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With sodium carbonate In water; toluene at 100℃; for 16 h;
a) 2-Phenyl-pyridin-4-ylamine To a stirred solution of 16.0 g (124 mmol) 2-chloro-4-aminopyridine in 200 ml toluene were added 18.2 g (149 mmol) phenylboronic acid, 7.19 g (6.22 mmol) tetrakis(triphenylphosphine)palladium(0) and 130 ml (260 mmol) 2 M aq. sodium carbonate solution. The mixture was heated at 100° C. for 16 h and then cooled to room temperature and extracted three times with ethyl acetate. The combined organic phases were extracted three times with 200 ml 1 M aq. hydrochloric acid. The combined acid extracts were then made alkaline by addition of 5 M aq. sodium hydroxide solution and extracted three times with dichloromethane. The combined organic extracts were dried over sodium sulfate, and concentrated in vacuo. Flash chromatography (acetone) followed by trituration in hexane containing a little ether afforded 18.5 g (87percent) 2-phenyl-pyridin-4-ylamine as a white solid. ES-MS m/e (percent): 171 (M+H+, 100).
75%
at 90℃; for 14 h; Sealed tube
A mixture of 4-chloropyridin-2-amine (64 g, 498 mmol), phenyl boronic acid (61 g, 500 mmol), Na2CO3 (159 g, 1.5 mol), Pd(PPh3)4 (6.4 g) in H20/EtOHJtoluene (500 mL) was heated to 90 °C in sealed vessel for 14 h. The crude mixture was cooled, filtered, and concentrated under reduced pressure. Purification (FCC, 5i02,PE:EtOAc (100:1) afforded the title compound (64 g, 75percent).
71%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In N,N-dimethyl-formamide at 110℃; for 16 h;
To a stirred solution of 2-chloropyridin-4-amine (64.0 g, 498 mmol) in toluene (800 mL) were added phenylboronic acid (72.9 g, 597 mmol), Pd(PPh3)4(28.8 g, 24.9 mmol), Na2C03(105.5 g, 995.6 mmol), and water (500 mL) and was heated at 100 °C for 16 hours. The reaction was cooled to room temperature, extracted three times with ethyl acetate, and the combined organic phases were concentrated to dryness. The residue was purified by normal phase flash column chromatography (S1O2) to give the title compound (60 g, 71percent yield) as a white solid.
Reference：
[1] Organic and Biomolecular Chemistry, 2014, vol. 12, # 38, p. 7598 - 7602
[2] Angewandte Chemie - International Edition, 2006, vol. 45, # 21, p. 3484 - 3488
[3] Advanced Synthesis and Catalysis, 2018, vol. 360, # 20, p. 3990 - 3998
[4] Patent: US2005/65151, 2005, A1, . Location in patent: Page/Page column 8; 19
[5] Advanced Synthesis and Catalysis, 2009, vol. 351, # 17, p. 2912 - 2920
[6] Patent: WO2018/103060, 2018, A1, . Location in patent: Page/Page column 116
[7] Patent: WO2017/100668, 2017, A1, . Location in patent: Page/Page column 567; 568
[8] Tetrahedron Letters, 2005, vol. 46, # 20, p. 3573 - 3577
[9] Advanced Synthesis and Catalysis, 2013, vol. 355, # 11-12, p. 2274 - 2284
[10] New Journal of Chemistry, 2017, vol. 41, # 24, p. 15420 - 15432
4
[ 14432-12-3 ]
[ 108-90-7 ]
[ 21203-86-1 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2017, vol. 359, # 4, p. 616 - 622
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%.
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