* 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.
step 1 : To a solution of 2-chloro-5-nitropyridin-4-amine (4.50 g, 25.93 mmol) in EtOAc (100 mL) was added Raney nickel (0.45 g) followed by stirring under hydrogen at RT for 2 h. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to afford 4.00 g (ca. 100percent) of crude 6- chloropyridine-3,4-diamine as yellow oil. MS (ESI): m/z = 144.3 [M+l]+.
Reference：
[1] Patent: US2004/116466, 2004, A1,
[2] Roczniki Chemii, 1956, vol. 30, p. 1139,1145[3] Chem.Abstr., <1957> 12089,
[4] Journal of Heterocyclic Chemistry, 1965, vol. 2, p. 196,200
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
[ 4487-56-3 ]
[ 2604-39-9 ]
Yield
Reaction Conditions
Operation in experiment
86%
With ammonia In methanol at 25 - 28℃; for 18 h;
A solution of 2,4-dichloro-5-nitropyridine (3 g, 15 mmol) in methanolic ammonia (15 mL) was stirred at 25-28°C for 18 h. The reaction mixture was concentrated by evaporation in vacuo, then the residue was isolated by filtration and purified by hexane wash (3 x 30 mL), to provide the title compound (2.3 g, 86percent) as a yellow solid. H (400MHz, DMSO-d6) 8.83 (s, 1H), 7.35 (br s, 2H), 7.03 (s, 1H). LCMS (ES+) 173.95 (M+H), RT 1.46 minutes.
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
6
[ 14432-12-3 ]
[ 2604-39-9 ]
Yield
Reaction Conditions
Operation in experiment
8.89%
at 0 - 100℃; for 2.5 h;
To a solution of 2-chloropyridin-4-amine (10 g, 78 mmol) in conc. sulfuric acid (60 mL) at 0° C. was slowly added fuming nitric acid (30 mL). Then reaction mixture was stirred for 30 min. The reaction mixture was slowly poured into ice; the pH was adjusted to ˜3 with using ammonia solution. The resultant white solid was isolated via filtration. The solid was dissolved in conc. sulfuric acid, then heated to 100° C. for 2 h. The reaction mixture was cooled to room temperature and poured into ice. The aqueous solution was adjusted to pH ˜3 using ammonia solution; then was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant residue was purified by silica gel chromatography using 30percent ethyl acetate in Pet-ether to afford 2-chloro-5-nitropyridin-4-amine (1.2 g, 6.91 mmol, 8.89percent yield) and 2-chloro-3-nitropyridin-4-amine (6 g, 34.6 mmol, 44.4percent yield) as yellow solids. 1H NMR (400 MHz, DMSO-d6): δ ppm 7.90 (d, J=5.77 Hz, 1H) 7.34 (br. s., 2H) 6.83 (s, 1H). MS: MS m/z 172.2 (M+-1).
Reference：
[1] Patent: US9643999, 2017, B2, . Location in patent: Page/Page column 80; 81
[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
[5] Patent: US2014/127156, 2014, A1, . Location in patent: Page/Page column
Reference：
[1] Chemical Communications, 1998, # 15, p. 1519 - 1520
9
[ 109-09-1 ]
[ 2604-39-9 ]
[ 2789-25-5 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 22, p. 5941 - 5952
10
[ 2402-95-1 ]
[ 2604-39-9 ]
[ 2789-25-5 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 22, p. 5941 - 5952
11
[ 14432-16-7 ]
[ 2604-39-9 ]
[ 2789-25-5 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 22, p. 5941 - 5952
12
[ 4548-45-2 ]
[ 4214-76-0 ]
[ 2604-39-9 ]
[ 5418-51-9 ]
[ 27048-04-0 ]
Reference：
[1] Journal of Organic Chemistry, 1985, vol. 50, # 4, p. 484 - 487
[2] Journal of Organic Chemistry, 1985, vol. 50, # 4, p. 484 - 487
13
[ 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
14
[ 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
15
[ 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
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
20
[ 4548-45-2 ]
[ 2604-39-9 ]
[ 27048-04-0 ]
Reference：
[1] Chemical Communications, 1998, # 15, p. 1519 - 1520
21
[ 4548-45-2 ]
[ 4214-76-0 ]
[ 2604-39-9 ]
[ 5418-51-9 ]
[ 27048-04-0 ]
Reference：
[1] Journal of Organic Chemistry, 1985, vol. 50, # 4, p. 484 - 487
[2] Journal of Organic Chemistry, 1985, vol. 50, # 4, p. 484 - 487
Reference：
[1] Synlett, 2010, # 18, p. 2759 - 2764
24
[ 2604-39-9 ]
[ 1268521-33-0 ]
Yield
Reaction Conditions
Operation in experiment
580 mg
at 60℃; for 4 h;
NBS (564 mg, 3.17 mmol) was added to a solution of 1 (500 mg, 2.88 mmol) in 8 mL of AcOH. The resulting mixture was stirred at 60 °C for 4 h. After cooled to room temperature, the mixture was diluted with water. The precipitate was collected by filtration to afford 580 mg of 2 as a yellow solid, which was used in the next step without further purification. [M+Hj : 251.91, 253.96.
2,4-Diamino-5-nitropyridine (5): A solution of <strong>[2604-39-9]4-amino-2-chloro-5-nitropyridine</strong> (4) (1.0 g, 5.76 mmol) in 50 ml 28percent NH4OH was heated in a sealed tube at 120° C. for overnight. After cooling the reaction mixture to room temperature afforded orange red solid 5 (0.770 g, 77percent). 1H NMR (DMSO-d6, 500 MHz): delta 8.66 (1H, s), 7.35 (1H, br s), 6.73 (1H, brs), 5.67 (1H, s); EIMS m/z: 155.2 (M+1), 153.2 (M-1)
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).
With sulfuric acid; nitric acid; at 0 - 100℃; for 2.5h;
To a solution of 2-chloropyridin-4-amine (10 g, 78 mmol) in conc. sulfuric acid (60 mL) at 0° C. was slowly added fuming nitric acid (30 mL). Then reaction mixture was stirred for 30 min. The reaction mixture was slowly poured into ice; the pH was adjusted to ?3 with using ammonia solution. The resultant white solid was isolated via filtration. The solid was dissolved in conc. sulfuric acid, then heated to 100° C. for 2 h. The reaction mixture was cooled to room temperature and poured into ice. The aqueous solution was adjusted to pH ?3 using ammonia solution; then was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant residue was purified by silica gel chromatography using 30percent ethyl acetate in Pet-ether to afford 2-chloro-5-nitropyridin-4-amine (1.2 g, 6.91 mmol, 8.89percent yield) and 2-chloro-3-nitropyridin-4-amine (6 g, 34.6 mmol, 44.4percent yield) as yellow solids. 1H NMR (400 MHz, DMSO-d6): delta ppm 7.90 (d, J=5.77 Hz, 1H) 7.34 (br. s., 2H) 6.83 (s, 1H). MS: MS m/z 172.2 (M+-1).
With ammonia; nitric acid; In sulfuric acid;
Step 1: Synthesis of 2-chloro-5-nitropyridin-4-amine To a solution of 2-chloropyridin-4-amine (10 g, 78 mmol) in conc. sulfuric acid (60 mL) at 0° C. was slowly added fuming nitric acid (30 mL). Then reaction mixture was stirred for 30 min. The reaction mixture was slowly poured into ice; the pH was adjusted to ?3 with using ammonia solution. The resultant white solid was isolated via filtration. The solid was dissolved in conc. sulfuric acid, then heated to 100° C. for 2 h. The reaction mixture was cooled to room temperature and poured into ice. The aqueous solution was adjusted to pH ?3 using ammonia solution; then was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant residue was purified by silica gel chromatography using 30percent ethyl acetate in Pet-ether to afford 2-chloro-5-nitropyridin-4-amine (1.2 g, 6.91 mmol, 8.89percent yield) and 2-chloro-3-nitropyridin-4-amine (6 g, 34.6 mmol, 44.4percent yield) as yellow solids. 1H NMR (400 MHz, DMSO-d6): delta ppm 7.90 (d, J=5.77 Hz, 1H) 7.34 (br. s., 2H) 6.83 (s, 1H). MS: MS m/z 172.2 (M+-1).
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%.
Compound 8; In a microwave tube, a solution of <strong>[2604-39-9]4-amino-2-chloro-5-nitropyridine</strong> (prepared, as described for compound 9) (200 mg; 1.16 mmol) in ethanol (2 ml) was treated sequentially with dimethylamine hydrochloride (471 mg; 5.78 mmol) and triethylamine (781 mu\\; 6.96 mmol). The tube was quickly sealed and irradiated in the microwave (CEM Discover, 150 W, 85 0C, 10 min). The ethanol was evaporated, dichloromethane (15 ml) was added to dissolve the products, and the solution washed with IM sodium hydroxide solution (2 x 10 ml). The organic layer was dried (sodium sulphate), the mixture filtered and the filtrate evaporated to dryness to afford N2,N2-dimethyl-5-nitro-pyridine-2,4-diamine (240 mg, 114percent).
Compound 9; To stirred concentrated sulphuric acid (100 ml) at 4 0C was added 2-chloro-4- aminopyridine (35.0 g; 0.273 mol) in portions. White fuming nitric acid (26 ml) was added drop wise over 20 minutes and the mixture stirred at 4 0C for 1 hour before being poured onto ice (1 L). The resultant mixture was taken to pH 2 with 6 M NaOH at which point a thick precipitate formed. This was filtered, washed with water and dried in air to afford the nitramine intermediate which was used in the next step without further purification.A solution of the nitramine (42 g) in concentrated sulphuric acid (100 ml) was heated at 85 0C for 2 hours, then at 110 0C for a further 1 hour. The mixture was cooled, poured into ice (IL) and basified with concentrated ammonia solution to pH 9. The resultant suspension was filtered and the solid washed with water. The solid was then extracted with hot toluene (3 x 250 ml), and the combined extracts evaporated and chromatographed (heptane: ethyl acetate 9:2) to afford 2-chloro-4- amino-5-nitropyridine as a white solid (4.57g, 10percent);
316.2 g of this intermediate compound are treated with 2.35 I concentrated sulfuric acid and stirred for 30 minutes at 88-94 °C. The mixture is cooled to room temperature and poured into 2 I of water containing 5 kg ice. 6.5 125percent (w/v) aqueous NH3 solution is slowly added. The resulting precipitate is filtered and pre-dried under reduced pressure. Finally the residue is dried by azeotropic distillation with benzene. After crystallization from benzene the title compound is obtained. 1H NMR (200 MHz, D6-DMSO): delta = 6.96 (s, 1 H), 8.07 (bs, 2H), 8.84 (s, 1 H).
2-Methoxy-5-nitropyridin-4-amine To a suspension of 36.9 g of <strong>[2604-39-9]2-chloro-5-nitropyridin-4-amine</strong> (example E6) in 500 ml methanol is added 250 ml of a freshly prepared solution of sodium methoxide in methanol (5.7 g sodium) and the reaction mixture is refluxed for 12 h. About 500 ml methanol are distilled off and 500 ml of water are added. The resulting precipitate is filtered, washed with ice water and dried under vacuum to the title compound. 1H NMR (400 MHz, D6-DMSO): delta = 8.82 (s, 1 H), 7.65 (bs, 2H), 6.15 (s, 1 H), 3.85 (s, 3H).
step 1 : To a solution of 2-chloro-5-nitropyridin-4-amine (4.50 g, 25.93 mmol) in EtOAc (100 mL) was added Raney nickel (0.45 g) followed by stirring under hydrogen at RT for 2 h. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to afford 4.00 g (ca. 100percent) of crude 6- chloropyridine-3,4-diamine as yellow oil. MS (ESI): m/z = 144.3 [M+l]+.
With hydrogen;palladium 10% on activated carbon; In ethanol; for 12h;
A suspension of 1.04 g of 2-chloro-5-nitropyridin-4-amine (example E6) in 100 ml ethanol is treated with 50 mg Pd/C (10percent Pd) and hydrogenated for 12 h under atmospheric pressure. The reaction mixture is filtered through a plug of celite and the filtrate is concentrated under vacuum. The resulting oil is treated with 4 ml diethoxymethyl acetate and stirred for 2 h at room temperature and for one hour at 90 °C. The reaction mixture is allowed to cool down to room temperature, 20 ml dichloromethane is added and the organic layer is extracted with water (4 x 20 ml). The combined aqueous layers are concentrated to a volume of 10 ml and purified by preparative HPLC to yield the title compound. 1H NMR (200 MHz, D6-DMSO): delta = 7.69 (d, J = 0.8 Hz, 1 H), 8.46 (s, 1 H), 8.75 (d, J = 0.8 Hz, 1 H), 13.0 (bs, 1 H). MS (MH+ found) = 154.1
A mixture of 169A (995 mg, 5.75 mmol), di-tert-butyl dicarbonate (1.50 g, 6.90 mmol) and DMAP (140 mg, 1.15 mmol) in 60 mL of CH2Cl2 was stirred for 1 hr. The reaction mixture was diluted with CH2Cl2 and washed with 1 N HCl (2X), sat'd NaCl and dried over Na2SO4. Concentration in vacuo gave 1.54 g of 169B.
With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 110℃; for 16h;Inert atmosphere;
To a 200 ml flask was added 4-amino-2-chloro-5-nitropyridine (1.00 g, 5.76 mmol), <strong>[461-98-3]4-amino-2,6-dimethylpyrimidine</strong> (1.42 g, 11.5 mmol), Pd2(dba)3 (0.528 g, 0.576 mmol), XantPhos (0.400 g, 0.691 mmol), Cs2CO3 (4.13 g, 12.7 mmol) and dioxane (45 mL). The mixture was degassed with N2 for 2 min and then heated at 110° C. for 16 hrs. After cooling to room temperature the reaction was filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-10percent methanol/dichloromethane) to give N-(2,6-dimethylpyrimidin-4-yl)-5-nitropyridine-2,4-diamine (0.348 g, yield: 23percent). LCMS (ESI) m/z: 261.2 [M+H+].
Into a 50-mL sealed tube, were placed a solution of <strong>[2604-39-9]2-chloro-5-nitropyridin-4-amine</strong> (500 mg, 2.88 mmol) in N,N- dimethylformamide (20 niL) and morpholine (503 mu,, 5.77 mmol). The reaction mixture was stirred overnight at 55 °C. The reaction was then quenched by the addition of 100 mL of water. The reaction mixture was extracted with 3 x 150 mL of ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. This resulted in 733 mg (crude) of the title compound as a yellow solid.
In N,N-dimethyl-formamide; at 55℃;Sealed tube;
Compound 151.1. 2-(Morpholin-4-yl)-5-nitropyridin-4-amine. Into a 50-mL sealed tube, were placed a solution of <strong>[2604-39-9]2-chloro-5-nitropyridin-4-amine</strong> (500 mg, 2.88 mmol) in NN- dimethylformamide (20 mL) and morpholine (503 iL, 5.77 mmol). The reaction mixture was stirred overnight at 55 °C. The reaction was then quenched by the addition of 100 mL of water. The reaction mixture was extracted with 3 x 150 mL of ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. This resulted in 733 mg (crude) of the title compound as a yellow solid.
Step 2: Synthesis of 2-methoxy-5-nitropyridin-4-amine To a solution of <strong>[2604-39-9]2-chloro-5-nitropyridin-4-amine</strong> (0.5 g, 2.88 mmol) in Methanol was added and sodium methoxide (0.233 g, 4.32 mmol) under nitrogen atmosphere and heated to reflux at t 70° C. for 3 h. Removed the volatiles under reduced pressure, quenched by pouring into ice water, filtered the resulting precipitate, washed with cold water and dried to afford 2-methoxy-5-nitropyridin-4-amine (0.4 g, 2.247 mmol, 78percent yield) as pale yellow solid. MS: MS m/z 170.2 (M++1).
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 90℃;Inert atmosphere;
To a solution of 58 (1.00 g, 5.76 mmol) in 1,4-dioxane (40 mL) and water (4 mL) was added 3,5-dirnethyl-4-(4,4,5,5-tetrarrethy -l,3/2--dioxaboroian-2-yi)isoxazoe (1.93 g, 8.64 mmol), potassium carbonate (1.59 g, 11.5 mmol), and tetrakis(triphenylphosphine)pailadium(0) (333 mg, 0.288 mmol). The reaction mixture was purged with nitrogen and heated at 90 °C overnight. The reaction mixture was cooled to room temperature, concentrated and purified bychromatography (silica gel, 0-100percent ethyl acetate in hexanes) to afford 59 (1.42 g, >99percent) as a yellow solid: H N (300 MHz, CDCI3) delta 9.26 (s, 1H), 6.67 (s, 1H), 6.90-6.00 (bs, 2H), 2.61 (s, 3H), 2.44 (s, 3H); ESI m/z 235 IM + H]+.
A solution of 2,4-dichloro-5-nitropyridine (3 g, 15 mmol) in methanolic ammonia (15 mL) was stirred at 25-28°C for 18 h. The reaction mixture was concentrated by evaporation in vacuo, then the residue was isolated by filtration and purified by hexane wash (3 x 30 mL), to provide the title compound (2.3 g, 86percent) as a yellow solid. H (400MHz, DMSO-d6) 8.83 (s, 1H), 7.35 (br s, 2H), 7.03 (s, 1H). LCMS (ES+) 173.95 (M+H), RT 1.46 minutes.
2-chloro-N-[(2,5-dichlorophenyl)methyl]-5-nitropyridin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
35%
With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0 - 28℃; for 18h;
To a stirred solution of Intermediate 1 (3 g, 17.3 mmol) in dry DMF (15 mL) was added NaH (40percent dispersion in oil, 0.832 g, 20.8 mmol) at 0°C, followed by the addition of <strong>[85482-13-9]2,5-dichlorobenzyl bromide</strong> (1.13 g, 17.3 mmol). The reaction mixture was stirred at 25-28°C for 18 h, then quenched with ice water and extracted with ethyl acetate (4 x 30mL). The combined organic layers were dried over Na2504 and concentrated by evaporation in vacuo. The residue was purified by column chromatography (100-200 mesh silica), using 10percent ethyl acetate in hexane as eluent, to obtain the title compound (2 g, 35percent) as a yellow solid. H (400 MHz, DMSO-d6) 8.98 (br s, 1H), 8.92 (s, 1H), 7.55 (d, J8 Hz, 1H), 7.43-7.41 (m, 2H), 6.94 (s,1H), 4.72 (d,J6 Hz, 2H). LCMS (ES+) 331.85(M+H), RT 2.80 minutes.
tert-butyl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-7-ethyl-2-((7-methoxy-2-(trifluoromethyl)pyrido[3,4-b]pyrazin-3-yl)oxy)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a, 14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate[ No CAS ]
tert-butyl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-7-ethyl-2-((2-hydroxy-7-methoxypyrido[3,4-b]pyrazin-3-yl)oxy)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate[ No CAS ]
To a solution of <strong>[2604-39-9]2-chloro-5-nitropyridin-4-amine</strong> (0.5 g, 2.88 mmol) in Methanol was added and sodium methoxide (0.233 g, 4.32 mmol) under nitrogen atmosphere and heated to reflux at t 70° C. for 3 h. Removed the volatiles under reduced pressure, quenched by pouring into ice water, filtered the resulting precipitate, washed with cold water and dried to afford 2-methoxy-5-nitropyridin-4-amine (0.4 g, 2.247 mmol, 78percent yield) as pale yellow solid. MS: MS m/z 170.2 (M++1).
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 20℃; for 4h;
To a solution of <strong>[2604-39-9]2-chloro-5-nitropyridin-4-amine</strong> (5.0 g, 28.8 mmol, 1.0 eq.) in DMF (20 mL) was added NBS (6.16 g, 34.6 mmol, l.2 eq.) in several portions. After stirring at room temperature for 4 hrs, most of the solvent was removed under reduced pressure, the residue was suspended in cool water (30 mL), and the solid was filtered and dried under reduced pressure to give 3- bromo-<strong>[2604-39-9]2-chloro-5-nitropyridin-4-amine</strong> (6.2 g, 85% yield) as an off-white solid. LC-MS (ESI): m/z 252, 254 [M+H]+.
580 mg
With N-Bromosuccinimide; acetic acid; at 60℃; for 4h;
NBS (564 mg, 3.17 mmol) was added to a solution of 1 (500 mg, 2.88 mmol) in 8 mL of AcOH. The resulting mixture was stirred at 60 C for 4 h. After cooled to room temperature, the mixture was diluted with water. The precipitate was collected by filtration to afford 580 mg of 2 as a yellow solid, which was used in the next step without further purification. [M+Hj : 251.91, 253.96.
The compound <strong>[2604-39-9]2-chloro-5-nitropyridin-4-amine</strong> 34a (500 mg, 2.88 mmol), sodium methanethiolate (2.02 g, 28.8 mmol) and methanol (15 ml) were mixed at room temperature. After stirring for 15 hours, The solvent was removed under reduced pressure, the residue was dissolved in ethyl acetate (100ml) and washed with water (50ml). The separated aqueous phase was extracted with additional ethyl acetate (100 mL). The organic phases were combined, dried over anhydrous sodium sulfate. After filtration, the filtrate solvent was removed under reduced pressure to give a yellow solid. The yellow solid was dissolved in tetrahydrofuran (120 mL).Then trifluoroacetic acid (16 ml) and m-chloroperoxybenzoic acid (5.56 g, 32.32 mmol) were added carefully.After stirring at room temperature for 20 minutes, most of the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate (400ml), and washed sequentially with saturated sodium bicarbonate solution (200ml) and saturated sodium chloride solution (200ml) and washed. The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate solvent was removed under reduced pressure, To give the desired product 2-methanesulfonyl-5-nitro-4-amine 34b (2.08g, yellow solid), yield: 89%
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