromatographic purification,Elution with ethyl acetate/petroleum gradient (10-20percent) gave product ( 6.00 g, 44percent).
Reference：
[1] Patent: CN108498504, 2018, A, . Location in patent: Paragraph 0022; 0023; 0024; 0025
[2] Nucleosides, nucleotides and nucleic acids, 2004, vol. 23, # 1-2, p. 67 - 76
[3] Roczniki Chemii, 1956, vol. 30, p. 1139,1144[4] Chem.Abstr., 1957, p. 12089
13
[ 5470-18-8 ]
[ 2789-25-5 ]
Reference：
[1] Chemical Communications, 1998, # 15, p. 1519 - 1520
[2] Journal of the American Chemical Society, 2017, vol. 139, # 33, p. 11622 - 11628
14
[ 5470-18-8 ]
[ 2789-25-5 ]
[ 84487-03-6 ]
Reference：
[1] Liebigs Annalen der Chemie, 1991, # 9, p. 875 - 878
[2] Chemical Communications, 1998, # 15, p. 1519 - 1520
15
[ 89282-12-2 ]
[ 2789-25-5 ]
Reference：
[1] Patent: WO2015/153683, 2015, A1,
16
[ 109-09-1 ]
[ 2604-39-9 ]
[ 2789-25-5 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 22, p. 5941 - 5952
17
[ 2402-95-1 ]
[ 2604-39-9 ]
[ 2789-25-5 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 22, p. 5941 - 5952
18
[ 14432-16-7 ]
[ 2604-39-9 ]
[ 2789-25-5 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 22, p. 5941 - 5952
19
[ 14432-13-4 ]
[ 7664-93-9 ]
[ 2604-39-9 ]
[ 2789-25-5 ]
Reference：
[1] Roczniki Chemii, 1956, vol. 30, p. 1139,1144[2] Chem.Abstr., 1957, p. 12089
With water In dimethyl sulfoxide at 130℃; for 4 h;
3c) 4-amino-2-hydroxy-3-nitropyridine A solution of 18.0 g (104 mmol) of 4-amino-2-chloro-3-nitropyridine in 120 ml dimethylsulphoxide and 30 ml of water was stirred for four hours at 130° C. The solution was then cooled and left to stand overnight while cooling with ice. The product that crystallized out was suction filtered, washed with a little water and dried at 50° C. Yield: 69percent of theory. C5H5N3O3 (155.11) Mass spectrum: (M+H)+=156 (M-H)-=154
2-ChloiO-4-nitroaminopyridine (10.0 g, mol) was carefully dissolved in 100 mL of concentrated sulfuric acid at room temperature and heated 100 0C for Ih. After the solution was cooled to room temperature, it was poured onto 250 g of crushed ice and treated with concentrated ammonium hydroxide until pH was reached at 3 while the temperature was kept below 200C with ice bath. The yellow solid was separated and extracted with ethyl acetate (200 ml x 3) from aqueous layer. The collected organic layer was concentrated and the residue was purified with silica gel column chromatography (hexane: EtOAc = 4: 1 to EtOAc v/v) to give 6.0 g of 4-Amino-2-chloro-3-nitropyridine in 70 percent yield and 2.0 g of 4-amino-2- Chloro-5-nitropyridine in 25 percent yield. 4-Amino-2-chloro-3-nitropyridine: mp 179-181 °C; UV (H2O) lambdamax 238.0 (epsilon 13586, pH 11), 1H-NMR (DMSO, 500 MHz) delta 7.91 (d, J= 6.0, IH), 7.37 (s, 2H), 6.83 (d, J = 6.0, IH); 13C-NMR (DMSO, 125 MHz) delta 149.54, 149.24, 142.69, 142.33, 122.45; 4-amino-2-chloro-5-nitropyridine: 1H-NMR (DMSO, 500 MHz) delta 8.85 (s, IH), 7.37 (s, 2H), 6.96 (s, IH).
A mixture of <strong>[2789-25-5]2-chloro-3-nitropyridin-4-amine</strong> (400 mg, 2.3 mmol, 1.0 eq.)and Raney Ni (40 mg, 10%) in MeOH (10 mL) was stirred at r.t. under H2 atmosphere for 2 h,then filtered and the filtrate was concentrated to afford 2-chloropyridine-3,4-diamine (320 mg,96%) as a yellow solid.
95%
With hydrogen;nickel; In ethanol; at 20℃; under 760.051 Torr; for 4h;
4-Amino-2-chloro-3-nitropyridine (6.0 g, 34.57 mmol) in 150 mL of ethanol was hydrogenated over Raney nickel catalyst (6.0 g wet) for 4h at room temperature under 1.0 atm ofH2 atmosphere. After addition of 4.0 g of celite to the solution, the mixture was stirred vigorously and filtered over celite pad. The filtrate was concentrated and purified with silica gel column chromatography (CH2Cl2 :MeOH = 20:1 v/v) to give 2-Chloro-3,4- diaminopyridine (4.72 g, 32.84 mmol) in 95% yield. 1H-NMR (DMSO, 500 MHz) delta 7.31 (d, J= 5.0, IH), 6.45 (d, J= 5.0, IH), 5.79 (s, 2H), 4.68 (s, 2H); 13C-NMR (DMSO, 125 MHz) delta 143.41, 138.03, 135.61, 126.66, 108.73. t ,
With sulfuric acid; potassium nitrate; at 0℃; for 1h;
Potassium nitrate (7.86 g, 0.0784 mol) was added portionwise to 2-chloro-4-aminopyridine (10.00 g, 0.078 mol) in concentrated sulfuric acid (80 mL) at 0 ° C, and the reaction was continued at 0 ° C for 1 hour. After completion, the reaction solution was poured into crushed ice, concentrated aqueous ammonia was added to adjust the pH to 3, stirred for 15 minutes, filtered, and a solid was collected. Add solid to concentrated sulfuric acid (80mL), heat to 80 ° C for 5 hours, cool, pour the reaction solution into crushed ice, add concentrated ammonia to adjust the pH to 3, stir for 15 minutes, filter, collect solids, through silica gel column Chromatographic purification,Elution with ethyl acetate/petroleum gradient (10-20percent) gave product ( 6.00 g, 44percent).
With water; In dimethyl sulfoxide; at 130℃; for 4h;
3c) 4-amino-2-hydroxy-3-nitropyridine A solution of 18.0 g (104 mmol) of <strong>[2789-25-5]4-amino-2-chloro-3-nitropyridine</strong> in 120 ml dimethylsulphoxide and 30 ml of water was stirred for four hours at 130° C. The solution was then cooled and left to stand overnight while cooling with ice. The product that crystallized out was suction filtered, washed with a little water and dried at 50° C. Yield: 69percent of theory. C5H5N3O3 (155.11) Mass spectrum: (M+H)+=156 (M-H)-=154
3b) 4-amino-2-chloro-3-nitropyridine A solution of 28.0 g (0.193 mol) of 2,4-dichloro-3-nitropyridine in 300 ml of ammonia-saturated ethanol was stirred for four days at ambient temperature, then evaporated to dryness and the crude product thus obtained was purified by column chromatography (silica gel, eluant:dichloromethane with 0-5percent ethanol). Yield: 71percent of theory. C5H4ClN3O2 (173.56) Mass spectrum: (M+H)+=174/6
40%
With ammonia; In ethanol; at 20℃; for 7h;
[1208] A solution of L-1 (20.00 g, 103.64 mmol, 1.00 eq) in ethanolic NH3 (600 ml of absolute ethanol saturated at 5°C with dry NH3) was stirred at rt for 7h. Then, the reaction solution was concentrated in vacuum to get a residue. The residue was triturated with boiling chloroform (120 ml). The resulting insoluble solid was filtered and dried in vacuum. Crystallization of this material from EA (200 ml) gave L-2 (7.20 g, 41.62 mmol, 40percent yield) as a brown solid.
Step b: M2)-r(lS)-2,3-dihydro-lH-inden-l-yn-3-nitropyridine-2/4-diamine; [0931] <strong>[2789-25-5]4-amino-2-chloro-3-nitropyridine</strong> (1.67 g, 9.6 mmol), (S)-(+)-l-aminoindan(1.85 mL, 14.4 mmol) and triethylamine (2.68 mL, 19.2 mmol) were refluxed in EtOH (20 mL) for 14 h. The reaction was concentrated and the residue was purified by flash chromatography (0 to 25percent DCM/EtOAc) to obtain the product (2.59 g, 72percent) as a yellow solid.[0932] LCMS: R.t = 1.16 min, ES+ 271 (formic acid).
Example 136: ((2R,3S,4JR/5K)-5-{4-[(lS)-2,3-dihydro-lH-inden-l-ylamino]-lH-imidazo[4,5- c]pyridin-l-yl}-3,4-dihydroxytetrahydrofuran-2-yl)memyl sulfamate (1-149)Step a: 4-amino-2-chloro-3-nitropyridine; [0929] To a solution of 4-amino-2-chloropyridine (10.0 g, 77.8 mmol) in concentratedH2SO4 (6OmL) at 00C was added 90% nitric acid (30 mL) dropwise. The solution was stirred at 0-5 0C for 30 min then poured onto ice (carefully). The pH was brought to ~3 with concentrated aq ammonium hydroxide (~150mL) to obtain a white precipitate which was isolated and dried by filtration. The white solid was dissolved in sulfuric acid (100 mL), heated at 80 C for 5h, stirred at r.t. overnight, then poured on crushed ice. At 0 0C the pH was adjusted to ~3 with concentrated aq ammonium hydroxide (~250 mL) to obtain a yellow precipitate which was isolated by filtration. The solid was dried under vacuum overnight to obtain ~13 g of a mixture of 3- and 5-nitro isomers. A sample (4.0 g) was purified by flash chromatography (0 to 20% DCM/EtOAc) to obtain 1.77 g of the product as a fluffy yellow solid.[0930] LCMS: R.t = 1.15 min, ES+ 174 (formic acid) .
With sulfuric acid; nitric acid; at 0 - 80℃;pH 1.5 - 3;
(1) at 0 C, 200 g of 2-chloro-4-aminopyridine was dissolved in 1200 mL of concentrated sulfuric acid, and 1000 mL of 65% nitric acid was added dropwise. After completion of the dropwise addition, the reaction was carried out at 15 C for 2 hours and then poured into ice water and stirred at 0 C, The NH3 was adjusted to pH 3, Precipitate a white powdery solid I, filtered. (2) The white powdery solid I was dissolved in 2000 mL of concentrated sulfuric acid, Heated to 80 C reaction 3h, stirring at room temperature overnight, and then into the ice water, 0 C into the NH3 first tune the pH to 1.5, the formation of orange precipitation, filtration, Discard the precipitate, the filtrate and then continue to NH3 to pH 3, filtration, To give a yellow powdery solid II, i.e., isomer 4-amino-2-chloro-3-nitropyridine and 4-amino-2-chloro-5-nitropyridine, the yield of the isomer was 98% Purity of 98%, among them, The yield of 4-amino-2-chloro-3-nitropyridine was 75%. Among them, the reaction at room temperature after stirring overnight there are two purposes: the first is fully responsive; the second is fully cooled; Because the reaction system concentrated sulfuric acid temperature is very high, a short period of time may not cool the internal temperature, concentrated sulfuric acid itself will be added to the water will be exothermic, if the cooling is not completely added to the ice water will be exothermic, prone to danger, so To stirred enough to cool down overnight. (3) The yellow powdery solid II was recrystallized (wherein: the recrystallization reagent was ethyl acetate and petroleum ether, the total amount was 3 times the volume of the yellow powdery solid II, the volume ratio of ethyl acetate to petroleum ether was 1:5), heated to reflux, and then reduced to 30 C to precipitate a yellow powdery solid III. The filtrate was decompressed under reduced pressure to remove the solvent. The residue was recrystallized from 95% ethanol to give the pale yellow powder The solid IV is pure 4-amino-2-chloro-5-nitropyridine in a yield of 22% and a purity of 98%.
NaH (0.46 g, 11.6 mmol, 60percent dispersion in mineral oil) was added in one portion to a cooled (0° C.) solution of <strong>[2789-25-5]2-chloro-3-nitropyridin-4-amine</strong> (1.00 g, 5.8 mmol) in DMF (15 mL). The mixture was stirred for 20 mins and then a solution of 2,6-dichloro-4-cyanobenzoyl chloride (0.68 g, 2.9 mmol) in DMF (5 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 4 hours and then poured onto ice-water (20 mL). The resulting precipitate was collected by filtration and then the filtrate was extracted by EtOAc (2.x.50 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The residue was combined with previously collected precipirate and the material was purified by silica gel column chromatography (MeOH:CH2Cl2 1:10) to afford N-(2-chloro-3-nitropyridin-4-yl)-2,6-dichloro-4-cyanobenzamide (0.5 g, yield: 23percent). LCMS (ESI) m/z: 372.6 [M+H+]
With potassium carbonate; In acetonitrile; at 20 - 80℃; for 5h;
[1209] To a solution of L-2 (7.20 g, 41.62 mmol, 1.00 eq) in MeCN (140 mL) was added K2C03 (11.49 g, 83.24 mmol, 2.00 eq) and CD3I (15.09 g, 104.05 mmol, 2.50 eq) at rt. The resulting mixture was stirred at 80°C for 3 h. Additional CD3I (15.09 g, 104.05 mmol, 2.50 eq) was added, and the solution was stirred at 80 C for additional 2h. Then, the reaction mixture was poured into water (100 mL) and extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified to afford L-3 (8.5 g, crude) as yellow solid
2-(3-fluorophenyl)-3-nitropyridin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71.2%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 75℃; for 15h;Inert atmosphere;
A solution of <strong>[2789-25-5]2-chloro-3-nitropyridin-4-amine</strong> (LXVII) (2.0 g, 11.5 mmol, 1.0 eq), (3-fluorophenyl)boronic acid (LXVIII) (1.93 g, 13.8 mmol, 1.2 eq), Pd(PPh3)4 (0.40 g, 0.34 mmol, 0.03 eq), Na2CO3 (2.44 g, 23.05 mmol, 2.0 eq) in a mixed solvent of toluene (20 mL), 0 (10 mL) and EtOH (4 mL) was stirred at 75°C for 15 h under nitrogen atmosphere. Then the reaction mixture was washed with brine (30 mL) and dried over anhydrous Na2SO4, filtered and concentrated in vacuo, the resultant residue was purified by chromatography on silica gel (PE:EtOAc = 1 : 1) to afford 2-(3-fluorophenyl)-3-nitropyridin-4-amine (LXIX) (1.91 g, 8.2 mmol, 71.2percent yield) as a yellow solid.E SIMS found for C11H8FN3O2 m/z 234.2 (M+H).
71.2%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; at 75℃; for 15h;Inert atmosphere;
j0667j A solution of <strong>[2789-25-5]2-chloro-3-nitropyridin-4-amine</strong> (LXVIII) (2.0 g, 11.5 mmol,1.0 eq), (3-fluorophenyl)boronic acid (LXIX) (1.93 g, 13.8 mmol, 1.2 eq), Pd(PPh3)4 (0.40 g, 0.34mmol, 0.03 eq), Na2CO3 (2.44 g, 23.05 mmol, 2.0 eq) in a mixed solvent of toluene (20 mL), H20(10 mL) and EtOH (4 mL) was stirred at 75°C for 15 h under nitrogen atmosphere. Then the reactionmixture was washed with brine (30 mL) and dried over anhydrous Na2504, filtered andconcentrated in vacuo, the resultant residue was purified by chromatography on silica gel(PE:EtOAc = 1:1) to afford 2-(3-fluorophenyl)-3-nitropyridin-4-amine (LXX) (1.91 g, 8.2 mmol,71.2percent yield) as a yellow solid. ESIMS found for C11H8FN302 m/z 234.2 (M+H).
71.2%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 75℃; for 15h;Inert atmosphere;
A solution of <strong>[2789-25-5]2-chloro-3-nitropyridin-4-amine</strong> (LXXXI) (2.0 g, 11.5 mmol, 1.0 eq), (3-fluorophenyl)boronic acid (DOOM) (1.93 g, 13.8 mmol, 1.2 eq), Pd(PPh3)4 (0.40 g, 0.34 mmol, 0.03 eq), Na2CO3 (2.44 g, 23.05 mmol, 2.0 eq) in a mixed solvent of toluene (20 mL), H2O (10 mL) and EtOH (4 mL) was stirred at 75° C. for 15 h under nitrogen atmosphere. Then the reaction mixture was washed with brine (30 mL) and dried over anhydrous Na2SO4, filtered and concentrated in vacuo, the resultant residue was purified by chromatography on silica gel (PE:EtOAc=1:1) to afford 2-(3-fluorophenyl)-3-nitropyridin-4-amine (LXXXIII) (1.91 g, 8.2 mmol, 71.2percent yield) as a yellow solid. ESIMS found for C11H8FN3O2 m/z 234.2 (M+H).
71.2%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 75℃; for 15h;Inert atmosphere;
Step 1 A solution of <strong>[2789-25-5]2-chloro-3-nitropyridin-4-amine</strong> (LXVI) (2.0 g, 11.5 mmol, 1.0 eq), (3-fluorophenyl)boronic acid (LXVII) (1.93 g, 13.8 mmol, 1.2 eq), Pd(PPh3)4 (0.40 g, 0.34 mmol, 0.03 eq), Na2CO3 (2.44 g, 23.05 mmol, 2.0 eq) in a mixed solvent of toluene (20 mL), H2O (10 mL) and EtOH (4 mL) was stirred at 75° C. for 15 h under nitrogen atmosphere. Then the reaction mixture was washed with brine (30 mL) and dried over anhydrous Na2SO4, filtered and concentrated in vacuo, the resultant residue was purified by chromatography on silica gel (PE:EtOAc=1:1) to afford 2-(3-fluorophenyl)-3-nitropyridin-4-amine (LXVIII) (1.91 g, 8.2 mmol, 71.2percent yield) as a yellow solid. ESIMS found for C11H8FN3O2 m/z 234.2 (M+H).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 80℃;Inert atmosphere;
To a solution of pyridin-4-ylboronic acid (LXXXIV) (2.00 g, 16.3 mmol), 2- chloro-3-nitropyridin-4-amine (LXVII) (2.35 g, 13.6 mmol), Na2CO3 (5.03 g, 47.5 mmol) and Pd(dppf)Cl2 (502.87 mg, 677.92 muiotaetaomicron) in dioxane (40 mL) and H2O (8 mL) was de-gassed and then heated to 80°C overnight under N2. TLC (100percent EtOAc) showed the starting material was consumed completely. The reaction mixture was poured into H2O (300 mL). The mixture was extracted with EtOAc (3 x 250 mL). The organic phase was washed with brine (300 mL), dried over anhydrous MgSO4, concentrated in vacuum to give a residue, which was purified by silica gel column chromatography (DCM/MeOH= 20/1) to afford 3-nitro-[2,4'-bipyridin]-4- amine (LXXXV) (1.60 g, 7.4 mmol, 54.6percent yield) as yellow solid. ESIMS found for C10H8N4O2 m/z 217.1 (M+H).
54.6%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 80℃;Inert atmosphere;
j0690j To a solution of pyridin-4-ylboronic acid (XC) (2.00 g, 16.3 mmol), 2-chloro- 3-nitropyridin-4-amine (LXVIII) (2.35 g, 13.6 mmol), Na2CO3 (5.03 g, 47.5 mmol) and Pd(dppf)C12 (502.87 mg, 677.92 tmol) in dioxane (40 mL) and H20 (8 mL) was de-gassed and then heated to 80°C overnight under N2. TLC (100percent EtOAc) 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 Mg504, concentrated in vacuum to give a residue, which was purified by silica gel column chromatography (DCM/MeOH= 20/1) to afford 3 -nitro- [2,4?-bipyridinj -4-amine (XCI) (1.60 g, 7.4 mmol, 54.6percent yield) as yellow solid. ESIMS found for C10H8N402 m/z 217.1 (M+H).
54.6%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 80℃;Inert atmosphere;
To a solution of pyridin-4-ylboronic acid (XCVIII) (2.00 g, 16.3 mmol), <strong>[2789-25-5]2-chloro-3-nitropyridin-4-amine</strong> (LXXXI) (2.35 g, 13.6 mmol), Na2CO3 (5.03 g, 47.5 mmol) and Pd(dppf)Cl2 (502.87 mg, 677.92 mumol) in dioxane (40 mL) and H2O (8 mL) was de-gassed and then heated to 80° C. overnight under N2. TLC (100percent EtOAc) 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 brine (300 mL), dried over anhydrous MgSO4, concentrated in vacuum to give a residue, which was purified by silica gel column chromatography (DCM/MeOH=20/1) to afford 3-nitro-[2,4?-bipyridin]-4-amine (XCIX) (1.60 g, 7.4 mmol, 54.6percent yield) as yellow solid. ESIMS found for C10H8N4O2 m/z 217.1 (M+H).
54.6%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 80℃;Inert atmosphere;
Step 1 To a solution of pyridin-4-ylboronic acid (LXXXIII) (2.00 g, 16.3 mmol), <strong>[2789-25-5]2-chloro-3-nitropyridin-4-amine</strong> (LXVI) (2.35 g, 13.6 mmol), Na2CO3 (5.03 g, 47.5 mmol) and Pd(dppf)Cl2 (502.87 mg, 677.92 mumol) in dioxane (40 mL) and H2O (8 mL) was de-gassed and then heated to 80° C. overnight under N2. TLC (100percent EtOAc) 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 brine (300 mL), dried over anhydrous MgSO4, concentrated in vacuum to give a residue, which was purified by silica gel column chromatography (DCM/MeOH=20/1) to afford 3-nitro-[2,4'-bipyridin]-4-amine (LXXXIV) (1.60 g, 7.4 mmol, 54.6percent yield) as yellow solid. ESIMS found for C10H8N4O2 m/z 217.1 (M+H).
With tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 100℃; for 1h;Inert atmosphere;
To a solution of 2-(tributylstannyl)pyridine (LXXXVII) (9.00 g, 24.5 mmol, 1.0 eq), <strong>[2789-25-5]2-chloro-3-nitropyridin-4-amine</strong> (LXVII) (4.24 g, 24.5 mmol, 1.0 eq), Pd(PPh3)4 (28.25 g, 24.5 mmol, 1.0 eq) in dioxane (40 mL) was de-gassed and then heated to 100°C for 1 h under N2. LC/MS showed that half of the starting material was consumed. The mixture was filtered and concentrated in vacuum to give a residue, which was purified by prep-HPLC (Base) to afford the 3-nitro-[2,2'-bipyridin]-4-amine (LXXXVIII) (0.70 g, 3.24 mmol, 13.2percent yield) as a light yellow oil. ESIMS found for C10H8N4O2 m/z 217.1 (M+H).
13.2%
With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); lithium chloride; In 1,4-dioxane; at 100℃; for 1h;Inert atmosphere;
j0693j To a solution of 2-(tributylstannyl)pyridine (XCIII) (9.00 g, 24.5 mmol, 1.0 eq), <strong>[2789-25-5]2-chloro-3-nitropyridin-4-amine</strong> (LXVIII) (4.24 g, 24.5 mmol, 1.0 eq), Pd(PPh3)4 (28.25 g, 24.5 mmol, 1.0 eq) in dioxane (40 mL) was de-gassed and then heated to 100°C for 1 h under N2. LC/MS showed that half of the starting material was consumed. The mixture was filtered and concentrated in vacuum to give a residue, which was purified by prep-HPLC (Base) to afford the 3-nitro-[2,2?-bipyridinj-4-amine (XCIV) (0.70 g, 3.24 mmol, 13.2percent yield) as a light yellow oil. ESIMS found for C10H8N402 m/z 217.1 (M+H).
13.2%
With tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 100℃; for 1h;Inert atmosphere;
To a solution of 2-(tributylstannyl)pyridine (CI) (9.00 g, 24.5 mmol, 1.0 eq), <strong>[2789-25-5]2-chloro-3-nitropyridin-4-amine</strong> (LXXXI) (4.24 g, 24.5 mmol, 1.0 eq), Pd(PPh3)4 (28.25 g, 24.5 mmol, 1.0 eq) in dioxane (40 mL) was de-gassed and then heated to 100° C. for 1 h under N2. LC/MS showed that half of the starting material was consumed. The mixture was filtered and concentrated in vacuum to give a residue, which was purified by prep-HPLC (Base) to afford the 3-nitro-[2,2?-bipyridin]-4-amine (CII) (0.70 g, 3.24 mmol, 13.2percent yield) as a light yellow oil. ESIMS found for C10H8N4O2 m/z 217.1 (M+H).
13.2%
With tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 100℃; for 1h;Inert atmosphere;
Step 1 To a solution of 2-(tributylstannyl)pyridine (LXXXVI) (9.00 g, 24.5 mmol, 1.0 eq), <strong>[2789-25-5]2-chloro-3-nitropyridin-4-amine</strong> (LXVI) (4.24 g, 24.5 mmol, 1.0 eq), Pd(PPh3)4 (28.25 g, 24.5 mmol, 1.0 eq) in dioxane (40 mL) was de-gassed and then heated to 100° C. for 1 h under N2. LC/MS showed that half of the starting material was consumed. The mixture was filtered and concentrated in vacuum to give a residue, which was purified by prep-HPLC (Base) to afford the 3-nitro-[2,2'-bipyridin]-4-amine (LXXXVII) (0.70 g, 3.24 mmol, 13.2percent yield) as a light yellow oil. ESIMS found for C10H8N4O2 m/z 217.1 (M+H).
3-nitro-2-(piperidin-1-yl)pyridin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75.6%
With potassium carbonate; In N,N-dimethyl-formamide; at 120℃;Inert atmosphere;
To a solution of <strong>[2789-25-5]2-chloro-3-nitropyridin-4-amine</strong> (LXVII) (4.00 g, 23.5 mmol, 1.0 eq) and piperidine (5.89 g, 69.1 mmol, 3.0 eq) in DMF (60 mL) was added K2CO3 (9.56 g, 69.1 mmol, 3.0 eq) in one portion and the mixture was stirred at 120°C under nitrogen overnight. The reaction mixture was diluted with EtOAc (30 mL) and washed with aqueous saturated NaHCO3 solution (80 mL). The organic phases were dried over Na2SO4 and concentrated in vacuo, the resultant residue was purified by silica gel column chromatography (PE:EtOAc = 5: 1?1 : 1) to give 3-nitro-2-(piperidin-1-yl)pyridin-4-amine (XC) (3.87g, 5.42 mmol, 75.6percent yield) as a black oil. ESIMS found for C10H14N4O2 m/z 223.1 (M+H).
75.6%
With potassium carbonate; In N,N-dimethyl-formamide; at 120℃;Inert atmosphere;
j0696j To a solution of <strong>[2789-25-5]2-chloro-3-nitropyridin-4-amine</strong> (LXVIII) (4.00 g, 23.5 mmol, 1.0 eq) and piperidine (5.89 g, 69.1 mmol, 3.0 eq) in DMF (60 mL) was added K2C03 (9.56 g, 69.1 mmol, 3.0 eq) in one portion and the mixture was stirred at 120°C under nitrogen overnight. The reaction mixture was diluted with EtOAc (30 mL) and washed with aqueous saturated NaHCO3 solution (80 mL). The organic phases were dried over Na2504 and concentrated in vacuo, the resultant residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 ?*1:1) to give 3-nitro-2-(piperidin-1-yl)pyridin-4-amine (XCVI) (3.87g, 5.42 mmol, 75.6percent yield) as a black oil. ESIMS found for C10H14N402 m/z 223.1 (M+H).
75.6%
With potassium carbonate; In N,N-dimethyl-formamide; at 120℃;Inert atmosphere;
To a solution of <strong>[2789-25-5]2-chloro-3-nitropyridin-4-amine</strong> (LXXXI) (4.00 g, 23.5 mmol, 1.0 eq) and piperidine (5.89 g, 69.1 mmol, 3.0 eq) in DMF (60 mL) was added K2CO3 (9.56 g, 69.1 mmol, 3.0 eq) in one portion and the mixture was stirred at 120° C. under nitrogen overnight. The reaction mixture was diluted with EtOAc (30 mL) and washed with aqueous saturated NaHCO3 solution (80 mL). The organic phases were dried over Na2SO4 and concentrated in vacuo, the resultant residue was purified by silica gel column chromatography (PE:EtOAc=5:1?1:1) to give 3-nitro-2-(piperidin-1-yl)pyridin-4-amine (CIV) (3.87 g, 5.42 mmol, 75.6percent yield) as a black oil. ESIMS found for C10H14N4O2 m/z 223.1 (M+H).
75.6%
With potassium carbonate; In N,N-dimethyl-formamide; at 120℃;Inert atmosphere;
Step 1 To a solution of <strong>[2789-25-5]2-chloro-3-nitropyridin-4-amine</strong> (LXVI) (4.00 g, 23.5 mmol, 1.0 eq) and piperidine (5.89 g, 69.1 mmol, 3.0 eq) in DMF (60 mL) was added K2CO3 (9.56 g, 69.1 mmol, 3.0 eq) in one portion and the mixture was stirred at 120° C. under nitrogen overnight. The reaction mixture was diluted with EtOAc (30 mL) and washed with aqueous saturated NaHCO3 solution (80 mL). The organic phases were dried over Na2SO4 and concentrated in vacuo, the resultant residue was purified by silica gel column chromatography (PE:EtOAc=5:1?1:1) to give 3-nitro-2-(piperidin-1-yl)pyridin-4-amine (LXXXIX) (3.87 g, 5.42 mmol, 75.6percent yield) as a black oil. ESIMS found for C10H14N4O2 m/z 223.1 (M+H).
2-(4-methylpiperazin-1-yl)-3-nitropyridin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73.2%
at 50℃; for 1h;Microwave irradiation;
A mixture of 1-methylpiperazine (XCVI) (20 mL) and 2-chloro-3- nitropyridin-4 -amine (LXVII) (4.0 g, 23.1 mmol, 1.0 eq) was stirred at 50°C for 1 h under microwave irradiation. The reaction mixture was diluted with water (100 mL) and filtered, the cake was washed with water (30 mL x 3), dried in vacuo to give 2-(4-methylpiperazin-1-yl)-3- nitropyridin-4-amine (XCVII) (4.0 g, 16.9 mmol, 73.2percent yield) as a yellow solid. ESIMS found for C10H15N5O2 m/z 238.1 (M+H).
73%
In ethanol; for 2h;Reflux;
General procedure: The suitable amine (6.3 mmol) was added into a solution of compound 5 (2.9 mmol) in absolute ethanol (10 mL) and this mixture was refluxed for 2 h. Upon completion of the reaction, the organic solvent was removed under reduced pressure, water was added to the residue and the precipitate was filtered in vacuo, washed with water and air-dried, to provide the pure aminosubstituted derivatives 13a?d.
73.2%
at 50℃; for 1h;Microwave irradiation;
j0702j A mixture of 1 -methylpiperazine (CII) (20 mL) and 2-chloro-3-nitropyridin- 4-amine (LXVIII) (4.0 g, 23.1 mmol, 1.0 eq) was stirred at 50°C for 1 h under microwaveirradiation. The reaction mixture was diluted with water(100 mL) and filtered, the cake was washed with water (30 mL x 3), dried in vacuo to give 2-(4-methylpiperazin-1-yl)-3-nitropyridin-4-amine (CIII) (4.0 g, 16.9 mmol, 73.2percent yield) as a yellow solid. ESIMS found for C,0H,5N502 m/z 238.1 (M+H).
73.2%
at 50℃; for 1h;Microwave irradiation;
A mixture of 1-methylpiperazine (CXII) (20 mL) and <strong>[2789-25-5]2-chloro-3-nitropyridin-4-amine</strong> (LXXXI) (4.0 g, 23.1 mmol, 1.0 eq) was stirred at 50° C. for 1 h under microwave irradiation. The reaction mixture was diluted with water (100 mL) and filtered, the cake was washed with water (30 mL×3), dried in vacuo to give 2-(4-methylpiperazin-1-yl)-3-nitropyridin-4-amine (CXIII) (4.0 g, 16.9 mmol, 73.2percent yield) as a yellow solid. ESIMS found for C10H15N5O2 m/z 238.1 (M+H).
73.2%
at 50℃; for 1h;Microwave irradiation;
Step 1 A mixture of 1-methylpiperazine (XCV) (20 mL) and <strong>[2789-25-5]2-chloro-3-nitropyridin-4-amine</strong> (LXVI) (4.0 g, 23.1 mmol, 1.0 eq) was stirred at 50° C. for 1 h under microwave irradiation. The reaction mixture was diluted with water (100 mL) and filtered, the cake was washed with water (30 mL*3), dried in vacuo to give 2-(4-methylpiperazin-1-yl)-3-nitropyridin-4-amine (XCVI) (4.0 g, 16.9 mmol, 73.2percent yield) as a yellow solid. ESIMS found for C10H15N5O2 m/z 238.1 (M+H).
N-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl) methanesulfonamide[ No CAS ]
N-(3-(4-amino-3-nitropyridin-2-yl)-5-fluorobenzyl)methanesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
3 g
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 100℃; for 10h;Inert atmosphere;
A solution of N-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzyl)methanesulfonamide (CII) (5.00 g, 15.19 mmol, 1.0 eq) and 2-chloro-3-nitropyridin-4- amine (LXVII) (2.64 g, 15.19 mmol, 1.0 eq), Cs2CO3 (9.90 g, 30.4 mmol, 2.0 eq) was dissolved in dioxane (40 mL) and water (8 mL). Then Pd(dppf)Ci2 (1.13 g, 1.52 mmol, 0.1 eq) was added to the mixture. The mixture was stirred at 100°C for 10 h under N2. The solvent was removed to get the residue which was purified by silica column to get N-(3-(4-amino-3-nitropyridin-2-yl)-5- fluorobenzyl)methanesulfonamide (CIII) (3.00 g, 8.81 mmol, 58.0percent yield) as an oil. ESIMS found C13H13FN4O4S m/z 341.1 (M+H).
3.0 g
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 100℃; for 10h;Inert atmosphere;
j0708j A solution of N-(3 -fluoro-5 -(4,4,5,5 -tetramethyl- 1,3 ,2-dioxaborolan-2- yl)benzyl) methanesulfonamide (C VIII) (5.00 g, 15.19 mmol, 1.0 eq) and 2-chloro-3-nitropyridin- 4-amine (LXVIII) (2.64 g, 15.19 mmol, 1.0 eq), Cs2CO3 (9.90 g, 30.4 mmol, 2.0 eq) was dissolved in dioxane (40 mL) and water (8 mL). Then Pd(dppf)C12 (1.13 g, 1.52 mmol, 0.1 eq) was added to the mixture. The mixture was stirred at 100°C for 10 h under N2. The solvent was removed to get the residue which was purified by silica column to get N-(3-(4-amino-3-nitropyridin-2-yl)-5- fluorobenzyl)methanesulfonamide (CIX) (3.00 g, 8.81 mmol, 58.0percent yield) as an oil. ESIMS found C13H13FN4045 mlz 341.1 (M+H).
3.00 g
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 100℃; for 10h;
A solution of N-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)methanesulfonamide (CXVIII) (5.00 g, 15.19 mmol, 1.0 eq) and <strong>[2789-25-5]2-chloro-3-nitropyridin-4-amine</strong> (LXXXI) (2.64 g, 15.19 mmol, 1.0 eq), Cs2CO3 (9.90 g, 30.4 mmol, 2.0 eq) was dissolved in dioxane (40 mL) and water (8 mL). Then Pd(dppf)Cl2 (1.13 g, 1.52 mmol, 0.1 eq) was added to the mixture. The mixture was stirred at 100° C. for 10 h under N2. The solvent was removed to get the residue which was purified by silica column to get N-(3-(4-amino-3-nitropyridin-2-yl)-5-fluorobenzyl)methanesulfonamide (CXIX) (3.00 g, 8.81 mmol, 58.0percent yield) as an oil. ESIMS found C13H13FN4O4S m/z 341.1 (M+H).
3 g
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 100℃; for 10h;Inert atmosphere;
Step 4 A solution of N-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzyl)methanesulfonamide (CI) (5.00 g, 15.19 mmol, 1.0 eq) and <strong>[2789-25-5]2-chloro-3-nitropyridin-4-amine</strong> (LXVI) (2.64 g, 15.19 mmol, 1.0 eq), Cs2CO3 (9.90 g, 30.4 mmol, 2.0 eq) was dissolved in dioxane (40 mL) and water (8 mL). Then Pd(dppf)Cl2 (1.13 g, 1.52 mmol, 0.1 eq) was added to the mixture. The mixture was stirred at 100° C. for 10 h under N2. The solvent was removed to get the residue which was purified by silica column to get N-(3-(4-amino-3-nitropyridin-2-yl)-5-fluorobenzyl)methanesulfonamide (CII) (3.00 g, 8.81 mmol, 58.0percent yield) as an oil. ESIMS found C13H13FN4O4S m/z 341.1 (M+H).
2-(morpholin-4-yl)-3-nitropyridin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
In ethanol; for 2h;Reflux;
General procedure: The suitable amine (6.3 mmol) was added into a solution of compound 5 (2.9 mmol) in absolute ethanol (10 mL) and this mixture was refluxed for 2 h. Upon completion of the reaction, the organic solvent was removed under reduced pressure, water was added to the residue and the precipitate was filtered in vacuo, washed with water and air-dried, to provide the pure aminosubstituted derivatives 13a?d.
N2-[2-(dimethylamino)ethyl]-3-nitropyridine-2,4-diamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
In ethanol; for 2h;Reflux;
General procedure: The suitable amine (6.3 mmol) was added into a solution of compound 5 (2.9 mmol) in absolute ethanol (10 mL) and this mixture was refluxed for 2 h. Upon completion of the reaction, the organic solvent was removed under reduced pressure, water was added to the residue and the precipitate was filtered in vacuo, washed with water and air-dried, to provide the pure aminosubstituted derivatives 13a?d.
General procedure: The suitable amine (6.3 mmol) was added into a solution of compound 5 (2.9 mmol) in absolute ethanol (10 mL) and this mixture was refluxed for 2 h. Upon completion of the reaction, the organic solvent was removed under reduced pressure, water was added to the residue and the precipitate was filtered in vacuo, washed with water and air-dried, to provide the pure aminosubstituted derivatives 13a?d.
95%
In ethanol; at 60℃;Reflux;
To a solution of <strong>[2789-25-5]2-chloro-3-nitro-4-aminopyridine</strong> (6.00 g, 0.035 mol) in absolute ethanol (50 mL), benzylamine (3.7 g, 0.035 mol) was added, and the mixture was heated and refluxed for 60 minutes. . After completion of the reaction, cooling, concentration under reduced pressure, the residue was poured into water, stirred for 15 minutes, filtered, and the solid was collected and washed with water.Drying gave a brown solid product (8.0 g, 95percent).
2-(3,5-dimethoxyphenoxy)-3-nitropyridin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With caesium carbonate; In tetrahydrofuran; at 70℃; for 12h;Inert atmosphere;
3,5-Dimethoxyphenol (450 mg, 2.9 mmol) and cesium carbonate (940 mg, 2.9 mmol) were added into a solution of compound 5 (500 mg, 2.9 mmol) in tetrahydrofuran (20 mL), under argon, and this mixture was heated at 70 °C for 12 h. Upon completion of the reaction, the organic solvent was removed under reduced pressure, water was added to the residue and the precipitate was filtered in vacuo, washed with water and air-dried, to provide the pure phenoxy derivative 13e, as a pale yellow solid in 89percent yield. Mp 166-7 °C (EtOAc). 1H NMR (600 MHz, DMSO-d6) delta 7.64 (d, 1H, J = 5.7 Hz, H-6), 7.43 (br s, 2H, D2O exch, NH2), 6.59 (d, 1H, J = 5.7 Hz, H-5), 6.35 (s, 1H, H-4'), 6.27 (s, 2H, H-2', H-6'), 3.71 (s, 6H, 2xOCH3). 13C NMR (151 MHz, DMSO-d6) delta 160.89 (C-3', C-5'), 156.49 (C-2), 154.90 (C-4), 150.77 (C-1'), 147.39 (C-6), 120.61 (C-3), 108.63 (C-5), 99.98 (C-2', C-6'), 97.07 (C-4'), 55.43 (2xOCH3). HR-MS (ESI) m/z: Calcd for C13H14N3O5: [M1+H]+ = 292.0928, found 292.0924. Anal. Calcd for C13H13N3O5: C, 53.61; H, 4.50; N, 14.43. Found: C, 53.78; H, 4.55; N, 14.37.
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