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USD 0.00
Limited Quantity
USD 15-60
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USD 80+
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Structure of 142-08-5 * Storage: {[proInfo.prStorage]}
* 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] Journal of Physical Chemistry, 1980, vol. 84, # 20, p. 2548 - 2551
3
[ 142-08-5 ]
[ 13466-38-1 ]
Reference：
[1] Patent: US5939439, 1999, A,
[2] Patent: WO2018/193387, 2018, A1, . Location in patent: Page/Page column 107
4
[ 142-08-5 ]
[ 13466-38-1 ]
[ 13466-43-8 ]
Reference：
[1] Synthesis, 2001, # 14, p. 2175 - 2179
5
[ 142-08-5 ]
[ 13472-79-2 ]
Reference：
[1] Asian Journal of Chemistry, 2011, vol. 23, # 1, p. 41 - 43
[2] Journal of Heterocyclic Chemistry, 2015, vol. 52, # 4, p. 1062 - 1074
[3] Journal of Organic Chemistry, 1990, vol. 55, # 18, p. 5287 - 5291
6
[ 142-08-5 ]
[ 13472-79-2 ]
Reference：
[1] Chemische Berichte, 1925, vol. 58, p. 116[2] Chem. Zentralbl., 1928, vol. 99, # I, p. 64
7
[ 142-08-5 ]
[ 5154-01-8 ]
Reference：
[1] Journal of the American Chemical Society, 1958, vol. 80, p. 3717
8
[ 142-08-5 ]
[ 19365-07-2 ]
Reference：
[1] Archiv der Pharmazie (Weinheim, Germany), 1984, vol. 317, # 4, p. 304 - 306
9
[ 142-08-5 ]
[ 69045-79-0 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 2015, vol. 52, # 4, p. 1062 - 1074
10
[ 142-08-5 ]
[ 13466-43-8 ]
Yield
Reaction Conditions
Operation in experiment
78%
With bromine; potassium bromide In water at 20℃; for 24.25 h;
3-l3romo-pyridin-2-ol. A stirred suspension of 2-pyridone (77-0, 19 g, 200 mmol) in 200 mE of 1 M aqueous K13r at room temperature was treated over 15 mm with bromine (32 g, 200 mmol; CAUTION: Large quantities of 13r2 should be handled careffilly) in 200 mE of 1 M aqueous K13r, then stirred vigorously at room temperature 0/N. After 24 h, this solution deposited crystals which were filtered off and then recrystallized from acetonitrile to give 27.2 g (78percent) of 3-bromo- pyridin-2-ol. (77-1) [J. Am. Chem. Soc. 1982, 104, 4142- 4146; Bioorg. Med. Chem. Lett. 2002, 12, 197-200; JMed Chem. 1979, 22, 1284-1290.] Molecular weight calcd. for C5H4I3rNO: 173; (M+H) found: 174
Reference：
[1] Patent: US2018/110824, 2018, A1, . Location in patent: Paragraph 0497; 0498; 0499
[2] Patent: US6110914, 2000, A,
11
[ 142-08-5 ]
[ 13466-38-1 ]
[ 13466-43-8 ]
Reference：
[1] Synthesis, 2001, # 14, p. 2175 - 2179
12
[ 142-08-5 ]
[ 16867-04-2 ]
Reference：
[1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1985, vol. 24, p. 972 - 973
13
[ 142-08-5 ]
[ 33630-99-8 ]
Reference：
[1] Angewandte Chemie, 1936, vol. 49, p. 486,488
Reference：
[1] Patent: US6465513, 2002, B1,
[2] Journal of Medicinal Chemistry, 2017, vol. 60, # 12, p. 4840 - 4860
16
[ 142-08-5 ]
[ 13472-81-6 ]
Reference：
[1] Synthesis, 2001, # 14, p. 2175 - 2179
[2] Tetrahedron Letters, 1997, vol. 38, # 14, p. 2467 - 2470
[3] Patent: US5939439, 1999, A,
17
[ 142-08-5 ]
[ 13472-81-6 ]
Reference：
[1] Chemische Berichte, 1886, vol. 19, p. 2433
[2] Chemische Berichte, 1884, vol. 17, p. 590
18
[ 7647-01-0 ]
[ 39856-50-3 ]
[ 142-08-5 ]
[ 13472-81-6 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1951, vol. 70, p. 182,190
19
[ 142-08-5 ]
[ 13472-80-5 ]
Reference：
[1] European Journal of Organic Chemistry, 2015, vol. 2015, # 18, p. 4024 - 4032
[2] Tetrahedron Letters, 1997, vol. 38, # 14, p. 2467 - 2470
[3] Patent: US1753170, 1926, ,
[4] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 17, p. 2439
20
[ 142-08-5 ]
[ 13472-80-5 ]
Reference：
[1] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 16, p. 2646
21
[ 142-08-5 ]
[ 71597-85-8 ]
[ 51035-40-6 ]
Reference：
[1] Chemical Communications, 2011, vol. 47, # 48, p. 12840 - 12842
22
[ 142-08-5 ]
[ 127406-56-8 ]
Reference：
[1] Chemistry - A European Journal, 2016, vol. 22, # 16, p. 5692 - 5697
23
[ 142-08-5 ]
[ 30418-59-8 ]
[ 15889-32-4 ]
Reference：
[1] Chemical Communications, 2011, vol. 47, # 48, p. 12840 - 12842
24
[ 26482-54-2 ]
[ 7664-93-9 ]
[ 142-08-5 ]
[ 4214-76-0 ]
[ 4214-75-9 ]
Reference：
[1] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1920, vol. 50, p. 476[2] Chem. Zentralbl., 1923, vol. 94, # III, p. 1020
[3] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1915, vol. 47, p. 1290[4] Chem. Zentralbl., 1916, vol. 87, # II, p. 15
[5] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1928, vol. 60, p. 345[6] Chemische Berichte, 1927, vol. 60, p. 2437
25
[ 142-08-5 ]
[ 6332-56-5 ]
Reference：
[1] Angewandte Chemie, 1936, vol. 49, p. 486,488
[2] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 13, p. 3983 - 3987
26
[ 142-08-5 ]
[ 5470-18-8 ]
Reference：
[1] Russian Journal of General Chemistry, 2001, vol. 71, # 7, p. 1076 - 1087
27
[ 142-08-5 ]
[ 5470-18-8 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 13, p. 3983 - 3987
28
[ 142-08-5 ]
[ 14529-54-5 ]
Reference：
[1] Patent: WO2018/109050, 2018, A1,
[2] Organic Process Research and Development, 2018, vol. 22, # 8, p. 978 - 990
29
[ 142-08-5 ]
[ 58530-50-0 ]
Reference：
[1] Journal of the American Chemical Society, 2004, vol. 126, # 1, p. 2 - 3
30
[ 142-08-5 ]
[ 58530-50-0 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1955, vol. 74, p. 175,177
[2] Recueil des Travaux Chimiques des Pays-Bas, 1955, vol. 74, p. 175,177
[3] Recueil des Travaux Chimiques des Pays-Bas, 1955, vol. 74, p. 175,177
31
[ 142-08-5 ]
[ 2980-33-8 ]
Reference：
[1] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1921, vol. 53, p. 235,237[2] Chem. Zentralbl., 1923, vol. 94, # III, p. 1025
32
[ 142-08-5 ]
[ 2980-33-8 ]
Reference：
[1] Chemistry of Heterocyclic Compounds, 2013, vol. 49, # 7, p. 1000 - 1008[2] Khim. Geterotsikl. Soedin., 2013, vol. 49, # 7, p. 1073 - 1081,9
33
[ 288-13-1 ]
[ 142-08-5 ]
[ 25700-11-2 ]
Reference：
[1] Journal of Organic Chemistry, 2011, vol. 76, # 20, p. 8262 - 8269
[2] Chemistry of Materials, 2013, vol. 25, # 19, p. 3910 - 3920
34
[ 56-86-0 ]
[ 636-41-9 ]
[ 616-45-5 ]
[ 142-08-5 ]
[ 541-59-3 ]
[ 123-56-8 ]
[ 109-97-7 ]
[ 3680-71-5 ]
[ 75-05-8 ]
Reference：
[1] Journal of Agricultural and Food Chemistry, 2013, vol. 61, # 32, p. 7696 - 7704
Was added to the reactorPyridine-2-one 19-1 (0.095 g, 1 mmol)Dicumyl peroxide (0.81 g, 3 mmol) and 2 ml of acetic acid,120 ° C reaction, TLC followed the reaction until complete.The crude product obtained after the completion of the reaction was purified by column chromatography (petroleum ether: ethyl acetate = 1: 1)Separation and purification to give the target product 19-2 (yield 85percent).
Reference：
[1] Patent: CN106496130, 2017, A, . Location in patent: Paragraph 0036; 0037
37
[ 142-08-5 ]
[ 32315-10-9 ]
[ 1659-31-0 ]
Yield
Reaction Conditions
Operation in experiment
57%
With triethylamine In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; ethyl acetate
(b) Dipyrid-2-ylcarbonate Triethylamine (10.5 ml, 75 mmol) was added slowly to a solution of triphosgene (3.0 g, 10 mmol) and 2-hydroxypyridine (5.7 g, 60 mmol) in dry DCM (500 ml) at 0° C. under argon. The mixture was allowed to warm to room temperature and was stirred overnight. The solvent was removed under reduced pressure and the residue taken up in ethyl acetate (500 ml), washed with saturated aqueous sodium hydrogen carbonate (2*150 ml) and brine (200 ml), dried over anhydrous sodium sulphate filtered and concentrated to give an orange oil. Crystallisation from ethyl acetate/hexane gave dipyrid-2-ylcarbonate as an off-white crystalline solid (3.70 g, 57percent). deltaH 8.42 (2H, dd, J 4.8, 1.1 Hz), 7.83 (2H, ddd, J 7.8, 7.7, 1.8 Hz), 7.30-7.23 (4H, m).
Reference：
[1] Journal of the American Chemical Society, 2004, vol. 126, # 24, p. 7452 - 7453
[2] Patent: US5563151, 1996, A,
38
[ 142-08-5 ]
[ 75-44-5 ]
[ 1659-31-0 ]
Reference：
[1] Tetrahedron Letters, 1984, vol. 25, # 43, p. 4943 - 4946
[2] Bulletin of the Chemical Society of Japan, 1985, vol. 58, # 12, p. 3570 - 3575
39
[ 142-08-5 ]
[ 52065-78-8 ]
Reference：
[1] Archiv der Pharmazie (Weinheim, Germany), 1984, vol. 317, # 4, p. 304 - 306
[2] Archiv der Pharmazie (Weinheim, Germany), 1984, vol. 317, # 4, p. 304 - 306
40
[ 142-08-5 ]
[ 75-30-9 ]
[ 16096-13-2 ]
Reference：
[1] Synthesis, 2009, # 16, p. 2725 - 2728
41
[ 142-08-5 ]
[ 24228-13-5 ]
Yield
Reaction Conditions
Operation in experiment
20%
With tris[2-phenylpyridinato-C2,N]iridium(III); potassium acetate In acetonitrile at 20℃; for 6 h; Irradiation; Inert atmosphere; Glovebox; Schlenk technique
General procedure: The reaction of 1a with 6ais representative (Table 2, entry 9). In a glovebox filled with nitrogen, Ir(ppy)3 (3.3 mg, 0.0050 mmol),Ph2IOTf (6a, 136.4 mg, 0.25 mmol), and potassium acetate (49.1 mg, 0.50 mmol) were placed in aSchlenk tube. The tube was sealed with a septum and then taken out of the glovebox. A solution ofN-methyl-2-pyridone (1a, 136.4 mg, 1.25 mmol) in MeCN (1 mL) was added using a syringe. Themixture was stirred for 6 h under blue light LED irradiation (12 DC/3 W). Water (20 mL) was added,and extraction was done with EtOAc (15 mL x 3). The combined organic phase was dried over sodium sulfate and then concentrated in vacuo. Purification via column chromatography (Wakosil C-200,hexane/EtOAc = 20/1 to EtOAc/CH2Cl2/Et3N = 1/1/0.05) followed by GPC provided pure1-methyl-3-phenylpyridin-2(1H)-one (7aa, 25.4 mg, 0.14 mmol, 55percent yield).
Reference：
[1] Bulletin of the Chemical Society of Japan, 1985, vol. 58, # 12, p. 3570 - 3575
50
[ 142-08-5 ]
[ 108-77-0 ]
[ 137-51-9 ]
Reference：
[1] Patent: US4039523, 1977, A,
51
[ 89985-91-1 ]
[ 142-08-5 ]
[ 20887-95-0 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1985, vol. 58, # 12, p. 3570 - 3575
52
[ 142-08-5 ]
[ 105125-43-7 ]
Yield
Reaction Conditions
Operation in experiment
91%
With thionyl chloride; triethylamine In tetrahydrofuran
(128-2) Under nitrogen atmosphere, to a solution of 2-hydroxypyridine (2.66 g) and NEt3 (4.05 mL) in THF (80 mL) was added dropwise SOCl2 (1.05 mL) under ice-cooling, and the mixture was stirred for one hour. The mixture was filtered, and the solvent was evaporated under reduced pressure to give di-2-pyridyl sulfite (3.02 g, 91percent).
91%
With thionyl chloride; triethylamine In tetrahydrofuran
(128-2) Under nitrogen atmosphere, to a solution of 2-hydroxypyridine (2.66 g) and NEt3 (4.05 mL) in THF (80 mL) was added dropwise SOCl2 (1.05 mL) under ice-cooling, and the mixture was stirred for one hour. The mixture was filtered, and the solvent was evaporated under reduced pressure to give di-2-pyridyl sulfite (3.02 g, 91 percent).
With magnesium sulfate In <i>N</i>-methyl-acetamide; hexane
EXAMPLE 1 2,3-Dibromo-5-chloropyridine (2) 3-bromo-5-chloropyridone (33.51 g, 161 mmol) was dissolved in dimethylformamide (251 ml) at ambient temperature. Phosphorus (V) tribromide oxide (52.12 g, 182 mmol) was added and the reaction heated to 80° C. for 72 hours. After cooling, the reaction was poured onto ice. Vacuum filtration provided the product as a tan solid. The crude product was taken up in ether and the pH of the water layer was adjusted to 13 with aqueous sodium hydroxide. The aqueous layer was extracted three times with ether, the combined organic extracts treated with magnesium sulfate, and the solvent removed under vacuum. The product was dissolved in boiling hexane and decolorizing carbon was added to the crude product, the contents heated to reflux and then filtered through celite. The clear colorless filtrate was tripped under vacuum to yield the title compound as a white solid (18.1 g, 45percent), mp=39.5°-43° C. The starting pyridone was recovered from the aqueous layer of the ether extraction by adjusting the pH to 1 with concentrated hydrochloric acid. Filtration of the precipate and drying in a vacuum provided 13.8 g (40percent) of the starting pyridone. IR(neat): 3060, 1538, 1405, 1370, 1135, 1030, 905 cm-1. 1 H NMR Bruker 250 MHZ (CDCl3) δ: 8.28 (d, J=2 Hz); 7.89 (d, J=2 Hz). 13 C NMR (CDCl3) δ: 146.93, 141.45, 141.02, 131.34, 124.01. Combustion analysis calculated for C5 H2 Br2 ClN: C, 22.13; H, 0.74; N, 5.16. Found: C, 21.93; H, 0.53; N, 4.90.
Reference：
[1] Patent: US5436344, 1995, A,
54
[ 142-08-5 ]
[ 263012-63-1 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 2015, vol. 52, # 4, p. 1062 - 1074
55
[ 385377-29-7 ]
[ 142-08-5 ]
[ 211555-30-5 ]
Reference：
[1] Patent: US8053212, 2011, B1,
56
[ 142-08-5 ]
[ 540-37-4 ]
[ 13143-47-0 ]
Yield
Reaction Conditions
Operation in experiment
95%
With 8-quinolinol; potassium carbonate In N,N-dimethyl-formamideInert atmosphere; Reflux; Large scale
In a 3000L reactor, iodoaniline 438kg, 2-hydroxypyridine 190kg, 8-hydroxyquinoline 58kg, potassium carbonate 207kg, N,N-dimethylformamide (DMF) 1500kg, nitrogen protection, stirring is turned on. The mixture was warmed to reflux and reacted overnight. Chromatography was followed up to the end of the reaction. The potassium iodide was removed by filtration. Part of the DMF was recovered under reduced pressure, cooled to 50° C., and filtered to give crude 1-(4-aminophenyl)-1H-pyridin-2-one. The crude product was added with 740 kg of ethanol, heated and dissolved, and 55 kg of activated carbon was added for decoloration. The solution was filtered while hot, and the filtrate was cooled and crystallized. The product was filtered, dried and packaged to give 1-(4-aminophenyl)-1H-pyridin-2-one with a yield of 95. percent,The purity is 99percent.
70%
With copper(l) iodide; 8-quinolinol; caesium carbonate In 1,4-dioxane; dimethyl sulfoxide at 120℃; for 15 h; Sealed tube
11128] In a similar manner as described in Example 114,(R)-5-(3-(4-methoxybenzamido)piperidin- 1 -yl)-3-(4-(2-ox-opyridin- 1 (2H)-yl)phenylamino)pyrazine-2-carboxamide(154) was prepared using 1 -(4-aminophenyl)pyridin-2(1H)-one. MS found for C29H29N704 as (M+H) 540.1, (M—H)538.3. UV: X=260, 285, 308, 346, 369 nm Synthesis of i-(4-aminophenyl)pyridin-2(1H)-one: The mixture of 4-iodoa-niline (1.00 g, 4.56 mmol), 2-hydroxypyridine (650 mg, 6.84mmol), fine powder Cs2CO3 (2.97 g, 9.12 mmol), fine powderCul (180mg, 0.92 mmol), 8-hydroxyquinoline (140mg, 0.92mmol) in 6 mE DMSO and 10 mE dioxane was stirred in asealed tube at 120° C. for 15 h. The mixture was diluted with300 mE EtOAc, filtered through celite, washed with brine,dried, concentrated and subjected to flash column with 0 to7percent MeOR in dichioromethane to isolate this compound (590mg, yield 70percent).
53.45%
With copper(l) iodide; 8-quinolinol; potassium carbonate In dimethyl sulfoxide at 130℃; for 12 h; Inert atmosphere
General procedure: Compound 1 (5g, 22.83mmol) was dissolved in DMSO (120mL), followed by the addition of 2-Piperidinone (4.53g, 45.66mmol), CuI (0.43g, 2.28mmol), 8-hydroxy-quinoline (0.66g, 4.57mmol) and K2CO3 (9.46g, 68.49mmol). The mixture was heated to 130°C under N2 for 12h, cooled, and quenched with water (120mL). The organics were extracted with ethyl acetate (2×150mL) and dried (Na2SO4). Purification by silica gel column chromatography (n-hexane/ethyl acetate, 5/1 to 3/1, as eluent) afforded compound 2 as faint yellow (2.80g, 64.47percent).
39.8%
With copper(l) iodide; 8-quinolinol; caesium carbonate In dimethyl sulfoxide at 120℃;
A mixture of pyridin-2-ol (2.00 g, 21.0 mmol), 4-iodoaniline (4.61 g, 21.0 mmol), 8-quinolinol (0.61 g, 4.2 mmol), Cul (0.80 g, 4.2 mmol) and Cs2C03 (10.26 g, 31.5 mmol) in DMSO (50 mL) was stirred at 120°C for overnight. After filtration, the filtrate was partitioned between EA and water and the aqueous layer was further extracted with EA. The combined organic layers was washed with water and brine, dried over anhydrous sodium sulfate and concentrated to afford the title compound as a green solid (1.56 g, 39.8 percent yield). MS (m/z): 186.9 (M+H)+.
39.8%
With copper(l) iodide; 8-quinolinol; caesium carbonate In dimethyl sulfoxide at 120℃;
A mixture of pyridin-2-ol (2.00 g, 21.0 mmol), 4-iodoaniline (4.61 g, 21.0 mmol), 8-quinolinol (0.61 g, 4.2 mmol), Cul (0.80 g, 4.2 mmol) and Cs2C03 (10.26 g, 31.5 mmol) in DMSO (50 mL) was stirred at 120°C for overnight. After filtration, the filtrate was partitioned between EA and water and the aqueous layer was further extracted with EA. The combined organic layers was washed with water and brine, dried over anhydrous sodium sulfate and concentrated to afford the title compound as a green solid (1.56 g, 39.8 percent yield). MS (m/z): 186.9 (M+H)+.
Reference：
[1] Patent: CN107382836, 2017, A, . Location in patent: Paragraph 0021; 0022
[2] Patent: US2015/158865, 2015, A1, . Location in patent: Paragraph 1127; 1128
[3] European Journal of Medicinal Chemistry, 2017, vol. 125, p. 411 - 422
[4] Patent: WO2014/139145, 2014, A1, . Location in patent: Page/Page column 37
[5] Patent: WO2014/139465, 2014, A1, . Location in patent: Page/Page column 38
[6] Patent: WO2006/55951, 2006, A2, . Location in patent: Page/Page column 59
[7] Patent: WO2008/86226, 2008, A2, . Location in patent: Page/Page column 123-124
[8] Patent: WO2005/32468, 2005, A2, . Location in patent: Page/Page column 158
[9] Patent: WO2006/63113, 2006, A2, . Location in patent: Page/Page column 118
[10] Patent: WO2006/63293, 2006, A2, . Location in patent: Page/Page column 48-49
[11] Patent: WO2005/32468, 2005, A2, . Location in patent: Page/Page column 158
57
[ 142-08-5 ]
[ 13143-47-0 ]
Reference：
[1] Patent: WO2014/135471, 2014, A1,
58
[ 142-08-5 ]
[ 2314-97-8 ]
[ 22245-83-6 ]
Yield
Reaction Conditions
Operation in experiment
50%
With ferrocene; dihydrogen peroxide; dimethyl sulfoxide In water at 40 - 50℃; for 0.333333 h;
0.19 g (2.0 mmol) of 2-hydroxypyridine and 0.11 g (0.6 mmol) of ferrocene were weighed and placed in a two-neck flask and the atmosphere in the flask was replaced with argon. The following materials were added thereinto: 8.0 ml of dimethyl sulfoxide, 2.0 ml of a 3.0 mol/l dimethyl sulfoxide solution of trifluoromethyl iodide and 0.4 ml of a 30percent hydrogen peroxide aqueous solution, and the mixture was stirred for 20 minutes. During the stirring, the temperature of the reaction system rose up in the range of from 40°C to 50°C. Thereafter, the resulting solution was cooled to room temperature. Formation of 2-hydroxy-3-trifluoromethylpyridine (19F-NMR yield: 64percent) was confirmed by 19F-NMR with 2,2,2-trifluoroethanol as an internal standard. The subsequent procedure was conducted in the same manner as in Example 1 and 2-hydroxy-3-trifluoromethylpyridine was obtained as a white solid (0.081 g, yield: 50percent). 1H-NMR(deuterated chloroform):δ6. 34(dd, J=6. 9, 5. 6Hz, 1H), 7. 65 (d, J=5. 6Hz, 1H), 7. 88 (d, J=6. 9Hz, 1H), 13. 25 (brs, 1H). 13C-NMR(deuterated chloroform):δ105. 6, 120. 4(q, JCF=31. 4H z), 122. 7(q, JCF=271. 3Hz), 139. 2, 140. 7(q, JCF=4. 9Hz), 161. 4. 19F-NMR(deuterated chloroform):δ-66. 0. MS(m/z):163[M]+.
Reference：
[1] Patent: EP2080744, 2009, A1, . Location in patent: Page/Page column 7-8
[2] Journal of Fluorine Chemistry, 2010, vol. 131, # 1, p. 98 - 105
Step 1 3,5-Dibromopyridin-2-ol A suspension of 2-pyridinol (3.00 g, 31.55 mmol) and bromine (1.79 ml, 34.7 mmol)) in 1,2-dichloroethane(35 mL) was stirred at room temperature and then at reflux for 18 hrs. The solids were collected by filtration and chromatographed (silica gel, MeOH: CH2 Cl2 5:95) to afford the dibromide. 1 H NMR (400 MHz, CD3 OD) delta 8.07 (d, J=2.9 Hz, 1H), and 7.62 (d, J=2.9 Hz, 1H) ppm.
With 8-quinolinol; potassium carbonate;copper(l) iodide; In dimethyl sulfoxide; at 130℃;
Example 11 5-Chloro-N-((1-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide (21) A mixture of <strong>[147808-02-4]2,5-diiodofluorobenzene</strong> II-4 (2.00 g, 5.75 mmol), 2-hydroxypyridine 1-7 (0.546 g, 5.75 mmol), 8-hydroxyquinoline (0.083 g, 0.57 mmol) and K2CO3 (1.00 g, 7.25 mmol) in DMSO (10 mL) was degassed before being charged with CuI (0.109 g, 0.57 mmol). The mixture in a sealed tube was heated at 130 C. overnight. Water and EtOAc were added. The mixture was filtered. The organic layer was separated, then applied to a silica gel column, which was eluted with 0-70% EtOAc in hexane to give 1-iodo-2-fluoro-4-(2-oxopyridin-1(2H)-yl)benzene 3-2 (0.820 g). MS 315.8 (M+H).
With potassium phosphate; 8-quinolinol;copper(l) iodide; In 1,4-dioxane;
A mixture of methyl 2,5-diiodobenzoate prepared above (1.04 g, 2.67 mmol), 2-hydroxypyridine 1-7 (0.254 g, 2.67 mmol), 8-hydroxyquinoline (0.077 g, 0.53 mmol) and K3PO4 (1.13 g, 5.33 mmol) in dioxane (8 mL) was degassed with Ar before being charged with CuI (0.101 g, 0.53 mmol). The mixture in a sealed tube was heated at 130 C. overnight. It was then purified by HPLC to give 2-iodo-5-(2-oxopyridin-1(2H)-yl)benzoic acid (0.220 g). MS 342.0 (M+H).
With 8-quinolinol; potassium carbonate; In N,N-dimethyl-formamide;Inert atmosphere; Reflux; Large scale;
In a 3000L reactor, iodoaniline 438kg, 2-hydroxypyridine 190kg, 8-hydroxyquinoline 58kg, potassium carbonate 207kg, N,N-dimethylformamide (DMF) 1500kg, nitrogen protection, stirring is turned on. The mixture was warmed to reflux and reacted overnight. Chromatography was followed up to the end of the reaction. The potassium iodide was removed by filtration. Part of the DMF was recovered under reduced pressure, cooled to 50 C., and filtered to give crude 1-(4-aminophenyl)-1H-pyridin-2-one. The crude product was added with 740 kg of ethanol, heated and dissolved, and 55 kg of activated carbon was added for decoloration. The solution was filtered while hot, and the filtrate was cooled and crystallized. The product was filtered, dried and packaged to give 1-(4-aminophenyl)-1H-pyridin-2-one with a yield of 95. %,The purity is 99%.
70%
With copper(l) iodide; 8-quinolinol; caesium carbonate; In 1,4-dioxane; dimethyl sulfoxide; at 120℃; for 15h;Sealed tube;
11128] In a similar manner as described in Example 114,(R)-5-(3-(4-methoxybenzamido)piperidin- 1 -yl)-3-(4-(2-ox-opyridin- 1 (2H)-yl)phenylamino)pyrazine-2-carboxamide(154) was prepared using 1 -(4-aminophenyl)pyridin-2(1H)-one. MS found for C29H29N704 as (M+H) 540.1, (M-H)538.3. UV: X=260, 285, 308, 346, 369 nm Synthesis of i-(4-aminophenyl)pyridin-2(1H)-one: The mixture of 4-iodoa-niline (1.00 g, 4.56 mmol), 2-hydroxypyridine (650 mg, 6.84mmol), fine powder Cs2CO3 (2.97 g, 9.12 mmol), fine powderCul (180mg, 0.92 mmol), 8-hydroxyquinoline (140mg, 0.92mmol) in 6 mE DMSO and 10 mE dioxane was stirred in asealed tube at 120 C. for 15 h. The mixture was diluted with300 mE EtOAc, filtered through celite, washed with brine,dried, concentrated and subjected to flash column with 0 to7% MeOR in dichioromethane to isolate this compound (590mg, yield 70%).
53.45%
With copper(l) iodide; 8-quinolinol; potassium carbonate; In dimethyl sulfoxide; at 130℃; for 12h;Inert atmosphere;
General procedure: Compound 1 (5g, 22.83mmol) was dissolved in DMSO (120mL), followed by the addition of 2-Piperidinone (4.53g, 45.66mmol), CuI (0.43g, 2.28mmol), 8-hydroxy-quinoline (0.66g, 4.57mmol) and K2CO3 (9.46g, 68.49mmol). The mixture was heated to 130C under N2 for 12h, cooled, and quenched with water (120mL). The organics were extracted with ethyl acetate (2×150mL) and dried (Na2SO4). Purification by silica gel column chromatography (n-hexane/ethyl acetate, 5/1 to 3/1, as eluent) afforded compound 2 as faint yellow (2.80g, 64.47%).
39.8%
With copper(l) iodide; 8-quinolinol; caesium carbonate; In dimethyl sulfoxide; at 120℃;
A mixture of pyridin-2-ol (2.00 g, 21.0 mmol), 4-iodoaniline (4.61 g, 21.0 mmol), 8-quinolinol (0.61 g, 4.2 mmol), Cul (0.80 g, 4.2 mmol) and Cs2C03 (10.26 g, 31.5 mmol) in DMSO (50 mL) was stirred at 120C for overnight. After filtration, the filtrate was partitioned between EA and water and the aqueous layer was further extracted with EA. The combined organic layers was washed with water and brine, dried over anhydrous sodium sulfate and concentrated to afford the title compound as a green solid (1.56 g, 39.8 % yield). MS (m/z): 186.9 (M+H)+.
39.8%
With copper(l) iodide; 8-quinolinol; caesium carbonate; In dimethyl sulfoxide; at 120℃;
A mixture of pyridin-2-ol (2.00 g, 21.0 mmol), 4-iodoaniline (4.61 g, 21.0 mmol), 8-quinolinol (0.61 g, 4.2 mmol), Cul (0.80 g, 4.2 mmol) and Cs2C03 (10.26 g, 31.5 mmol) in DMSO (50 mL) was stirred at 120C for overnight. After filtration, the filtrate was partitioned between EA and water and the aqueous layer was further extracted with EA. The combined organic layers was washed with water and brine, dried over anhydrous sodium sulfate and concentrated to afford the title compound as a green solid (1.56 g, 39.8 % yield). MS (m/z): 186.9 (M+H)+.
With 8-quinolinol; potassium carbonate;copper(l) iodide; In dimethyl sulfoxide; at 130℃;
A mixture of 4-iodoaniline (1.00 g, 4.57 mmol), 2-hydroxypyridine (0.477 g, 5.02 mmol), 8-hydroxyquinoline (0.110 g, 0.759 mmol) and K2CO3 (0.945 g, 6.85 mmol) in DMSO (10 mL) was degassed with Ar before being charged with CuI (0.145 g, 0.763 mmol). The mixture in a sealed tube was then heated at 1300C overnight. Water and n-BuOH were added. The mixture was filtered. The n-BuOH phase was separated, and concentrated in vacuo to give a solid (0.666 g), which was pure enough for subsequent reactions. MS 187.3 (M+H).
With copper(l) iodide; 8-quinolinol; caesium carbonate; In 1,4-dioxane; dimethyl sulfoxide; at 120℃; for 6h;
EXAMPLE 1255-Chloro-N-(( 1 -(4-(2-oxopyridin- 1 (2H)-yl)-2-(pyridin-4-yl)phenyl)- 1 H- 1 ,2,3-triazol-4- yl)methyl)thiophene-2-carboxamide (125); SCHEME 12 <n="125"/>Step 1 :4-Iodoaniline (12.1, 10.0 g, 45.6 mmol) was dissolved in 80 niL dioxane and 40 niL DMSO. To it were added 2-hydroxypyridine (8.68 g, 91.2 mmol), 8-hydroxyquinoline (1.32 g, 9.12 mmol), cesium carbonate (30.0 g, 91.2 mmol) and CuI (1.73 g, 9.12 mmol). The mixture was stirred at 120 0C for 6 hrs. It was filtered, concentrated, and taken into 800 mL chloroform. The organic solution washed with brine twice and concentrated to its 1A volume. The solid crashed out was isolated by filtration, washed with cold DCM, and dried in vacuo to give compound 12.2 (4.62 g, 54 %). MS found for C11H10N2O (M+H)+ 187.1.
With potassium carbonate;copper(l) iodide; 8-quinolinol; In dimethyl sulfoxide; at 130℃;Heating in a sealed tube;
EXAMPLE 137 Preparation of (2S) N-[4-(2-rhoyridon-l-yl)rhohenyl]-2-phenyl-2-(4- chlorophenylaminocarbonylamino)-acetamide; A. Preparation of 4-(2-pyridon- 1 -yl)phenylamine; [0496] A mixture of 4-iodoaniline (1.00 g, 4.57 mmol), 2-hydroxyrhoyridine (0.477 g, 5.02 mmol), 8-hydroxyquinoline (0.110 g, 0.759 mmol) and K2CO3 (0.945 g, 6.85 mmol) in DMSO (10 mL) was degassed with Ar before being charged with CuI (0.145 g, 0.763 mmol). The mixture in a sealed tube was then heated at 130 0C overnight. Water and nBuOH were added. The mixture was filtered. The nBuOH phase was separated, and concentrated in vacuo to give a solid (0.666 g), which was pure enough for subsequent reactions. MS 187.3 (M+H).
With copper(l) iodide; 8-quinolinol; potassium carbonate; In dimethyl sulfoxide; at 130℃;
A. Preparation of 4-(2-pyridon-l-yl)phenylamme; EPO <DP n="50"/>[0186] A mixture of 4-iodoaniline (1.00 g, 4.57 mmol), 2-hydroxypyridine (0.477 g, 5.02 mmol), 8-hydroxyquinoline (0.110 g, 0.759 mmol) and K2CO3 (0.945 g, 6.85 mmol) in DMSO (10 mL) was degassed with Ar before being charged with CuI (0.145 g, 0.763 mmol). The mixture in a sealed tube was then heated at 130 0C overnight. Water and nBuOH were added. The mixture was filtered. The nBuOH phase was separated, and concentrated in vacuo to give a solid (0.666 g), which was pure enough for subsequent reactions. MS 187.3 (M+H).
With magnesium sulfate; In N-methyl-acetamide; hexane;
EXAMPLE 1 2,3-Dibromo-5-chloropyridine (2) 3-bromo-5-chloropyridone (33.51 g, 161 mmol) was dissolved in dimethylformamide (251 ml) at ambient temperature. Phosphorus (V) tribromide oxide (52.12 g, 182 mmol) was added and the reaction heated to 80 C. for 72 hours. After cooling, the reaction was poured onto ice. Vacuum filtration provided the product as a tan solid. The crude product was taken up in ether and the pH of the water layer was adjusted to 13 with aqueous sodium hydroxide. The aqueous layer was extracted three times with ether, the combined organic extracts treated with magnesium sulfate, and the solvent removed under vacuum. The product was dissolved in boiling hexane and decolorizing carbon was added to the crude product, the contents heated to reflux and then filtered through celite. The clear colorless filtrate was tripped under vacuum to yield the title compound as a white solid (18.1 g, 45%), mp=39.5-43 C. The starting pyridone was recovered from the aqueous layer of the ether extraction by adjusting the pH to 1 with concentrated hydrochloric acid. Filtration of the precipate and drying in a vacuum provided 13.8 g (40%) of the starting pyridone. IR(neat): 3060, 1538, 1405, 1370, 1135, 1030, 905 cm-1. 1 H NMR Bruker 250 MHZ (CDCl3) delta: 8.28 (d, J=2 Hz); 7.89 (d, J=2 Hz). 13 C NMR (CDCl3) delta: 146.93, 141.45, 141.02, 131.34, 124.01. Combustion analysis calculated for C5 H2 Br2 ClN: C, 22.13; H, 0.74; N, 5.16. Found: C, 21.93; H, 0.53; N, 4.90.
(E)-methyl 2-[2-(pyridin-2-yloxymethyl)phenyl]-3-methoxypropenoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
silver carbonate; In hexane;
EXAMPLE 10 This Example illustrates the preparation of (E)-methyl 2-[2-(pyridin-2-yloxymethyl)phenyl]-3-methoxypropenoate (Compound No. 67 of Table I). A mixture of 2-hydroxypyridine (0.50 g) and (E)-methyl 2-[2-(bromomethyl)phenyl]-3-methoxypropenoate (2.25 g) was suspended in dry n-hexane (10 ml) and silver carbonate (0.73 g) was added. The mixture was stirred and heated under reflux for 2 hours in the dark. The cooled mixture was then concentrated and the residue was extracted with dichloromethane. The extracts were filtered through Hyflosupercel, washed successively with saturated aqueous sodium bicarbonate solution and water, then dried, concentrated and chromatographed using a 2:1 mixture of ether and petrol to give the title compound as a colourless oil which crystallized on standing (0.80 g, 51% yield from 2-hydroxypyridine). Recrystallisation from petrol gave a white powder, m.p. 65-66 C. 1 H NMR (400 MHz): delta 3.68 (3H, s), 3.80 (3H, s), 5.26 (2H, s), 6.74 (1H, d), 6.82-6.90 (1H, m), 7.14-7.21 (1H, m), 7.28-7.42 (2H, m), 7.49-7.63 (2H, m), 7.54 (1H, s), 8.15 (1H, d) ppm.
EXAMPLE 15 18.5 Parts of cyanuric chloride are added at 0 C. and a pH of 5 to 350 parts by volume of an aqueous solution containing 35 parts of pyridone coupling component of the formula STR20 and the mixture is stirred at this temperature, a pH is 4 to 5 being maintained by the dropwise addition of dilute sodium hydroxide solution. Upon completion of the condensation, a diazo solution of 25.3 parts of aniline-2,4-disulphonic acid which is prepared in the convention manner is added, the pH is adjusted to 6 by the dropwise addition of sodium hydroxide solution and the mixture is stirred until the coupling is complete.
3-(2-Pyridon-1-yl)-5-(pyridin-2-yl)-1-phenyl-1,2-dihydropyridin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With ammonium hydroxide; potassium carbonate; In N-methyl-acetamide;
Example 191. 3-(2-Pyridon-1-yl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one 40mg of <strong>[381248-06-2]3-bromo-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one</strong> and 23mg of 2-hydroxypyridine were dissolved in 10ml of dimethylformamide. 34mg of potassium carbonate and 3mg of copper iodide were added thereto, followed by stirring at 140C overnight. After cooling the reaction mixture to room temperature, an aqueous ammonia was added thereto, followed by extracting with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (NH silica) (chloroform/methanol system), to give 10mg of the title compound. 1H-NMR (400MHz, CDCl3); delta(ppm) 6.24(td,1H), 6.69(dd,1H), 7.22(dd,1H), 7.37-7.42(m,2H), 7.45-7.57(m,6H), 7.73(td,1H), 8.33(d,1H), 8.36(d,1H), 8.58-8.60(m,1H).
1-(4-amino-3,5-difluoro-phenyl)-1H-pyridin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With 8-quinolinol; caesium carbonate;copper(l) iodide; In dimethyl sulfoxide; at 150℃;
Using the same procedure described in example 1 (with 1-(4-amino-3,5-difluoro-phenyl)-1H-pyridin-2-one prepared from <strong>[67567-26-4]4-bromo-2,6-difluoroaniline</strong> by reaction with 2-hydroxypyridine, Cu(I)I, potassium carbonate, 8-hydroxyquinoline in DMSO at 150° C.) the title compound was obtained as a white solid (110 mg). MS: 525.3 (M+H)+
With ferrocene; dihydrogen peroxide; dimethyl sulfoxide; In water; at 40 - 50℃; for 0.333333h;
0.19 g (2.0 mmol) of 2-hydroxypyridine and 0.11 g (0.6 mmol) of ferrocene were weighed and placed in a two-neck flask and the atmosphere in the flask was replaced with argon. The following materials were added thereinto: 8.0 ml of dimethyl sulfoxide, 2.0 ml of a 3.0 mol/l dimethyl sulfoxide solution of trifluoromethyl iodide and 0.4 ml of a 30% hydrogen peroxide aqueous solution, and the mixture was stirred for 20 minutes. During the stirring, the temperature of the reaction system rose up in the range of from 40C to 50C. Thereafter, the resulting solution was cooled to room temperature. Formation of 2-hydroxy-3-trifluoromethylpyridine (19F-NMR yield: 64%) was confirmed by 19F-NMR with 2,2,2-trifluoroethanol as an internal standard. The subsequent procedure was conducted in the same manner as in Example 1 and 2-hydroxy-3-trifluoromethylpyridine was obtained as a white solid (0.081 g, yield: 50%). 1H-NMR(deuterated chloroform):delta6. 34(dd, J=6. 9, 5. 6Hz, 1H), 7. 65 (d, J=5. 6Hz, 1H), 7. 88 (d, J=6. 9Hz, 1H), 13. 25 (brs, 1H). 13C-NMR(deuterated chloroform):delta105. 6, 120. 4(q, JCF=31. 4H z), 122. 7(q, JCF=271. 3Hz), 139. 2, 140. 7(q, JCF=4. 9Hz), 161. 4. 19F-NMR(deuterated chloroform):delta-66. 0. MS(m/z):163[M]+.
With potassium carbonate;copper(l) iodide; In dichloromethane; at 130℃; for 3h;
1-(6-Amino-3-pyridazinyl)-2(1H)-pyridinone A microwave vial was charged with copper(I) iodide (10.01 mg, 0.053 mmol) and potassium carbonate (291 mg, 2.103 mmol), evacuated and backfilled with nitrogen. 2(1H)-pyridinone (100 mg, 1.052 mmol), <strong>[88497-27-2]6-bromo-3-pyridazinamine</strong> (183 mg, 1.052 mmol) and N,N-Dimethylformamide (4 ml) was added under nitrogen. The vial was sealed and the reaction mixture was stirred at 130 C. for 3 hours. The solvent was evaporated. Dichloromethane (5 ml) was added to the residue and it was filtered washing with more dichloromethane (2*1 ml). The residue was purified by silica gel chromatography via Biotage (10%-50% DCMMeOH) to give 1-(6-amino-3-pyridazinyl)-2(1H)-pyridinone (51 mg, 0.271 mmol, 26%). 1H NMR (400 MHz, CDCl3): delta 4.93 (br s, 1H), 5.05 (br s, 1H), 5.46 (br s, 1H), 6.04 (br s, 2H), 6.22 (brs, 1H); UPLC-MS: 0.36 min, 189 [M+H]+.
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 7h;
To a stirred solution of 9.5 g (0.10 mol) of 2-hydroxypyridine in 250 mL of DMF was added 16.6 g (0.120 mol) of potassium carbonate followed by 25.0 g (0.120 mol) of 2-bromopropionic acid tert-butyl ester. The resulting mixture was stirred at ambient temperature for 7 h then diluted with 1 L of water. The aqueous phase was extracted with ethyl acetate (3.x.200 mL) and the combined organics were washed with water (2.x.100 mL), brine (100 mL), dried over magnesium sulfate, filtered and evaporated in vacuo. The crude residue was purified by silica gel chromatography eluting with 25percent ethyl acetate in hexanes to afford the title compound as a clear gum 16 g (72percent). LC-MS: m/z (ES) 224 (MH)+
72%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 7h;
To a stirred solution 9.5 g (0.10 mol) of 2-hydroxypyridine in 250 mL of DMF was added 16.6 g (0.120 mol) of potassium carbonate followed by 25.0 g (0.120 mol) of 2- bromopropionic acid fert-butyl ester. The resulting mixture was stirred at ambient temperature for 7 h then diluted with IL of water. The aqueous phase was extracted with ethyl acetate (3 x 200 mL) and the combined organics were washed with water (2 x 100 mL), brine (100 mL), dried over magnesium sulfate, filtered and evaporated in vacuo. The crude residue was purified by silica gel chromatography eluting with 25percent ethyl acetate in hexanes to afford the title compound as a clear gum 16 g (72percent). LC-MS: m/z (ES) 224 (MH)+
With potassium acetate; In methanolic ammonia; ethanol; water; acetic anhydride;
6-Amino-5-nitro-1H-pyridin-2-one from the N-oxide A suspension of 2-amino-3-nitropyridine 1-oxide (506 mg; 3.3 mmol) and KOAc (330 mg; 3.3 mmol) in acetic anhydride (6 mL) was stirred at room temperature for 30 min and then heated under reflux in a preheated oil-bath (150 C.) for another 15 min. The dark brown solution was cooled to room temperature and the solvent removed under high vacuum. The residue was resuspended in ethanol (20 mL) and the solvent removed under high vacuum. The residue was extracted with refluxing dichloromethane (30 mL) for 3 days. A large amount of dark, fine solid remained, which was insoluble in water, acetone or DMSO. The dichloromethane solution was dried and the residue redissolved in methanolic ammonia (10 mL) and stirred at room temperature for 20 h. The volatiles were then removed to yield the pyridone as a slightly brownish powder. Treating the insoluble solids from the extraction with methanolic ammonia for several days did not yield any significant further amount of product. The analytical data were identical with those from method b) below.
With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; triethylsilane; triethylamine; bis(dibenzylideneacetone)-palladium(0); In 1,4-dioxane; at 100℃; for 16h;Inert atmosphere;
General procedure: To a sparge-degassed solution of Et3N (0.405 g, 0.554 mL,4 mmol) and 1,4-dimethoxybenzene (internal standard) (0.138 g, 1 mmol) inanhydrous 1,4-dioxane (12 mL) under a nitrogen atmosphere was added 6-amino-2-chloro-5-fluoronicotinonitrile (343 mg, 2 mmol), [(1,10-bis-(di-tertbutyl-phosphino)ferrocene)PdCl2] (64 mg, 0.1 mmol) and Et3SiH (1.160 g,1.592 mL, 10 mmol). The mixture was then heated to 100 C with stirring.The reaction was monitored using 1H NMR spectroscopy, taking aliquots of thecrude reaction mixture. Upon completion, the mixture was diluted with CH2Cl2(20 mL) and washed with H2O (1 20 mL). The aqueous layer was thenextracted with CH2Cl2 (2 20 mL). The combined organics were dried overanhydrous MgSO4, filtered, and the solvent was removed under reducedpressure to leave the crude reaction product. The crude product was purifiedby flash silica chromatography with 0-5% methanolic NH3 (7 M) in CH2Cl2 asthe eluent. The solvent was then removed from fractions containing thedesired product to leave 6-amino-5-fluoronicotinonitrile (3) (148 mg,1.076 mmol).
(±)-(1R,2R,4R,6S)-2-(tert-butoxycarbonylamino)-4-(3-(tert-butoxycarbonylamino)pyridin-4-yl)-6-methylcyclohexyl methanesulfonate[ No CAS ]
tert-butyl ((1R,2S,3S,5R)-5-(3-aminopyridin-4-yl)-3-methyl-2-(2-oxopyridin-1(2H)-yl)cyclohexyl)carbamate[ No CAS ]
tert-butyl ((1S,2R,3R,5S)-5-(3-aminopyridin-4-yl)-3-methyl-2-(2-oxopyridin-1(2H)-yl)cyclohexyl)carbamate[ No CAS ]
tert-butyl ((1R,2S,3S,5R)-5-(3-aminopyridin-4-yl)-3-methyl-2-(pyridin-2-yloxy)cyclohexyl)carbamate[ No CAS ]
tert-butyl ((1S,2R,3R,5S)-5-(3-aminopyridin-4-yl)-3-methyl-2-(pyridin-2-yloxy)cyclohexyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
8%; 9%; 14%; 15%
Synthesis of tert-butyl ((lR,2S.3S.5R -5-(3-aminopyridin-4-vn-3-methyl-2-(2- oxopyridin-l(2H)-yl)cyclohexyl)carbamate, tert-butyl ((l S,2R,3R,5S)-5-(3- aminopyridin-4-yl)-3-methyl-2-(2-oxopyridin- 1 (2H)-yl)cyclohexyl)carbamate, tert-butyl ((lR,2S,3S,5R -5-(3-aminopyridin-4-vn-3-methyl-2-(pyridin-2- yloxy)cyclohexyl)carbamate and tert-butyl ((l S,2R,3R,5S)-5-(3-aminopyridin-4-yl)-3- methyl-2-(pyridin-2-yloxy)cyclohexyl)carbamate Single Enantiomer Single Enantiomer Single Enantiomer Single Enantiomer To a solution of (lR,2R,4R,6S)-2-(tert-butoxycarbonylamino)-4-(3-(tert- butoxycarbonylamino)pyridin-4-yl)-6-methylcyclohexyl methanesulfonate (1.0 equiv.) CS2CO3 (3.0 equiv.) in DMF (0.15 M) was added pyridin-2-ol (1.0 equiv). The mixture was stirred at 70 C for 5 hrs. The reaction was worked up with EtOAc and Brine. The organic layer was concentrated and was treated with 4N HCl (30.0 equiv.) in Dioxane for 2 hrs at which time the volatiles were removed in vacuo. The redisue was dissolved in THF (0.15 M) and tert-butyl 2,5-dioxopyrrolidin-l-yl carbonate (1.5 equiv.) was added, followed by DIEA (3.0 equiv.). After stirring at rt for 3 hrs, the reaction was quenched with sat. NaHC03 and extracted with EtOAc. The organic layer was washed with Brine, dried over Na2S04 and concentrated. The crude was purified by prep HPLC to yield two major peaks. The fractions of the first product peak was combined and neutralized with sat. NaHC03 and extrtcted with EtOAc. The organic layer was washed with Brine, dried over Na2S04 and concentrated. Purification was completed via SFC (20% (MeOH with 10% DEA), 100 mL/min, AD column) to yield tert-butyl ((lR,2S,3S,5R)-5-(3- aminopyridin-4-yl)-3-methyl-2-(2-oxopyridin-l(2H)-yl)cyclohexyl)carbamate (8% yield, 99%ee) and tert-butyl ((lS,2R,3R,5S)-5-(3-aminopyridin-4-yl)-3-methyl-2-(2- oxopyridin-l(2H)-yl)cyclohexyl)carbamate (9% yield, 99%ee). LC/MS (m/z) = 399.2 (MH+), R, = 0.60 min. 1H NMR (400 MHz, <dmso>) delta ppm 0.72 (s, 3 H), 1.30 (s, 9 H), 1.63 - 1.81 (m, 2 H), 1.89 - 2.00 (m, 2 H), 2.02 - 2.18 (m, 2 H), 3.04 - 3.13 (m, 1 H), 4.03 - 4.12 (m, 1 H), 4.91 - 5.02 (m, 1 H), 5.04 - 5.13 (m, 2 H), 6.17 - 6.26 (m, 1 H), 6.31 - 6.41 (m, 1 H), 6.98 - 7.07 (m, 1 H), 7.32 - 7.41 (m, 2 H), 7.68 - 7.74 (m, 1 H), 7.74 - 7.82 (m, 1 H), 7.85 - 7.90 (m, 1 H). The fractions of the second product peak was combined and neutralized with sat. NaHC03 and extrtcted with EtOAc. The organic layer was washed with Brine, dried over Na2S04 and concentrated. Purification was completed via SFC (20% (MeOH with 10% DEA), 100 mL/min, AD column) to yield tert-butyl ((lR,2S,3S,5R)-5-(3-aminopyridin-4-yl)-3-methyl-2-(pyridin-2- yloxy)cyclohexyl)carbamate (14% yield, 99%ee) and tert-butyl ((lS,2R,3R,5S)-5-(3- aminopyridin-4-yl)-3-methyl-2-(pyridin-2-yloxy)cyclohexyl)carbamate (15% yield, 99%ee). LC/MS (m/z) = 399.2 (MH+), R, = 0.65 min. 1H NMR (400 MHz, <cdcl3>) delta ppm 0.95 (d, J=6.65 Hz, 3 H), 1.35 - 1.78 (m, 12 H), 1.97 - 2.08 (m, 2 H), 2.76 (t, J=1 1.93 Hz, 1 H), 3.72 (br. s., 2 H), 3.88 (d, J=4.70 Hz, 1 H), 5.43 (d, J=7.43 Hz, 1 H), 5.59 (br. s., 1 H), 6.79 - 6.94 (m, 2 H), 7.08 (d, J=5.09 Hz, 1 H), 7.56 - 7.65 (m, 1 H), 7.98 - 8.17 (m, 3 H).
With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 90℃;Inert atmosphere; Sealed tube;
General procedure: To a degassed solution of 3-substituted-2-halo imidazo[4,5b]pyridine derivative, 3b (1 equiv.) and 2a(1.3 equiv.) in 1, 4- dioxane were added Cs2CO3 (3equiv.), Xantphos (8 mol %) and Pd(OAc)2 (4 mol %). The reactionmixture heated at 90C in a sealed vial about 6 h. When TLC andLCMS showed full consumption of starting materials, the reaction mixture was diluted with ethyl acetate, separated the ethyl acetate layer, washed with water, followed by brine wash and was dried over anhydrous sodium sulphate and concentrated to get the crude material. The crude product was directly purified by column chromatography (48-53 % ethyl acetate in petroleum ether) yielded product as white solid (60 mg, 94 %). Mp(135.6-136.7C)
With potassium tert-butylate; In N,N-dimethyl-formamide; at 0 - 20℃;Inert atmosphere;
Example 3, Procedure A N*3*-[3,5-Dichloro-4-(pyridin-2-yloxy)-phenyl]-lH-[l,2,4]triazole-3,5-diamine (Compound 26) 2-(2,6-Dichloro-4-nitro-phenoxy)-pyridine O In a 50 mL round-bottomed flask, potassium tert-butoxide (3.53 g, 31.5 mmol, Eq: 1.50) and pyridin-2(lH)-one (2 g, 21.0 mmol, Eq: 1.00) were combined with DMF (25.0 ml) to give a light brown suspension at 0C under nitrogen. l,3-Dichloro-2-fluoro-5-nitrobenzene (4.42 g, 21.0 mmol, Eq: 1.00) was added. The reaction was stirred overnight at room temperature. The reaction mixture was diluted with CH2CI2 (50 mL), washed with H2O (25 mL) and brine (25 mL). The organic layer was dried over anhydrous MgS04, filtered and volatiles were removed under reduced pressure to yield an oil from which the compound was isolated by column chromatography (Hexanes/EtOAc = 70/30) to give an off-white solid 2.4 g (40%). MH+ 284.9
1-(2,6-dichloro-4-nitro-phenyl)-1H-pyridin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
47%
With potassium tert-butylate; In N,N-dimethyl-formamide; at 0 - 20℃;Inert atmosphere;
In a 50 mL round-bottomed flask, potassium tert-butoxide (3.54 g, 31.5 mmol, Eq: 1.50) and pyridin-2(1H)-one (2 g, 21.0 mmol, Eq: 1.00) were combined with DMF (25.0 ml) to give a light brown suspension at 0C under nitrogen. <strong>[3107-19-5]1,3-dichloro-2-fluoro-5-nitrobenzene</strong> (4.42 g, 21.0 mmol, Eq: 1.00) was added. The reaction was stirred overnight at room temperature. Thereaction mixture was diluted with CH2Ch (50 mL), washed with H20 (25 mL) and brine (25 mL). The organic layer was dried over anhydrous MgS04, filtered and volatiles were removed under reduced pressure to yield an oil from which the compound was isolated by columnchromatography (Hexanes/EtOAc = 70/30) to give an off-white solid 2.8 g (47%). MH+ 284.9
methyl 3-chloro-4-((2-oxopyridin-1(2H)-yl)methyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
With potassium carbonate; In acetonitrile; at 85℃;
To a suspension of <strong>[74733-30-5]methyl 4-(bromomethyl)-3-chlorobenzoate</strong> (500 mg, 1.8 mmol, 1.0 eq) and pyridin-2(lH)- one (360 mg, 3.8 mmol, 2.0 eq) in MeCN (10 mL) was added K2C03 (523 mg, 3.8 mmol, 2.0 eq). The mixture was heated to 85 C overnight. After cooled to rt, the mixture was concentrated in vacuo to give a solid, whihc was purified by flash chromatography to afford methyl 3-chloro-4-((2-oxopyridin-l (2H)-yl)methyl)benzoate as a white solid (413 mg, 78%
methyl 2,5-difluoro-4-((2-oxopyridin-1(2H)-yl)methyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
With potassium carbonate; In acetonitrile; at 70.0℃; for 2.0h;
To a solution of <strong>[1355488-72-0]methyl 4-(bromomethyl)-2,5-difluorobenzoate</strong> (500 mg, 2.0 mmol, 1.0 eq), pyridin-2(lH)- one (232 mg, 2.44 mmol) in CH3CN (10 mL) was added K2CO3 (841 mg, 6.1 mmol, 3.0 eq). The mixture was stirred at 70 C for 2 h. The mixture was evaporated to dryness, the residue was purified via silica column (PE/EtOAc = 1/1) to afford methyl 2,5-difluoro-4-((2-oxopyridin-l(2H)-yl)methyl)benzoate as a white solid (528 mg, 78%).
1-(2-methoxy-4-nitrophenyl)pyridin-2(1H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92 mg
With caesium carbonate; In N,N-dimethyl-formamide; at 120℃;
(i) 1-(2-Methoxy-4-nitrophenyl)pyridin-2(1 H)-one To a stirred solution of <strong>[454-16-0]1-fluoro-2-methoxy-4-nitrobenzene</strong> (250 mg, 1.461 mmol) and 2- hydroxypyridine (140 mg, 1.472 mmol) in DMF (4 mL) was added cesium carbonate (625 mg, 1.918 mmol). The mixture was heated to 120°C and stirred overnight. The reaction was cooled to rt and quenched with water (15 mL). On standing, a solid slowly precipitated from the mixture and was removed by filtration, washing with additional water. The filtrate was extracted with DCM and the organic phase dried via hydrophobic frit and concentrated in vacuo affording a yellow oil. The oil was purified by chromatography on the Companion (24g column, 0.5-3percent MeOH in DCM) to afford the sub-title compound (92 mg) as a yellow solid. LCMS m/z 247 (M+H)+ (ES+)
diphenyl(trifluoromethanesulfonato)-λ3-iodane[ No CAS ]
[ 142-08-5 ]
[ 24228-13-5 ]
Yield
Reaction Conditions
Operation in experiment
20%
With tris[2-phenylpyridinato-C2,N]iridium(III); potassium acetate; In acetonitrile; at 20℃; for 6.0h;Irradiation; Inert atmosphere; Glovebox; Schlenk technique;
General procedure: The reaction of 1a with 6ais representative (Table 2, entry 9). In a glovebox filled with nitrogen, Ir(ppy)3 (3.3 mg, 0.0050 mmol),Ph2IOTf (6a, 136.4 mg, 0.25 mmol), and potassium acetate (49.1 mg, 0.50 mmol) were placed in aSchlenk tube. The tube was sealed with a septum and then taken out of the glovebox. A solution ofN-methyl-2-pyridone (1a, 136.4 mg, 1.25 mmol) in MeCN (1 mL) was added using a syringe. Themixture was stirred for 6 h under blue light LED irradiation (12 DC/3 W). Water (20 mL) was added,and extraction was done with EtOAc (15 mL x 3). The combined organic phase was dried over sodium sulfate and then concentrated in vacuo. Purification via column chromatography (Wakosil C-200,hexane/EtOAc = 20/1 to EtOAc/CH2Cl2/Et3N = 1/1/0.05) followed by GPC provided pure1-methyl-3-phenylpyridin-2(1H)-one (7aa, 25.4 mg, 0.14 mmol, 55% yield).
2-oxo-6'-(trifluoromethyl)-2H-[1,2'-bipyridine]-4'-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 20℃; for 12h;
To a stirred solution of <strong>[1196155-38-0]2-chloro-6-(trifluoromethyl)isonicotinonitrile</strong> 1 (500 mg, 2.43 mmol) in N-methyl-2-pyrrolidone (10 mL) at RT, were added pyridin-2-ol (461 mg, 4.85 mmol) followed by K2C03 (1 g, 7.28 mmol). The mixture was stirred at RT for 12 h. Water (30 mL) was added and extracted with Et20 (2 x 30 mL). The combined organic extracts were washed with brine (15 mL), dried (Na2S04), filtered and concentrated. The residue was purified (silica gel; eluting 10percent EtOAc/hexanes) to afford compound 2 (520 mg, 81percent) as a pale yellow solid. 1H MR (500MHz, DMSO-i): delta 8.71 (s, 1H), 8.62 (s, 1H), 7.90 (m, 1H), 7.61 (m, 1H), 6.59 (m, 1H), 6.47 (m, 1H); LCMS Mass: 265.9 (M++l).
Was added to the reactorPyridine-2-one 19-1 (0.095 g, 1 mmol)Dicumyl peroxide (0.81 g, 3 mmol) and 2 ml of acetic acid,120 C reaction, TLC followed the reaction until complete.The crude product obtained after the completion of the reaction was purified by column chromatography (petroleum ether: ethyl acetate = 1: 1)Separation and purification to give the target product 19-2 (yield 85%).
With caesium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 40℃;
Take a 250mL eggplant-shaped bottle,Weigh 1.0 g of intermediate III-2 (5.0 mmol; 1.0 equiv),0.48 g of 2-hydroxypyridine (5.0 mmol; 1.0 equiv),2.5 g cesium carbonate (7.5 mmol; 1.5 equiv),0.6g potassium iodide (3.0mmol;0.6equiv),40mL of N,N-dimethylformamide added to the bottle,Stir well,Then it was heated to 40C and reacted overnight.Thin layer TLC board,An ultraviolet analyzer (254 nm) monitors the progress of the reaction.Then the reaction solution was filtered and evaporated to dryness.The resulting residue was treated with 2 mol/L NaOH aqueous solution,The ethyl acetate was re-dissolved and added to a separatory funnel.The aqueous phase is extracted 2 to 3 times with an equal volume of ethyl acetate.Combine the ethyl acetate layers,Add saturated aqueous sodium chloride,Then,The organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight.Filter out the desiccant,Weigh about 5g of 60-100 mesh silica gel powder into the filtrate.Rotary to dry sand,Silica gel column chromatography separation,The elution system selected was petroleum ether:ethyl acetate = 10:1.The resulting etherification reaction product is collected,A total of 0.27 g of a yellow solid IV-2a was obtained.Yield: 25.2%.
With potassium phosphate; copper(l) iodide; N,N`-dimethylethylenediamine; In toluene; at 120℃; for 2h;Inert atmosphere;
General procedure: Following a reported procedure,1 copper iodide (5 mol %), potassium phosphate tribasic (2.00 equiv), the corresponding 2-hydroxypyridine (1.00 equiv) and the corresponding 2-bromopyridine (2.00 equiv) were suspended in toluene [0.4 M] under N2. N,N?-Dimethylethylenediamine (0.10 equiv) was added and the resulting mixture was stirred 20 h at 120 C. The resulting mixture was allowed to cool to rt and then quenched with water. A small amount of N,N?-dimethylethylenediamine was added to dissolve the residual copper salts into the aqueous phase. The layers were separated and the aqueous layer was extracted three times with EtOAc (20 mL). The organic layers were combined, dried over MgSO4 and concentrated under reduced pressure. A purification by flash chromatography (eluent DCM/EtOAc 1:1 with 4%vv of NEt3) affordeded the desired product.
Step 1: Synthesis of Compounds of the Formula (IV) 6'-Bromo-[1(2H), 3'-bipyridin]-2-one (IV-2) 1.2 g (12.3 mmol) of 2(1H)-pyridinone were stirred in a mixture of 180 ml of dichloromethane and 30 ml of N,N-dimethylformamide, and 4.5 g (24.7 mmol) of copper(I) acetate, 2.0 ml of pyridine and 5.0 g (24.7 mmol) of 6-bromo-3-pyridinylboronic acid were added in succession. 4A molecular sieve was then added, and the mixture was stirred vigorously in an open vessel for three days Ammonium hydroxide solution was then added to the reaction mixture, resulting in the precipitation of a greasy residue. The supernatant was decanted off and the oil that remained was washed and concentrated under reduced pressure. The residue that remained was purified by column chromatography on silica gel (mobile phase: cyclohexane-acetone gradient). This gave 2.5 g (98.5% pure, 39.5% yield) of 6'-bromo-[1(2H),3'-bipyridin]-2-one. Log P value (HCOOH)=0.95 1H-NMR (400.0 MHz, d6-DMSO): delta=8.507 (12.1); 8.502 (12.0); 8.501 (11.9); 7.926 (7.2); 7.919 (7.0); 7.905 (11.0); 7.898 (11.0); 7.831 (15.4); 7.829 (16.0); 7.809 (10.0); 7.808 (10.3); 7.737 (6.7); 7.733 (7.2); 7.732 (6.7); 7.719 (7.1); 7.716 (7.2); 7.715 (6.7); 7.569 (4.5); 7.564 (4.5); 7.553 (4.9); 7.547 (6.9); 7.541 (4.9); 7.530 (5.0); 7.525 (4.6); 6.529 (9.1); 6.506 (8.6); 6.389 (5.1); 6.386 (5.3); 6.372 (9.3); 6.369 (9.5); 6.355 (5.0); 6.352 (5.0); 3.308 (45.2); 2.674 (0.5); 2.670 (0.7); 2.665 (0.5); 2.505 (83.4); 2.501 (109.7); 2.496 (81.8); 2.332 (0.5); 2.327 (0.7); 2.323 (0.5); 1.398 (0.5); 0.008 (0.8); 0.000 (23.6); -0.008 (1.0).
(1s,4s)-4-(pyridin-2-yloxy)cyclohexan-1-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
20.38%
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran;
[00466] Step A: (1r,4r)-<strong>[6995-79-5]cyclohexane-1,4-diol</strong> (500 mg, 4.304 mmol), pyridin-2-ol (272.9 mg, 2.870 mmol) and triphenylphosphine (752.7 mg, 2.870 mmol) were dissolved in THF (10 mL). DIAD (565.0 muL, 2.870 mmol) was added dropwise and stirred overnight. The reaction mixture was partitioned between 50percent brine and EtOAc, dried over sodium sulfate, filtered and concentrated. The residue was purified over silica gel (30 to 80percent EtOAc in hexanes) to afford (1s,4s)-4-(pyridin-2-yloxy)cyclohexan-1-ol (113 mg, 0.5847 mmol, 20.38 percent yield).
With potassium phosphate; copper(l) iodide; 1,10-Phenanthroline; In N,N-dimethyl-formamide; at 160℃; for 24h;
3.26 g of <strong>[10016-52-1]2,8-dibromodibenzofuran</strong>, 1.9 g of pyridin-2-ol, 0.2 g of CuI, 0.2 g of 1,10-phenanthroline, and 6.3 g of K3PO4 were added to 200 mL of dimethylformamide (DMF) and stirred at a temperature of 160 C. for 24 hours. After cooling, 400 mL of a mixed solution including brine ice was added thereto, and a reaction mixture was precipitated, filtered, and washed with water. An organic layer obtained therefrom by washing the reaction mixture with ethyl acetate and water three times was dried by using MgSO4 and dried under reduced pressure. Column chromatography was used to obtain 1.77 g (yield: 50%) of Intermediate 1-1.
tert-butyl N-[4-(pyridin-2-yloxy)cyclohexyl]carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40%
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 25℃; for 3h;Inert atmosphere;
Under nitrogen, a solution of <strong>[224309-64-2]tert-butyl N-(4-hydroxycyclohexyl)carbamate</strong> (1.2 g, 5.57 mmol, 1.00 equiv), pyridin-2-ol (795 mg, 8.36 mmol, 1.50 equiv), PPh3 (2.19 g, 8.35 mmol, 1.50 equiv), and DIAD (1.69 g, 8.36 mmol, 1.50 equiv) in THF (10 mL) was stirred for 3 h at 25 C. After concentration, the residue was applied onto a silica gel column eluting with EtOAc/petroleum ether (15:85) to afford 650 mg (40%) of the title compound as a colorless solid. LCMS (ESI, m/z): 293.18 [M+H]+.
With potassium phosphate; copper(l) iodide; 1,10-Phenanthroline; In N,N-dimethyl-formamide; at 160℃; for 24h;
General procedure: 3.26 g of <strong>[10016-52-1]2,8-dibromodibenzofuran</strong>, 1.9 g of pyridin-2-ol, 0.2 g of CuI, 0.2 g of 1,10-phenanthroline, and 6.3 g of K3PO4 were added to 200 mL of dimethylformamide (DMF) and stirred at a temperature of 160 C. for 24 hours. After cooling, 400 mL of a mixed solution including brine ice was added thereto, and a reaction mixture was precipitated, filtered, and washed with water. An organic layer obtained therefrom by washing the reaction mixture with ethyl acetate and water three times was dried by using MgSO4 and dried under reduced pressure. Column chromatography was used to obtain 1.77 g (yield: 50%) of Intermediate 1-1.
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