* 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 Polymer Science, 1959, vol. 40, p. 377,384
2
[ 626-64-2 ]
[ 5382-16-1 ]
Reference：
[1] Patent: US6018048, 2000, A,
[2] Journal of the American Chemical Society, 1958, vol. 80, p. 6412,6419
[3] Journal of Polymer Science, 1959, vol. 40, p. 377,384
3
[ 1692-15-5 ]
[ 626-64-2 ]
Yield
Reaction Conditions
Operation in experiment
76%
With copper(ll) sulfate pentahydrate; ellagic acid In methanol at 60℃; for 8 h; Green chemistry
General procedure: In a typical reaction, 10 molpercent CuSO4·5H2O, (0.049 g, 0.2 mmol)and 6.7 molpercent EA (20 mg) were mixed in methanol followed by2 mmol of phenylboronic acid. This reaction mixture was kept ina preheated oil bath by maintaining the temperature at 60 °C andstirred under atmospheric pressure. After completion of the reac-tion, modified by TLC, the mixture was washed twice with hot ethylacetate to remove the reactant and product. The hot ethyl acetatewas removed from the reaction mixture and the resulting crudeproduct was purified by a column chromatography using silicagel 260 mesh (pet ether:ethyl acetate) ratio (25:75). The recov-ered catalyst was reused for the next run. All the products werecharacterized by1H and13C NMR spectra.
Reference：
[1] Journal of Molecular Catalysis A: Chemical, 2014, vol. 395, p. 500 - 505
4
[ 1338215-40-9 ]
[ 626-64-2 ]
Yield
Reaction Conditions
Operation in experiment
95%
Stage #1: With cesium fluoride In N,N-dimethyl-formamide at 60℃; for 1 h; Inert atmosphere Stage #2: With water In N,N-dimethyl-formamideInert atmosphere
General procedure: To a solution of [2-(phenoxy)-ethyl]-trimethyl-silane (Table-3, entry-1) (195mg, 1.0 mmol) in dry DMF (2 ml) was added cesium fluoride (576 mg, 3.0 mmol) and heated at 60°C for 1 h. Reaction mass was diluted with water and extracted with ethyl acetate (3 x 20 ml). The combined organic layer was washed with water, brine solution, dried over anhydrous sodium sulphate and concentrated under reduce pressure to give phenol 92mg (93percent yield). Phenols of Table-3 are commercially available from Aldrich and its identity was confirmed by comparison of 1H NMR data with authentic sample.
General procedure: In a typical experiment, benzyl 4-methoxyphenyl carbamate (1a, 1 mmol) and 10 cm3 methanol were placed in a 100 cm3 round-bottomed flask fitted with a water condenser and placed over a magnetic stirrer. Nickel(II) chloride hexahydrate (5 mmol) was added to the flask, followed by slow addition of sodium borohydride (15 mmol) with vigorous stirring. A vigorous reaction took place and the reaction mixture turned black due to in situ formation of nickel boride. The progress of the reaction was monitored by TLC (petroleum ether: ethyl acetate 80:20, v/v). After completion, the reaction mixture was filtered through a Celite pad (~2.5 cm) and washed with methanol (3x10 cm3). The solution was concentrated ona rotavapor and diluted with water (~50 cm3), followed by extraction with dichloromethane (3x10 cm3). The combined dichloromethane extract was washed with water and dried over anhyd. K2CO3. The solvent was removed ona rotary evaporator and the product was dried. 4-Anisidine(2a) was obtained as colourless solid in 88percent yield. The products were identified by m.p., IR, and NMR spectra. The products Scheme 1, entry 24 and Scheme 2, entry 8 were purified by flash column chromatography on silica gel using petroleum ether:ethyl acetate (95:5, v/v) as eluent.
Reference：
[1] Chemistry - A European Journal, 2010, vol. 16, # 8, p. 2366 - 2370
[2] Tetrahedron Letters, 2011, vol. 52, # 41, p. 5338 - 5341
8
[ 6890-62-6 ]
[ 626-64-2 ]
Reference：
[1] Yakugaku Zasshi, 1945, vol. 65, # 4/8, p. 435,439[2] Chem.Abstr., 1951, p. 8527
[3] Yakugaku Zasshi, 1951, vol. 71, p. 1097[4] Chem.Abstr., 1952, p. 5042
[5] Yakugaku Zasshi, 1955, vol. 75, p. 127[6] Chem.Abstr., 1956, p. 1817
[7] Yakugaku Zasshi, 1955, vol. 75, p. 127[8] Chem.Abstr., 1956, p. 1817
[9] Journal of the Chemical Society, 1958, p. 1263,1264, 1266
9
[ 5421-92-1 ]
[ 626-64-2 ]
Reference：
[1] Chemische Berichte, 1931, vol. 64, p. 1045,1047
[2] Journal of the American Chemical Society, 1945, vol. 67, p. 79
[3] Journal of the Chemical Society, 1954, p. 1795,1797
[4] Acta Chemica Scandinavica (1947-1973), 1954, vol. 8, p. 390,392
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1988, p. 2335 - 2338
17
[ 1381932-78-0 ]
[ 626-64-2 ]
Reference：
[1] Journal of Organic Chemistry, 2012, vol. 77, # 13, p. 5781 - 5787
18
[ 36228-61-2 ]
[ 626-64-2 ]
Reference：
[1] Journal of Organic Chemistry, 2012, vol. 77, # 13, p. 5781 - 5787
19
[ 24762-89-8 ]
[ 626-64-2 ]
Reference：
[1] Journal of Organic Chemistry, 2012, vol. 77, # 13, p. 5781 - 5787
20
[ 74669-53-7 ]
[ 626-64-2 ]
Reference：
[1] Journal of Organic Chemistry, 2012, vol. 77, # 13, p. 5781 - 5787
21
[ 74669-51-5 ]
[ 626-64-2 ]
Reference：
[1] Journal of Organic Chemistry, 2012, vol. 77, # 13, p. 5781 - 5787
22
[ 74669-54-8 ]
[ 626-64-2 ]
Reference：
[1] Journal of Organic Chemistry, 2012, vol. 77, # 13, p. 5781 - 5787
23
[ 74669-55-9 ]
[ 626-64-2 ]
Reference：
[1] Journal of Organic Chemistry, 2012, vol. 77, # 13, p. 5781 - 5787
24
[ 74669-56-0 ]
[ 626-64-2 ]
Reference：
[1] Journal of Organic Chemistry, 2012, vol. 77, # 13, p. 5781 - 5787
25
[ 74669-62-8 ]
[ 626-64-2 ]
Reference：
[1] Journal of Organic Chemistry, 2012, vol. 77, # 13, p. 5781 - 5787
26
[ 108-96-3 ]
[ 626-64-2 ]
Reference：
[1] Journal of Organic Chemistry, 1980, vol. 45, # 8, p. 1354 - 1362
[2] Journal of Organic Chemistry USSR (English Translation), 1984, vol. 20, p. 1153 - 1158[3] Zhurnal Organicheskoi Khimii, 1984, vol. 20, # 6, p. 1268 - 1274
[4] Journal fuer Praktische Chemie (Leipzig), 1982, vol. 324, # 3, p. 369 - 378
27
[ 626-61-9 ]
[ 626-64-2 ]
Reference：
[1] Monatshefte fuer Chemie, 1885, vol. 6, p. 315[2] Chemische Berichte, 1885, vol. 18, p. 930
28
[ 110-89-4 ]
[ 36228-61-2 ]
[ 626-64-2 ]
[ 776-75-0 ]
Reference：
[1] Bulletin of the Korean Chemical Society, 2011, vol. 32, # 6, p. 1907 - 1911
[2] Bulletin of the Korean Chemical Society, 2016, vol. 37, # 10, p. 1577 - 1581
29
[ 110-91-8 ]
[ 36228-61-2 ]
[ 626-64-2 ]
[ 1468-28-6 ]
Reference：
[1] Bulletin of the Korean Chemical Society, 2011, vol. 32, # 6, p. 1907 - 1911
[2] Bulletin of the Korean Chemical Society, 2016, vol. 37, # 10, p. 1577 - 1581
30
[ 110-85-0 ]
[ 36228-61-2 ]
[ 626-64-2 ]
[ 13754-38-6 ]
Reference：
[1] Bulletin of the Korean Chemical Society, 2011, vol. 32, # 6, p. 1907 - 1911
[2] Bulletin of the Korean Chemical Society, 2016, vol. 37, # 10, p. 1577 - 1581
31
[ 103-76-4 ]
[ 36228-61-2 ]
[ 626-64-2 ]
[ 56227-56-6 ]
Reference：
[1] Bulletin of the Korean Chemical Society, 2011, vol. 32, # 6, p. 1907 - 1911
[2] Bulletin of the Korean Chemical Society, 2016, vol. 37, # 10, p. 1577 - 1581
32
[ 110-89-4 ]
[ 74669-53-7 ]
[ 626-64-2 ]
[ 13707-23-8 ]
Reference：
[1] Bulletin of the Korean Chemical Society, 2011, vol. 32, # 6, p. 1907 - 1911
33
[ 110-89-4 ]
[ 74669-51-5 ]
[ 626-64-2 ]
[ 26163-40-6 ]
Reference：
[1] Bulletin of the Korean Chemical Society, 2011, vol. 32, # 6, p. 1907 - 1911
34
[ 110-89-4 ]
[ 74669-54-8 ]
[ 626-64-2 ]
[ 57700-94-4 ]
Reference：
[1] Bulletin of the Korean Chemical Society, 2011, vol. 32, # 6, p. 1907 - 1911
35
[ 110-89-4 ]
[ 74669-56-0 ]
[ 626-64-2 ]
[ 26163-45-1 ]
Reference：
[1] Bulletin of the Korean Chemical Society, 2011, vol. 32, # 6, p. 1907 - 1911
36
[ 7755-92-2 ]
[ 36228-61-2 ]
[ 626-64-2 ]
[ 57238-77-4 ]
Reference：
[1] Bulletin of the Korean Chemical Society, 2011, vol. 32, # 6, p. 1907 - 1911
37
[ 36228-61-2 ]
[ 626-56-2 ]
[ 626-64-2 ]
[ 19202-02-9 ]
Reference：
[1] Bulletin of the Korean Chemical Society, 2011, vol. 32, # 6, p. 1907 - 1911
38
[ 110-89-4 ]
[ 626-64-2 ]
[ 15563-40-3 ]
Reference：
[1] Bulletin of the Korean Chemical Society, 2016, vol. 37, # 10, p. 1577 - 1581
39
[ 626-56-2 ]
[ 626-64-2 ]
Reference：
[1] Bulletin of the Korean Chemical Society, 2016, vol. 37, # 10, p. 1577 - 1581
40
[ 110-85-0 ]
[ 626-64-2 ]
Reference：
[1] Bulletin of the Korean Chemical Society, 2016, vol. 37, # 10, p. 1577 - 1581
41
[ 103-76-4 ]
[ 626-64-2 ]
Reference：
[1] Bulletin of the Korean Chemical Society, 2016, vol. 37, # 10, p. 1577 - 1581
42
[ 110-91-8 ]
[ 626-64-2 ]
[ 2032-36-2 ]
Reference：
[1] Bulletin of the Korean Chemical Society, 2016, vol. 37, # 10, p. 1577 - 1581
43
[ 110-86-1 ]
[ 109-00-2 ]
[ 142-08-5 ]
[ 626-64-2 ]
Reference：
[1] Journal of Physical Chemistry, 1980, vol. 84, # 20, p. 2548 - 2551
44
[ 101349-88-6 ]
[ 67-66-3 ]
[ 7719-12-2 ]
[ 626-64-2 ]
Reference：
[1] Journal of Organic Chemistry, 1953, vol. 18, p. 534,541
[2] Yakugaku Zasshi, 1951, vol. 71, p. 263,265[3] Yakugaku Zasshi, 1955, vol. 75, p. 130,133[4] Chem.Abstr., 1956, p. 1817
45
[ 110-86-1 ]
[ 7664-93-9 ]
[ 626-64-2 ]
[ 5402-20-0 ]
[ 636-73-7 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1958, vol. 77, p. 963,968, 970
46
[ 7732-18-5 ]
[ 5421-92-1 ]
[ 626-64-2 ]
Reference：
[1] Chemische Berichte, 1931, vol. 64, p. 1045,1047
[2] Journal of the Chemical Society, 1954, p. 1795,1797
47
[ 626-64-2 ]
[ 36953-41-0 ]
[ 25813-25-6 ]
Reference：
[1] Synthesis, 2001, # 14, p. 2175 - 2179
48
[ 626-64-2 ]
[ 36953-41-0 ]
Reference：
[1] Patent: WO2012/148808, 2012, A1,
49
[ 626-64-2 ]
[ 89282-03-1 ]
Yield
Reaction Conditions
Operation in experiment
65%
With sodium hydroxide; iodine In water at 85℃; for 16 h;
Step 1. 3-iodopyridin-4-ol (46)[00370] To a stirred solution of 4-hydroxypyridine (5.0 g, 52.6 mmol) in water (90 ml) were successively added sodium hydroxide (5.4 g, 135 mmol) and iodine (28.0 g,1 10 mmol). The reaction mixture was heated 85°C for 16 hours then cooled-down to room temperature. The product was collected by filtration and dry under high vacuum to afford the title compound 46 (7.56 g, 34.2 mmol, 65percent) as a white solid. MS: 222.0(M+l).
32%
With potassium iodide; iodine; sodium carbonate In water
4-Hydroxy-pyridine (23.8 g, 250 mmol) and Na2CO3 (7.4 g, 70 mmol) are added to 80 mL water. The reaction mixture is heated to reflux and a solution of iodine (23.2 g, 92 mmol) and potassium iodide (80 g, 482 mmol) in 250 mL water is slowly added drop-wise. The reaction is refluxed for 1 h after the addition. The mixture is filtered hot to remove a by-product, and the filtrate is cooled to rt, a solid is removed and dried to afford 3-iodo-4-pyridinol (C10) (32percent yield). HRMS (FAB) calculated for C5H4INO+H: 221.9418, found 221.9416 (M+H)+.
31%
With iodine; sodium carbonate In water at 20℃; for 12 h;
Add 10.6 g (0.10 mol) of Na2CO3 and 12.7 g (0.05 mol) of I2 to a solution of 4.76 g (0.05 mol) pyridin-4-ol in 200 ml of water. Stir the reaction mass at room temperature for 12 h; use the TLC method to ensure the completeness of the reaction. Add 12 ml of HCl to =5, Na2S2O3 till color removal. Filtrate the resulting precipitate, mix the precipitate with 200 ml of boiling ethanol and filtrate one more time. Concentrate the filtrate under reduced pressure, re-crystallize residue from methanol. Yield: 3.4 g (31percent).
37a. 4-hydroxy-3-iodopyridine To a solution of 4-hydroxypyridine (4.76 g, 50.1 mmol) and Na2 CO3 (10.8 g, 100 mmol) in 200 mL of water was added I2 (12.7 g, 50.1 mmol). The reaction mixture was stirred for 14 h then adjusted to pH 5 with concentrated HCl. The resulting solids were suspended in boiling ethanol and hot filtered. The solvent was removed and the resulting solids recrystallized from MeOH to afford 5.1 g (46percent) of the title compound: 1 H NMR (DMSO-d6) d 8.26 (br s, 1H), 7.70 (s, 1H), 7.69 (d, J=7 Hz, 1H), 6.14 (d, J=7 Hz, 1H); MS (DCI/NH3) m/z: 222 (M+H)+, 239 (M+NH4)+.
Reference：
[1] Patent: US6001849, 1999, A,
51
[ 626-64-2 ]
[ 54-96-6 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1986, vol. 23, # 3, p. 669 - 672
[2] Journal of Heterocyclic Chemistry, 1986, vol. 23, # 3, p. 669 - 672
[3] Journal of Heterocyclic Chemistry, 1986, vol. 23, # 3, p. 669 - 672
52
[ 626-64-2 ]
[ 33631-09-3 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2012, vol. 10, # 33, p. 6693 - 6704
[2] Inorganic Chemistry, 2013, vol. 52, # 7, p. 3653 - 3662
53
[ 626-64-2 ]
[ 4783-86-2 ]
Reference：
[1] Chemical Science, 2015, vol. 6, # 2, p. 1277 - 1281
54
[ 626-64-2 ]
[ 24388-23-6 ]
[ 4783-86-2 ]
Reference：
[1] Journal of the American Chemical Society, 2017, vol. 139, # 13, p. 4769 - 4779
With N-Bromosuccinimide In tetrachloromethane at 20℃; for 24 h;
Step 36-1.; To a solution of 4-hydroxypyridine (T96-1, 7.0 g, 74 mmol) in CCl4 (360 mL) at rt was added NBS (26.2 g, 0.147 mol). The solution was stirred for 24 h in the dark (covered with aluminum foil). The mixture was concentrated under reduced pressure and the resulting residue triturated with MeOH, then with acetone to give 18.9 g (100percent) of T96-2.
88%
With N-Bromosuccinimide In tetrachloromethane at 25℃; for 30 h; Inert atmosphere
In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 500 mL of tetrachloromethane, 23.75 g (250 mmol) of 4-hydroxypyridine, and 89 g (500 mmol) of N-bromosuccinimide. Stir at 25 °C for 30 hours. Filter the precipitate, wash with 50 mL of tetrachloromethane; stir the precipitate in a mixture of 500 mL of acetone and 150 mL of methanol for 15 minutes. Filter the suspension; stir the precipitate in a mixture of 400 mL of acetone and 400 mL of dichloromethane for 15 minutes. Filter the suspension; mix the precipitate vigorously in 400 mL of acetonitrile for 20 minutes. Filter the suspension; dry the precipitate under vacuum at 40 °C. Yield: 56 g (88percent).
86%
With N-Bromosuccinimide In tetrachloromethane at 20℃; for 24 h;
4-Pyridinol (M-40) (20.0 g, 210 mmol) was suspended in carbon tetrachloride (400 mL), NBS (77.0 g, 431mmol) was added, and the mixture was stirred under shading at room temperature for 24 hr. The solvent was evaporatedunder reduced pressure, and the residue was suspended in acetone (400 mL)/methanol (120 mL), and the mixture wasstirred at room temperature for 30 min. The precipitated solid was collected by filtration and suspended in acetonitrile(1.0 L), and the suspension was stirred at room temperature for 1 hr. The solid were collected by filtration, and driedunder reduced pressure to give compound (M-41) (yield 46.0 g, 86percent) as a white solid
86%
With N-Bromosuccinimide In tetrachloromethane at 20℃; for 24 h;
4-pyridinol (M-40) (20.0 g, 210 mmol)Was suspended in carbon tetrachloride (400 mL)NBS (77.0 g, 431 mmol) was added and, under light shielding,And the mixture was stirred at room temperature for 24 hours.After distilling off the solvent under reduced pressure,The residue was suspended in acetone (400 mL) / methanol (120 mL) and stirred at room temperature for 30 minutes.The precipitated solid was collected by filtration,This was suspended in acetonitrile (1.0 L)And the mixture was stirred at room temperature for 1 hour. After collecting the solid by filtration,After drying under reduced pressure, the compound (M-41)(Yield 46.0 g, yield 86percent)As a white solidIt was.
68%
With N-Bromosuccinimide In tetrachloromethane at 20℃; for 24 h; Darkness
To a stirring solution of pyridine-4-ol (5g, 52.6 mmol) in CC14 (100 mL) at room temperature was added N-bromosuccinimide (18.72g, 105 mmol). The reaction mixture was allowed to stir under cover of darkness for 24 hours. The solvent was removed under reduced pressure, and the obtained solid was dissolved with acetone (100 mL) and MeOH (30 mL) and stirred for 5 min. The resulting slurry was filtered and the solid was rinsed with excess acetone/CH2Cl2. The solid material was vigorously stirred with acetonitrile, and filtered to yield Intermediate 31A (9.04g, 35.7 mmol, 68percent yield) as an off-white solid. MS (ES): m/z=253.8 [M+H]+. 3/4 NMR (400 MHz, MeOD) δ ppm 8.30 (2 H, s).
Reference：
[1] Synthesis, 2001, # 14, p. 2175 - 2179
61
[ 626-64-2 ]
[ 7153-08-4 ]
Yield
Reaction Conditions
Operation in experiment
94%
With iodine; sodium acetate; sodium hydroxide In water for 0.333333 h; Reflux
To a solution of starting material 4-hydroxypyridine (9) (5.01 g, 52.6mmol, 1.0equiv) in H2O (67 mL) was added a solution of NaOH (13.2 g, 330mmol, 6.3 equiv) and NaOAc (40.1 g, 489mmol, 9.3 equiv) in H2O (167 mL). After the solution was stirred and refluxed,powdered I2 (46.9 g, 184mmol, 3.5 equiv) was added to the solution. The solution was then acidified with 50percent AcOH, and neutralized with 40percent NaOH. This acidification neutralization procedure was conducted under reflux and repeated three times in 20min. The forth acidification was made until free iodine was precipitated. After sublimation of the I2 by boiling, the residue was filtered, washed with boiling water, and then dried to give the product 12 as a colorless powder (17.18 g, 49.5mmol, 94percent); mp 280 °C with decomposition; IR (KBr, cm-1): 3166, 2952, 2880, 2805, 2360, 1605, 1525, 1334, 1270, 1038, 846, 746, 712, 597; 1HNMR (300 MHz, DMSO-d6): δ 11.95 (1H, s, OH), 8.27 (2H, s, H2/6); 13CNMR (75 MHz, DMSO-d6): δ 170.52, 143.04, 86.59; ESI-HRMS (m/z) calcd for C5H2I2NO [M-H]- 345.8231, found 345.8231.
Reference：
[1] Tetrahedron Letters, 1997, vol. 38, # 14, p. 2467 - 2470
[2] Chemical Communications, 2012, vol. 48, # 26, p. 3233 - 3235
[3] Bulletin of the Chemical Society of Japan, 2015, vol. 88, # 5, p. 673 - 683
[4] Journal of Materials Chemistry, 2001, vol. 11, # 9, p. 2271 - 2281
[5] Angewandte Chemie - International Edition, 2016, vol. 55, # 40, p. 12398 - 12402[6] Angew. Chem., 2016, vol. 128, # 40, p. 12586 - 12590,5
[7] Patent: US6642237, 2003, B1, . Location in patent: Page/Page column 79; 186
62
[ 626-64-2 ]
[ 100-39-0 ]
[ 49826-70-2 ]
Yield
Reaction Conditions
Operation in experiment
82%
at 80℃; for 2 h; Green chemistry
General procedure: Phenol (0.5 mmol), benzyl bromide(1.2 mmol) and KOH (2.0 mmol) was added to the DES (1 mL) and heated at temperature (80°C) for 2 h. After cooling to room temperature water was added and the product was extracted with ethyl acetate (1 3 mL) andanalyzed by GC–MS after the addition of hexamethylbenzene as an internal standard. The product was purified using column chromatography on silica gel(hexane/EtOAc::99:1). The pure product was characterized by 1H NMR and 13CNMR.Table 4 Comparison of different methodologies for benzylation of phenols with benzyl bromide
Reference：
[1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1982, vol. 21, # 8, p. 800 - 802
[2] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1982, vol. 21, # 8, p. 800 - 802
64
[ 626-64-2 ]
[ 33544-42-2 ]
Reference：
[1] Journal of Medicinal Chemistry, 1989, vol. 32, # 11, p. 2474 - 2485
[2] Journal of Heterocyclic Chemistry, 1986, vol. 23, # 3, p. 669 - 672
65
[ 626-64-2 ]
[ 1681-37-4 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1986, vol. 23, # 3, p. 669 - 672
66
[ 626-64-2 ]
[ 5435-54-1 ]
Yield
Reaction Conditions
Operation in experiment
76%
at 60 - 70℃; for 3 h; Inert atmosphere
Pyridin-4-ol 29 (300g, 3.15mol, 1wt) was charged portionwise to concentrated sulphuric acid (1500mL, 5vol) in a 20000mL flask under an atmosphere of nitrogen. The nitrating mixture was prepared by the cautious addition of concentrated sulphuric acid to concentrated nitric acid with stirring. The nitrating mixture was then carefully charged to the 20000mL reactor. The reaction mixture was heated at 60oC to 70oC over a period of 3 hours and allowed to cool to ambient temperature over 16 hours. The resulting reaction mixture was poured into 10000mL of ice/water. The mixture was basified to pH 11-12 by the dropwise addition of concentrated ammonia solution (8000mL, 26.7vol). The reaction mixture was concentrated under reduced pressure, the residue stirred in pyridine (10000mL, 33vol) and filtered. The resulting inorganic solids were dissolved in water (10000mL, 33vol) and extracted with 3 portions of pyridine (3x 2500L, 3x 8.3vol) the combined pyridine extractions were concentrated. The residue was stirred in acetone (6600mL, 22vol) for 1.5 hours, filtered and dried over 16 hours to give 716.1g of crude product. Crude 4-hydroxy-3-nitropyridine (623.6g) was slurried in water (1250mL, 2vol) for 60 minutes to remove residual inorganic material. The resulting slurry was filtered and dried for 72 hours to give the title compound (334.4g, 76percent, KF: 0.25percent).1H NMR (400MHz, DMSO): d 6.58 (d, J=6Hz, 1H), 7.85 (d, J=6Hz, 1H), 8.88 (s, 1H).
Reference：
[1] Organic Process Research and Development, 2004, vol. 8, # 6, p. 903 - 908
[2] Chemistry of Heterocyclic Compounds, 2012, vol. 48, # 8, p. 1235 - 1250[3] Khim. Geterotsikl. Soedin., 2012, vol. 48, # 8, p. 1235 - 1250,16
[4] Journal of Materials Chemistry C, 2014, vol. 2, # 48, p. 10343 - 10356
[5] Heterocycles, 1999, vol. 51, # 4, p. 721 - 726
[6] Tetrahedron Letters, 2011, vol. 52, # 41, p. 5292 - 5296
[7] Journal of Medicinal Chemistry, 1989, vol. 32, # 11, p. 2474 - 2485
[8] Tetrahedron, 2006, vol. 62, # 48, p. 11054 - 11062
[9] Journal of Heterocyclic Chemistry, 1986, vol. 23, # 3, p. 669 - 672
[10] Inorganic Chemistry, 2013, vol. 52, # 7, p. 3653 - 3662
[11] Organic and Biomolecular Chemistry, 2012, vol. 10, # 33, p. 6693 - 6704
[12] Patent: CN105622495, 2016, A, . Location in patent: Paragraph 0020; 0021
67
[ 626-64-2 ]
[ 13091-23-1 ]
Reference：
[1] Tetrahedron, 2006, vol. 62, # 48, p. 11054 - 11062
[2] Journal of Medicinal Chemistry, 1989, vol. 32, # 11, p. 2474 - 2485
[3] Patent: US5550118, 1996, A,
[4] Tetrahedron Letters, 2011, vol. 52, # 41, p. 5292 - 5296
[5] Chemistry of Heterocyclic Compounds, 2012, vol. 48, # 8, p. 1235 - 1250[6] Khim. Geterotsikl. Soedin., 2012, vol. 48, # 8, p. 1235 - 1250,16
[7] Journal of Materials Chemistry C, 2014, vol. 2, # 48, p. 10343 - 10356
68
[ 626-64-2 ]
[ 31872-62-5 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2012, vol. 10, # 33, p. 6693 - 6704
[2] Inorganic Chemistry, 2013, vol. 52, # 7, p. 3653 - 3662
Hydrogenation of <strong>[626-64-2]4-hydroxypyridine</strong> was performed in the same manner as in Example 1 except that 2.0 g of the R-Ru catalyst prepared in Example 1, 5.0 g of <strong>[626-64-2]4-hydroxypyridine</strong>, 15 g of deignized water, and 15 g of methanol were used, the reaction temperature was increased from room temperature to 40 C., and the reaction time was 1.7 hours. The reaction results were as follows. 4-Hydroxypyridine conversion was 100%, and yield of 4-hydroxypiperidine was 95% by mole.
99.5%Chromat.
With hydrogenchloride; 5% active carbon-supported ruthenium; hydrogen; In water; at 95℃; under 26252.6 Torr; for 24h;Autoclave;
The method for screening <strong>[626-64-2]4-hydroxypyridine</strong> catalytic hydrogenation reaction by means of ORP data in the present embodiment is as follows: 1. Dissolving 1.9 g of <strong>[626-64-2]4-hydroxypyridine</strong> in 15-20 mL of water, 30%-50% glacial acetic acid and 5-15% hydrochloric acid aqueous solution (V/V) to obtain a possible medium environment for catalytic hydrogenation of the substrate;2. The ORP of each of the above systems was tested separately, and the catalytic hydrogenation reaction of 25% acetic acid, 40% acetic acid, 5% hydrochloric acid and 10% hydrochloric acid aqueous solution, which may have higher oxidation performance, was selected based on the measurement results. ;3. Dissolve 19g of <strong>[626-64-2]4-hydroxypyridine</strong> in about 200mL of acetic acid or hydrochloric acid solution, catalyze with 5% Ru/C, add 5%, 10%, 15% substrate mass; hydrogen pressure in the reactor is controlled at 3-5MPa , temperature 80-100 C, when the hydrogen pressure is no longer reduced, sample and monitor separately, filter the reaction solution under different schemes, carry out GC or GC-MS (Fig. 1) of ORP and 4-hydroxypiperidine products, combined with 4 -Hydroxypyridine conversion, 4-hydroxypiperidine content and initial ORP, etc. Analysis of <strong>[626-64-2]4-hydroxypyridine</strong> hydrogenation reaction The appropriate reaction medium ORP range is 320-400 mV, catalyst addition amount is 5-10%; hydrogen pressure is 3.5 MPa, temperature 95-100 C;4. The amount of fixed Ru/C is 8%, the reaction pressure is 3.5 MPa and the temperature is 95 C. The concentration of <strong>[626-64-2]4-hydroxypyridine</strong> substrate is adjusted to 1.5-2.0 mol/L and the acidity of the medium is adjusted to make the ORP be around 330-350 and 370-390 mV. Then, the catalytic hydrogenation reaction was carried out again, and the reaction was sampled at 16h and 24h respectively. The area percentage of <strong>[626-64-2]4-hydroxypyridine</strong> and 4-hydroxypiperidine was determined by GC area normalization method under different ORP schemes:Considering the data of <strong>[626-64-2]4-hydroxypyridine</strong> conversion rate and 4-hydroxypiperidine product content, the preferred preparation process of 4-hydroxypiperidine is as follows: 2mol/L substrate concentration, 35% acetic acid aqueous solution (about ORP 340mV) or 10% hydrochloric acid aqueous solution (ORP 380mV) is the reaction medium, 5% ruthenium charcoal catalytic addition amount 8%, temperature 95 C, hydrogen pressure 3.5 MPa, It takes about 24 hours to complete the reaction under these conditions.
With sulfuric acid; nitric acid; at 60 - 70℃; for 3h;Inert atmosphere;
Pyridin-4-ol 29 (300g, 3.15mol, 1wt) was charged portionwise to concentrated sulphuric acid (1500mL, 5vol) in a 20000mL flask under an atmosphere of nitrogen. The nitrating mixture was prepared by the cautious addition of concentrated sulphuric acid to concentrated nitric acid with stirring. The nitrating mixture was then carefully charged to the 20000mL reactor. The reaction mixture was heated at 60oC to 70oC over a period of 3 hours and allowed to cool to ambient temperature over 16 hours. The resulting reaction mixture was poured into 10000mL of ice/water. The mixture was basified to pH 11-12 by the dropwise addition of concentrated ammonia solution (8000mL, 26.7vol). The reaction mixture was concentrated under reduced pressure, the residue stirred in pyridine (10000mL, 33vol) and filtered. The resulting inorganic solids were dissolved in water (10000mL, 33vol) and extracted with 3 portions of pyridine (3x 2500L, 3x 8.3vol) the combined pyridine extractions were concentrated. The residue was stirred in acetone (6600mL, 22vol) for 1.5 hours, filtered and dried over 16 hours to give 716.1g of crude product. Crude 4-hydroxy-3-nitropyridine (623.6g) was slurried in water (1250mL, 2vol) for 60 minutes to remove residual inorganic material. The resulting slurry was filtered and dried for 72 hours to give the title compound (334.4g, 76%, KF: 0.25%).1H NMR (400MHz, DMSO): d 6.58 (d, J=6Hz, 1H), 7.85 (d, J=6Hz, 1H), 8.88 (s, 1H).
<strong>[626-64-2]4-hydroxypyridine</strong> 5mol and ionic liquid mixing evenly, while stirringAnd the mixture was stirred for 10 minutes. Then, 1 mol of mesoporous silica was added, the temperature was raised to 95 C, and the mixture was stirred for 2 hours. The mixture was cooled to room temperature and concentrated to pH 5-7 in an ice-salt bath. Deionized water, stirring until the precipitation is complete, filtering and washing with deionized water for 2-5 times and drying to obtain 4-hydroxy-3-nitropyridine;
With L-Selectride; In tetrahydrofuran; for 2h;Reflux; Inert atmosphere;
General procedure: Toa solution of 1 (1.00 mmol) in THF (7.0 mL) was added L-selectride(1 M in THF, 3.0 mL, 3.00 mmol, 3 equiv) under an argonatmosphere. After being refluxed and monitored by TLC, thereaction mixture was quenched with MeOH and evaporated invacuo. The residue was purified by silica gel column chromatographyto give the desired compound 2.
With N-Bromosuccinimide; In tetrachloromethane; at 20℃; for 24h;
Step 36-1.; To a solution of <strong>[626-64-2]4-hydroxypyridine</strong> (T96-1, 7.0 g, 74 mmol) in CCl4 (360 mL) at rt was added NBS (26.2 g, 0.147 mol). The solution was stirred for 24 h in the dark (covered with aluminum foil). The mixture was concentrated under reduced pressure and the resulting residue triturated with MeOH, then with acetone to give 18.9 g (100%) of T96-2.
88%
With N-Bromosuccinimide; In tetrachloromethane; at 25℃; for 30h;Inert atmosphere;
In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 500 mL of tetrachloromethane, 23.75 g (250 mmol) of <strong>[626-64-2]4-hydroxypyridine</strong>, and 89 g (500 mmol) of N-bromosuccinimide. Stir at 25 C for 30 hours. Filter the precipitate, wash with 50 mL of tetrachloromethane; stir the precipitate in a mixture of 500 mL of acetone and 150 mL of methanol for 15 minutes. Filter the suspension; stir the precipitate in a mixture of 400 mL of acetone and 400 mL of dichloromethane for 15 minutes. Filter the suspension; mix the precipitate vigorously in 400 mL of acetonitrile for 20 minutes. Filter the suspension; dry the precipitate under vacuum at 40 C. Yield: 56 g (88%).
86%
With N-Bromosuccinimide; In tetrachloromethane; at 20℃; for 24h;
4-Pyridinol (M-40) (20.0 g, 210 mmol) was suspended in carbon tetrachloride (400 mL), NBS (77.0 g, 431mmol) was added, and the mixture was stirred under shading at room temperature for 24 hr. The solvent was evaporatedunder reduced pressure, and the residue was suspended in acetone (400 mL)/methanol (120 mL), and the mixture wasstirred at room temperature for 30 min. The precipitated solid was collected by filtration and suspended in acetonitrile(1.0 L), and the suspension was stirred at room temperature for 1 hr. The solid were collected by filtration, and driedunder reduced pressure to give compound (M-41) (yield 46.0 g, 86%) as a white solid
86%
With N-Bromosuccinimide; In tetrachloromethane; at 20℃; for 24h;
4-pyridinol (M-40) (20.0 g, 210 mmol)Was suspended in carbon tetrachloride (400 mL)NBS (77.0 g, 431 mmol) was added and, under light shielding,And the mixture was stirred at room temperature for 24 hours.After distilling off the solvent under reduced pressure,The residue was suspended in acetone (400 mL) / methanol (120 mL) and stirred at room temperature for 30 minutes.The precipitated solid was collected by filtration,This was suspended in acetonitrile (1.0 L)And the mixture was stirred at room temperature for 1 hour. After collecting the solid by filtration,After drying under reduced pressure, the compound (M-41)(Yield 46.0 g, yield 86%)As a white solidIt was.
68%
With N-Bromosuccinimide; In tetrachloromethane; at 20℃; for 24h;Darkness;
To a stirring solution of pyridine-4-ol (5g, 52.6 mmol) in CC14 (100 mL) at room temperature was added N-bromosuccinimide (18.72g, 105 mmol). The reaction mixture was allowed to stir under cover of darkness for 24 hours. The solvent was removed under reduced pressure, and the obtained solid was dissolved with acetone (100 mL) and MeOH (30 mL) and stirred for 5 min. The resulting slurry was filtered and the solid was rinsed with excess acetone/CH2Cl2. The solid material was vigorously stirred with acetonitrile, and filtered to yield Intermediate 31A (9.04g, 35.7 mmol, 68% yield) as an off-white solid. MS (ES): m/z=253.8 [M+H]+. ¾ NMR (400 MHz, MeOD) delta ppm 8.30 (2 H, s).
With bromine; potassium hydroxide; In water; at 0℃; for 3h;
To a stirred solution of potassium hydroxide (2.35 g, 0.042 mol) in water (40 mL) was added <strong>[626-64-2]pyridin-4-ol</strong> ( 2.0 g, 0.021 mol) and mixture was cooled to 0 C. To the above solution bromine was added slowly at 0 C and stirred for 3 h. The reaction mixture was filtered and washed the solid with cold water, hexane and dried under vacuum to obtain the title compound. MS (M+l): 251.8.
REFERENCE EXAMPLE 43 1-tert-Butoxycarbonyl-4-(4-pyridinyloxy)piperidine By a similar manner to Reference Example 35, 1-tert-butoxycarbonyl-4-hydroxypiperidine (1.01 g, 5.0 mmol) was reacted with <strong>[626-64-2]4-hydroxypyridine</strong> (0.57 g, 6.0 mmol) to give the titled compound as pale yellow solid substance(1.05 g, 75%). IR (KBr) 2975, 2870, 1694 cm-1; 1H-NMR (CDCl3) delta 1.47 (9H, s), 1.7-2.0 (4H, m), 3.37 (2H, ddd, J=3.6, 7.2, and 13.4Hz), 3.69 (2H, ddd, J=4.0, 7.6, and 13.4Hz), 4.58 (1H, tt, J=3.6 and 7.0Hz), 6.8-6.9 (2H, m), 8.4-8.5 (2H, m).
67%
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20 - 55℃; for 15h;
To a stirred solution of <strong>[626-64-2]4-hydroxypyridine</strong> (2 g, 21.03 mmol) in 70 mL of anhydrous THF at room temperature was added 4-hydroxypiperidine (5.29 g, 26.28 mmol). Triphenyl phosphine (6.9 g, 26.31 mmol) was then added followed by dropwise addition of diisopropylazodicarboxylate (5.2 mL, 26.41 mmol). The reaction was heated to 55C and allowed to stir at this temperature for about 15 hours. The reaction mixture was then cooled to RT and concentrated in vacuo. The resulting oily residue was treated with a 1.0 M HCl aqueous solution (30 mL), and the acidic solution was washed with CH2Cl2 (30 mL x 2). The combined CH2Cl2 washings were re-extracted with a 1.0 M HCl aqueous solution (10 mL) and H2O (20 mL), then discarded. The aqueous fractions were combined, basified to pH ~ 12 using a 1.0 M NaOH aqueous solution, and the basic solution was extracted with CH2Cl2 (50 mL x 4). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, then concentrated in vacuo to provide a crude residue, which was purified using flash column chromatography, eluting with EtOAc - Hexanes- MeOH (5:1 :0.1, v/v/v) to provide 3.92 g of pyridyl ether IA (67%, MH+ = 279.2).
46%
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20 - 55℃;
Stage (i): tert-Butyl 4-(pyridin-4-yloxy)piperidine-1-carboxylate tert-Butyl 4-hydroxypiperidine-1-carboxylate (6.348 g, 31.546 mmol) and triphenylphosphine (10.256 g, 39.432 mmol) were added to a solution of <strong>[626-64-2]4-hydroxypyridine</strong> (3 g, 31.456 mmol) in tetrahydrofuran (50 ml) at room temperature. Diisopropyl azodicarboxylate (7.66 ml, 39.432 mmol) was subsequently added dropwise and the mixture was then stirred at 55 C. for 15 h. Saturated sodium bicarbonate solution (50 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate (4*80 ml). The combined organic phases were washed with sat. sodium chloride solution (20 ml), dried over sodium sulfate and concentrated in vacuo. The crude product was subsequently purified by column chromatography (silica gel) with ethyl acetate/hexane (4:1). Yield: 4.11 g (46%)
46%
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20 - 55℃;
tert-Butyl-4-hydroxypiperidine-1-carboxylate (6.348 g, 31.546 mmol) and triphenylphosphine (10.256 g, 39.432 mmol) were added to a solution of <strong>[626-64-2]4-hydroxypyridine</strong> (3 g, 31.546 mmol) in tetrahydrofuran (50 ml) at room temperature. Then diisopropyl azodicarboxylate (7.66 ml, 39.432 mmol) was added dropwise and the mixture was then stirred for 15 h at 55 C. Saturated sodium hydrogen carbonate solution (50 ml) was added to the reaction mixture and it was extracted with ethyl acetate (4×80 ml). The combined organic phases were washed with saturated sodium chloride solution (20 ml), dried (Na2SO4) and concentrated to small volume under vacuum. Then the crude product was purified by column chromatography (silica gel) with ethyl acetate/hexane (4:1). Yield: 4.11 g (46%)
10 g
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20℃; for 3h;
To a 500 ml round bottom flask were added <strong>[626-64-2]pyridin-4-ol</strong> (5 g, 52.6mmol), THF (200 ml), fe/ -butyl 4-hydroxypiperidine-1 -carboxylate (13.3 g, 65.8mmol), and triphenylphosphine (18 g, 68.4 mmol). DEAD (12 g, 68.4 mmol) was added dropwise at RT and after the addition the RM was stirred at RT for 3 h. The RM was concentrated and purified by chromatography on silica gel eluting with methanol in DCM (1 :30) yielding the title compound as a solid (10 g). Method E: Rt = 1 .35 min; MS m/z [M+H]+279.
10 g
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20℃; for 3h;
In a 500 ml round bottom flask were mixed <strong>[626-64-2]pyridin-4-ol</strong> (5 g, 52.6mmol), dry THF (200 ml), tert- butyl 4-hydroxypiperidine-1 -carboxylate (13.3 g, 65.8mmol) and PPh3 (18 g, 68.4 mmol). Then DEAD (12 g, 68.4 mmol) was added dropwise at RT. The RM was stirred at RT for 3 h, then the RM was concentrated. Purification by chromatography on silica gel eluting with 3% MeOH in DCM afforded 10 g of the title compound as a white solid. LC-MS (method H): Rt = 1 .35 min, [M+H]+ = 279.3
1,1-dimethylethyl 3-(4'-pyridinyloxy)-1-azetidinecarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57.1%
With di-isopropyl azodicarboxylate; triphenylphosphine; In toluene; at 150℃; for 3h;Sealed tube; Microwave irradiation;
To a solution of the commercially available 4-pyridinol, 17, (500 mg, 5.26mmol) in anhydrous toluene (15 mL) was added tert-butyl 3-hydroxyazetidine-1-carboxylate, R-24, (910 mg, 5.26 mmol), Ph3P (1.67 g, 6.2 mmol) and DIAD(1 .27 g, 6.3 mmol), the sealed vial was irradiated in the microwave on aBiotage Smith Synthesis at 15000 for 3 h. The resulting mixture was cooledto room temperature and concentrated under vacuo. The mixture was quenched into water, extracted with DOM, dried with anhydrous Na2504, concentrated to give the crude product which was purified by prep-TLO to give KR-30 (60 mg, 57.1%) as a pale yellow solid. ESI-MS (Mi-i): 251.1 calc.for 013H18N203: 250.1.
53%
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 70℃;
To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate 1 (4.55 g, 26.3 mmol) inTHF (100 mL) was added <strong>[626-64-2]pyridin-4-ol</strong> (2.0 g, 21.0 mmol), PPh3 (6.89 g, 26.3 mmol)and DEAD (4.57 g, 26.3 mmol). The resulting reaction mixture was stirred at 70 Covernight. TLC indicated that the reaction was complete. The reaction mixture wasconcentrated in vacuum. The resulting oil was dissolved in 1 .0 M aqueous HCI solution C 20 mL) and extracted with DCM (50 mL x 3), The combined organic phases were washed with HCI (aq) solution (0.5 M, 150 mL). The aqueous fractions were combined and basified to pH12 using NaOH (1.0 M) and extracted with DCM(100 mL x 3) . The combined organic phases were dried over anhydrous Na2SO4,filtered and concentrated in vacuum. The residue was purified by column chromatography on silica gel to afford to afford 4 (2.81 91 53% yield) as a solid.1HNMR (400 MHz, DMSO-d6): 5 8.41 (d, J 6.0 Hz, 2 H), 6.88 (d, J = 6.0 Hz, 2 H),5.07-5.09 (m, 1 H), 4.32-4.33 (m, 2 H), 3.80-3.82 (m, 2 H)3 1.39 (s, 9 H). MS Calcd.:250; MS Found: 251 ([M+Hfl.
53%
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 70℃;
To a solution of fert-butyl 3-hydroxyazetidine-l-carboxylate 1 (4.55 g, 26.3 mmol) in THF (100 mL) was added <strong>[626-64-2]pyridin-4-ol</strong> (2.0 g, 21.0 mmol), PPh3 (6.89 g, 26.3 mmol) and DEAD (4.57 g, 26.3 mmol). The resulting reaction mixture was stirred at 70 C overnight. TLC indicated that the reaction was complete. The reaction mixture was concentrated in vacuum. The resulting oil was dissolved in 1.0 M aqueous HCI solution (, 20 mL) and extracted with DCM (50 mL chi 3), The combined organic phases were washed with HCI (aq) solution (0.5 M, 150 mL). The aqueous fractions were combined and basified to pH12 using NaOH (1.0 M) and extracted with DCM (100 mL chi 3) . The combined organic phases were dried over anhydrous Na2S04, filtered and concentrated in vacuum. The residue was purified by column chromatography on silica gel to afford to afford 4 (2.81 g, 53% yield) as a solid. 1HNMR (400 MHz, DMSO- 6): delta 8.41 (d, J= 6.0 Hz, 2 H), 6.88 (d, J= 6.0 Hz, 2 H), 5.07-5.09 (m, 1 H), 4.32-4.33 (m, 2 H), 3.80-3.82 (m, 2 H), 1.39 (s, 9 H). MS Calcd.: 250; MS Found: 251 ([M+Hf).
With tributylphosphine; N-ethyl-N,N-diisopropylamine; 1,1'-azodicarbonyl-dipiperidine; In tetrahydrofuran; at 20℃; for 16h;
A solution of an alcohol (0.4 mmol), a phenol/thiophenol (0.4 mmol), diisopro-pylethylamin (0.44 mmol) and tributylphosphine (0.52 mmol) in THF (5 mL) was stirred undernitrogen at rt. 1,1'-(Azodicarbonyl)dipiperidine (ADDP, 0.52 mmol) dissolved in THF (5 mL)was added and the reaction mixture was stirred at rt for 16 h. The reaction mixture was fil- tered and the filtrate was evaporated to dryness, which gave a crude which was either puri- fied by flash chromatography (Quad flash 25, EtOAc-heptane) or redissolved in MeCN andpurified by preparative HPLC (Gilson).Example 1 (General procedure 1)Methyl-phenyl-carbamic acid 4-[2-(pyridin-4-yloxy)-ethyl]-phenyl esterThe title compound (99%) was prepared as an oil using methyl-phenyl-carbamic acid 4-(2-hydroxy-ethyl)-phenyl ester and <strong>[626-64-2]4-hydroxypyridine</strong>.HPLC-MS : mlz = 349.2 (M+1); R, = 2.64 min.
With sulfuric acid; nitric acid; at 140℃; for 12h;
Example A1; N,1-Dimethyl-iodo-7-phenyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-4-amine; A1.1: 3,5-Dinitro-1H-pyridin-4-one; 4-Hydroxypyridine (40.0 g, 0.42 mol) was added portionwise to fuming nitric acid (140 ml) and sulfuric acid (500 ml). The resulting mixture was heated to 140 C. for 12 hours. The reaction mixture was cooled in an ice-bath and cautiously poured onto ice (500 ml). The yellow solid which precipitated was collected by filtration and dried under vacuum to yield A1.1 (70.0 g, 90%). 1H-NMR (DMSO-d6) delta: 4.06 (2H, s). HPLC: 98.9%, ret. time=0.173 min., LC/MS (M-H)+=184.
90%
With sulfuric acid; nitric acid; In water; at 140℃; for 12h;
Al.l 4-Etaydroxypyridine ( 40.Og, 0.42 mol ) was added portionwise to fuming nitric acid (140 ml) and sulfuric acid (500ml). The resulting mixture was heated to 1400C for 12 hours. The reaction mixture was cooled in an ice-bath and cautiously poured onto ice (500ml). The yellow solid which precipitated was collected by filtration and dried under vacuum to yield Al.l ( 70.Og, 90%). 1H-NMR ( DMSO-d6) 6: 4.06 ( 2H, s). HPLC (B): 98.9%, ret. time = 0.173 min., LC/MS (M-H)+ = 184.
90%
With sulfuric acid; nitric acid; at 140℃; for 12h;
Example A1; N-[(S) 1-[3-[7-Chloro-8-methyl-8H-imidazo[4,5-d]thiazolo[5,4-b]pyridin-2-yl]phenyl]ethyl]amine; A1.1: 3,5-Dinitro-1H-pyridin-4-one; 4-Hydroxypyridine (40.0 g, 0.42 mol) was added portionwise to fuming nitric acid (140 ml) and sulfuric acid (500 ml). The resulting mixture was heated to 140 C. for 12 hours. The reaction mixture was cooled in an ice-bath and cautiously poured onto ice (500 ml). The yellow solid which precipitated was collected by filtration and dried under vacuum to yield A1.1 (70.0 g, 90%). 1H-NMR (DMSO-d6) delta: 4.06 (2H, s). HPLC: 98.9%, ret. time=0.173 min., LC/MS (M-H)+=184.
90%
With sulfuric acid; nitric acid; at 140℃; for 12h;
4-Hydroxypyridine ( 40.Og, 0.42 mol ) was added portionwise to fuming nitric acid (140 ml) and sulfuric acid (500ml). The resulting mixture was heated to 14O0C for 12 hours. The reaction mixture was cooled in an ice-bath and cautiously poured onto ice (500ml). The yellow solid which precipitated was collected by filtration and dried under vacuum to yield Al.l ( 70.Og, 90%). 1H-NMR ( DMSOd6) delta: 4.06 ( 2H, s). HPLC (B): 98.9%, ret. time = 0.173 min., LC/MS (M-H)+ - 184.
52 - 98.9%
With sulfuric acid; nitric acid; at 0 - 140℃; for 12h;Heating / reflux;
4-Hydroxypyridine (40. 0g, 0.42 mol) was added portionwise to fuming nitric acid (140 ml) and sulfuric acid (500ml). The resulting mixture was heated to 140C for 12 hours. The reaction mixture was cooled in an ice-bath and cautiously poured onto ice (500ml). The yellow solid which precipitated was collected by filtration and dried under vacuum to yield Al. 1 (70. 0g, 90%). 1H-NMR (DMSO-D6) 8 : 4.06 (2H, s). HPLC : 98.9%, ret. time = 0.173 min., LC/MS (M-H) + = 184. Scale-up: 250 g of <strong>[626-64-2]4-hydroxy pyridine</strong> was mixed with 3.2 L of concentrated sulfuric acid at 0-5 C and 900ML fuming nitric acid was added dropwise to it maintaining the temperature in the same range. The reaction mass was refluxed over night. The mass was cooled down and and poured over crushed ice. It was then filtered and washed with 2L of water, to provide AL. l in 52% yield as a pale yellow solid.
With sodium hydroxide; iodine; In water; at 85℃; for 16h;
Step 1. 3-iodo<strong>[626-64-2]pyridin-4-ol</strong> (46)[00370] To a stirred solution of <strong>[626-64-2]4-hydroxypyridine</strong> (5.0 g, 52.6 mmol) in water (90 ml) were successively added sodium hydroxide (5.4 g, 135 mmol) and iodine (28.0 g,1 10 mmol). The reaction mixture was heated 85C for 16 hours then cooled-down to room temperature. The product was collected by filtration and dry under high vacuum to afford the title compound 46 (7.56 g, 34.2 mmol, 65%) as a white solid. MS: 222.0(M+l).
32%
With potassium iodide; iodine; sodium carbonate; In water;
4-Hydroxy-pyridine (23.8 g, 250 mmol) and Na2CO3 (7.4 g, 70 mmol) are added to 80 mL water. The reaction mixture is heated to reflux and a solution of iodine (23.2 g, 92 mmol) and potassium iodide (80 g, 482 mmol) in 250 mL water is slowly added drop-wise. The reaction is refluxed for 1 h after the addition. The mixture is filtered hot to remove a by-product, and the filtrate is cooled to rt, a solid is removed and dried to afford 3-iodo-4-pyridinol (C10) (32% yield). HRMS (FAB) calculated for C5H4INO+H: 221.9418, found 221.9416 (M+H)+.
31%
With iodine; sodium carbonate; In water; at 20℃; for 12h;
Add 10.6 g (0.10 mol) of Na2CO3 and 12.7 g (0.05 mol) of I2 to a solution of 4.76 g (0.05 mol) <strong>[626-64-2]pyridin-4-ol</strong> in 200 ml of water. Stir the reaction mass at room temperature for 12 h; use the TLC method to ensure the completeness of the reaction. Add 12 ml of HCl to =5, Na2S2O3 till color removal. Filtrate the resulting precipitate, mix the precipitate with 200 ml of boiling ethanol and filtrate one more time. Concentrate the filtrate under reduced pressure, re-crystallize residue from methanol. Yield: 3.4 g (31%).
With sodium hydroxide; potassium iodide; iodine; sodium carbonate; In hydrogenchloride; water;
Reference Example 50 3-iodo-<strong>[626-64-2]pyridin-4-ol</strong>. To a solution of <strong>[626-64-2]4-hydroxypyridine</strong> (12 g, 126 mmol) in H2O (30 mL) is added sodium carbonate (11.32 g, 107 mmol) and the resulting mixture heated to reflux (100 C.) followed by the dropwise addition of a solution of potassium iodide (19.8 g, 119 mmol) and iodine (18 g, 71 mmol) in H2O (50 mL). The resulting hot solution is adjusted to pH 6 using 2N HCl soln. and filtered hot through a cintered glass funnel. The filtrate is cooled and the precipitated product collected by filtration. The filtrate is heated to reflux and the above procedure repeated. The crude product is heated to reflux in 0.3M HCl soln. and filtered through a cintered glass funnel. The filtrate is kept near reflux while adjusting pH to 6 with 1N NaOH soln. then cooled to 5 C., the precipitate collected and dried under high vacuum giving 8 g of title compound as a yellow solid. 1H NMR (DMSO) delta 86.16 (d, J=7 Hz, 1H), 7.70 (d, J=7 Hz, 1H), 8.27 (s, 1H), 11.70 (bs, 1H). MS (EI) m/z221 (M+.).
With 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; NaH; In 1,4-dioxane;
Preparation of 4-aminopyridine To a solution of 4-hydroxypyridine (352 mg, 3.70 mmol) in dioxane (20 mL) was added NaH (Aldrich, dry, 300 mg, 12.2 mmol) and Cs2 CO3 (4.00 g, 12.2 mmol). The resulting mixture was stirred at room temperature for about 30 minutes, then 2-bromo-2-methyl-propanamide (2.03 g, 12.2 mmol) was added and the resulting mixture was stirred at reflux for 16 h. After the reflux period, NMP (20 mL), DMPU (2 mL), and NaH (Aldrich, dry, 100 mg, 4.07 mmol) were added. The resulting mixture was stirred at 150 C. for 72 h. The reaction was cooled to room temp., and partitioned between water (50 mL) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (100 mL) and the combined organics washed with water (2*50 mL), dried (Na2 SO4), and concentrated to about 3 g of material. The brown oil was distilled by Kugelrohr to remove most of the residual NMP and DMPU. At this point there was evidence of 4-aminopyridine in the crude NMR: 1 H NMR (300 MHz, CDCl3) delta8.2 (d, 2 H), 6.6 (d, 2 H) as well as peaks characteristic of NMP and DMPU.
With potassium hydroxide; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; dimethyl sulfoxide;
REFERENCE EXAMPLE 6 STR14 4-Amino-5-nitro-2-(4-oxo-4H-pyridin-1-yl)-benzotrifluoride First, a mixture containing 2.40 g of 4-amino-2-chloro-5-nitrobenzotrifluoride, 2.0 g of 4-hydroxypyridine, 684 mg of 86% potassium hydroxide, 15 ml of dimethylsulfoxide was heated in an oil bath at 70 C. for 2 hours. The mixture was cooled and ice water was added to the mixture. Precipitated crude crystals were filtered and recrystallized with methanol/ethyl acetate to give 2.69 g of crystals of 4-amino-5-nitro-2-(4-oxo-4H-pyridin-1-yl)-benzotrifluoride. Melting point: 274-275 C. Elemental analysis (analyzed as C12 H8 N3 O3 F3) Calculated: C,48.17; H,2.70; N,14.04; F,19.05 (%) Found: C,48.12; H,2.78; N,13.98; F,19.11 (%) H1 -NMR (d6 -DMSO)delta: 6.19 (2H, d, J=8 Hz), 7.17 (1H, s), 7.74 (2H, d, J=8 Hz), 8.17 (2H, br.s), 8.38 (1H, s).
EXAMPLE 1 There are prepared 4-dibutylaminopyridine by adding 0.1 mole of 4-hydroxypyridine and 15 grams of phosphorous pentoxide in the presence of 0.2 mole of dibutylamine at 250° C. for 16 hours. The dimethylaminopyridine was obtained from the Aldrich Chemical Company of Milwaukee, Wis. and the 4-pyrrolidinopyridine was obtained from the Reilley Tar and Chemical Company, Indianapolis, Ind.
In dibutylamine;
Example 1. There was prepared 4-dibutylaminopyridine by adding 0.1 mole of 4-hydroxypyridine and 15 grams of phosphorous pentoxide in the presence of 0.2 mole of dibutylamine at 250oC for 16 hours. The dimethylaminopyridine was obtained from the Aldrich Chemical Company of Milwaukee, Wisconsin and the 4-pyrrolidinopyridine was obtained from the Reilley Tar and Chemical Company, Indianapolis, Indiana.
With 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; NaH; caesium carbonate; In 1,4-dioxane;
Preparation of 4-aminopyridine. To a solution of 4-hydroxypyridine (352 mg, 3.70 mmol) in dioxane (20 mL) was added NaH (Aldrich, dry, 300 mg, 12.2 mmol) and Cs2CO3 (4.00 g, 12.2 mmol). The resulting mixture was stirred at room temperature for about 30 minutes, then 2-bromo-2-methyl-propanamide (2.03 g, 12.2 mmol) was added and the resulting mixture was stirred at reflux for 16 h. After the reflux period, NMP (20 mL), DMPU (2 mL), and NaH (Aldrich, dry, 100 mg, 4.07 mmol) were added. The resulting mixture was stirred at 150 C for 72 h. The reaction was cooled to room temp., and partitioned between water (50 mL) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (100 mL) and the combined organics washed with water (2 x 50 mL), dried (Na2SO4), and concentrated to about 3 g of material. The brown oil was distilled by Kugelrohr to remove most of the residual NMP and DMPU. At this point there was evidence of 4-aminopyridine in the crude NMR: 1H NMR (300 MHz, CDCl3) delta 8.2 (d, 2 H), 6.6 (d, 2 H) as well as peaks characteristic of NMP and DMPU.
(a) (S)-4-(1-methoxypropan-2-yloxy)pyridine (91) Pyridin-4-ol (10 g, 105.15 mmol), <strong>[4984-22-9](R)-1-methoxypropan-2-ol</strong> (9.48 g, 105.15 mmol) and triphenylphosphine (30.3 g, 115.67 mmol) were added to THF (250 mL) and stirred for 10 minutes. To this was slowly added DIAD (22.49 mL, 115.67 mmol) and the reaction was stirred for 1 hour at 25 C. The solvent was evaporated and diethyl ether (100 mL) was added. To this was added a little triphenyl phosphine oxide and the reaction was stirred for 20 minutes to afford a solid, which was discarded. The solvent was evaporated and the pale yellow gum was acidified with 2.0HCl, extracted with Et2O (1*75 mL) and the aqueous was then basified with solid KOH. This was then extracted with Et2O (3*75 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford yellow gum. This was purified by distillation at 0.43 mBar, collecting fractions that distilled at 80 C. to afford the desired material as a colourless oil (15.30 g, 87% yield); 1H NMR (400.132 MHz, CDCl3) delta 1.34 (3H, d), 3.40 (3H, s), 3.50 (1H, dd), 3.58 (1H, dd), 4.68-4.60 (1H, m), 6.82 (2H, d), 8.40 (2H, d); m/z (LC-MS, ESI+), RT=1.28 (M+H 168).
5-methyl-0-pyridin-4-ylcarbonodithioate (12); At 0 0C, <strong>[626-64-2]4-hydroxypyridine</strong> (4.8 g, 50 mmol, 1 eq) in NN-dimethylformamide (40ml) is added to a suspension of sodium hydride (60%, 8.0 g, 0.15 mol, 3 eq) in NN-dimethylacetamide (40 mL). The reaction mixture is then stirred vigorously i h at 25 0C and 30 min at 55C. At 0 C, carbon disulfide (18.9 g, 15 mL, 0.25 mol, 5 eq) is added dropwise and the reaction mixture is allowed to reach 25 0C during 16 h. At 0 0C, iodomethane (13.7g, 6.0 mL, 0.1 mol, 2 eq) is then added dropwise and the reaction mixture is allowed to reach 25 0C during 60 min. After addition of ice water (100 mL), the product precipitates. The mixture is cooled over night at 00C before being filtrated. The crude product is purified by chromatography on silica gel using ethyl acetate/cyclohexane (1:4) as eluent which affords pure S-methyl-O-pyridin-4-ylcarbonodithioate (12, 7.4 g, 39,9 mmol, 80%) as a yellow powder; m.p. 132-134 0C.1H NMR (CDCl3, 300 MHz): delta = 8.53 (d, J = 8.2 Hz, 2 H), 6.24 (d, J = 8.2 Hz, 2 H), 2.72 (s, 3 H). - 13C NMR (CDCl3, 75 MHz): delta = 202.3, 180.7, 135.4 (2 C), 118.1 (2 C), 21.6. - MS(EI): m/z = 186 [M+].
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 55℃;
Stage (ii): (1R,3s,5S)-tert-Butyl 3-(pyridin-4-yloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate(1R,3r,5S)-tert-Butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (1 eq) was dissolved in tetrahydrofuran (50 eq), and <strong>[626-64-2]4-hydroxypyridine</strong> (1 eq) and triphenylphosphine (1.25 eq) were added. Thereafter, diisopropyl azodicarboxylate (1.25 eq) was added dropwise and the reaction mixture was heated to 55 C. After 15 h tetrahydrofuran was removed in vacuo, the residue was taken up in ethyl acetate (50 ml) and the mixture was extracted with aqueous hydrogen chloride solution (2×40 ml, 1 mol/l). The aqueous phase was rendered alkaline (pH=8) with sodium hydroxide solution and extracted with ethyl acetate (3×50 ml). The organic phases were combined, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) with ethyl acetate/hexane (3:1). Yield: 65% The other isomer can be obtained analogously from the corresponding exo product from stage (i).
65%
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 55℃;
Stage (ii): (1 R,3S,5S)-tert-Butyl 3-(pyridin-4-yloxy)-8-azabicyclo[3.2.1]octane-8- carboxylate(1 R,3R,5S)-tert-Butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (1 eq.) was dissolved in tetrahydrofuran (50 eq.) and <strong>[626-64-2]4-hydroxypyridine</strong> (1 eq.) and triphenylphosphine (1.25 eq.) were added. Diisopropyiazodicarboxylate (1.25 eq.) was then added dropwise and the reaction mixture was heated to 55C. After 15 h tetrahydrofuran was removed under vacuum, the residue was taken up in ethyl acetate (50 ml) and extracted with aqueous hydrogen chloride solution (2 x 40 ml, 1 mol/l). The aqueous phase was alkalised with sodium hydroxide solution (pH = 8) and extracted with ethyl acetate (3 x 50 ml). These organic phases were combined, dried over Na2SO4 and concentrated to small volume under vacuum. The crude product was purified by column chromatography (silica gel) with ethyl acetate/hexane(3:1).Yield: 65%
With caesium carbonate; potassium iodide; In acetonitrile; at 80℃;Inert atmosphere;
General procedure: Method C: 2-Chloromethyl-1-methyl-5-nitro-1H-imidazol (6a) (1 g, 5.7 mmol), Cs2CO3 (6.6 g, 34.2 mmol) and KI (0.095 g, 0.57 mmol) were stirred in MeCN under inert atmosphere. 2-Piperazin-1-yl-<strong>[626-64-2]pyridin-4-ol</strong> (1.02 g, 5.7 mmol) in MeCN was added via a pressure equalized dropping funnel. The mixture was reflux at 80 C overnight under inert atmosphere. The reaction mixture was filtered and the solvent evaporated. The residue was dissolved in CHCl3 and washed with 10% K2CO3 (3 x 15 mL). The organic layer was collected, dried over MgSO4, concentrated to give crude in the form of colorless oil. Purification of product 9e (1 g, 55%) was done by the same procedure as described in method A.
1',1''-(2,4,6-trimethylbenzene-1,3,5-triyl)tris(methylene)tris(pyridine-4(1H)-one)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
49%
With sodium hydroxide; In N,N-dimethyl-formamide; at 70℃; for 25.5h;
A mixture of <strong>[626-64-2]4-hydroxypyridine</strong> (2.85 g, 30 mmol) and NaOH (1.2 g, 30 mmol) in N,N?-dimethylformamide (DMF) (20 mL) was stirred at 70 C for 1.5 h, and the 1,3,5-tris(bromomethyl)-2,4,6-trimethylbenzene (3.99 g, 10 mmol) was added. The mixture was cooled to room temperature after being stirred at 70 C for 24 h and poured into 100 mL of water. Then after a few days the colorless crystals were formed and filtered off, washed with water, and dried (yield in 49%). Anal. Calc. for C27H27N3O3 (Mr = 441.52): C, 73.45; H, 6.16; N, 9.52. Found: C, 73.51; H, 6.14; N, 9.48%. IR (KBr, cm-1): 3396(w), 3047(m), 1638(w), 1538(w), 1455(m), 1378(s), 1339(m), 1199(s), 1163(w), 1015(m), 850(w), 766(m), 665(s), 640(s), 529(s). 1H NMR (D2O, 500 MHz): delta = 1.99 (s, 9H), 5.22 (s, 6H), 6.33 (d, J = 7.0 Hz, 6H), 7.49 (d, J = 7.0 Hz, 6H) ppm. 13C NMR (D2O, 125 MHz): delta = 16.2, 55.0, 117.3, 117.4, 129.9, 141.9, 178.7 ppm.
General procedure: To a solution of [2-(phenoxy)-ethyl]-trimethyl-silane (Table-3, entry-1) (195mg, 1.0 mmol) in dry DMF (2 ml) was added cesium fluoride (576 mg, 3.0 mmol) and heated at 60C for 1 h. Reaction mass was diluted with water and extracted with ethyl acetate (3 x 20 ml). The combined organic layer was washed with water, brine solution, dried over anhydrous sodium sulphate and concentrated under reduce pressure to give phenol 92mg (93% yield). Phenols of Table-3 are commercially available from Aldrich and its identity was confirmed by comparison of 1H NMR data with authentic sample.
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 0.5h;
A typical synthetic procedure is as follows. 1,7-dibromo perylene diimide (1, 77 mg, 0.1 mmol) was dissolved into 5 mL of dimethylformamide (DMF). To which alkyl alcohol (R-OH, 0.5 mmol) and potassium carbonate (K2CO3, 70 mg, 0.5 mmol) were added. The resulted mixture was then allowed reacted under 80C for 1-4 hours. The reaction mixture was then powered into 15 mL water and the red solid was then re-dissolved in 20 mL dichloromethane (DCM) and washed with 1N hydrochloric acid and then water each for 3 times. Then, DCM layer was dried over Na2SO4. After removal of DCM, the residue was applied to chromatography with CH2Cl2/ethyl acetate (100:0-100:2) as eluents to afford the desired products 4.
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 1h;
1,7-dibromo perylene diimide (7, 56 mg, 0.1 mmol) was dissolved into 5 mL of DMF. To which <strong>[626-64-2]4-hydroxypyridine</strong> (47.6 mg, 0.5 mmol) and potassium carbonate (K2CO3, 70 mg, 0.5 mmol) were added. The resulted mixture was then allowed reacted under 80C for 1 hours. The reaction mixture was then powered into 50 mL of water and the red solid was then re-dissolved in 50 mL DCM and washed with 50 mL of 1N hydrochloric acid and then 50 mL of water each for 3 times. Then, DCM layer was dried over Na2SO4. After removal of DCM, the residue was applied to chromatography with CH2Cl2/ethyl acetate (100:0-100:2) as eluents to afford the desired products 9 as red solid (68.7 mg, 0.93 mmol, yield = 93%). 1H-NMR (400MHz, CDCl3) d ppm: 8.66 (s, 1H), 8.63 (s, 1H), 8.56 (d, J = 8.00 Hz, 2H), 7.60 (m, J = 8.00 Hz, 5H), 7.44 (d, J = 7.20 Hz, 1H), 6.69 (d, J = 8.00 Hz, 4H), 5.01 (t, 2H), 2.53 (q, J = 10.32 Hz, 4H), 1.93 (d, J = 10.00 Hz, 4H), 1.75 (d, J = 10.32 Hz, 6H), 1.48 -1.32 (m, J = 13.2 Hz, 12.00 Hz, 10.60 Hz, 11.60 Hz, 11.72 Hz, 6H). 13C-NMR (100 MHz, CDCl3) d ppm: 163.7, 163.4, 162.9, 155.5, 152.7, 152.5, 148.4, 148.3, 133.4, 130.2, 129.1, 128.7, 127.7, 126.5, 125.0, 123.8, 123.7, 123.6, 122.6, 122.1, 119.5, 119.3, 114.9, 59.6, 59.4, 30.8, 30.6, 26.1, 25.9, 24.5, 24.3. TOF MS: m/z = 740.2 [M+H]+.
4-hydroxy-pyridine-2,6-diamine hydronitrate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
4-Hydroxypyridine (15 g, 157.7 mmol) was suspended in mineral oil (220 mL) under argon atmosphere, sodium amide (24.6 g, 630.8 mmol, 4 eq) was added and stirred over night at room temperature. The homogeneous suspension was heated within 25 min to 70 C for 15 min. At 65 C ammonia was released. The temperature was raised stepwise within 30 min to 140C, whereupon the orange color of the suspension changed to brown. Within 20 min the mixture was heated to 190 C, and hydrogen was released at 130 C. The color change to dark brown and a foam was formed. The mixture was heated within 25 min to 220 C, the reaction was controlled by TLC(MeOH/AcOH 1:0.1). After 2 h at 220 C the hydrogen release stopped, and the reaction was cooled to room temperature. The suspension was filtered, washed with petroleum ether (4x 100 mL)and Et2O (2x 100 mL). The brown solid was transferred to an Erlenmeyer flask, the salt was quenched carefully with water (50 mL), activated charcoal was added, stirred for 30 min and filtrated over Celite. Nitric acid 65 % was added until a pH of one was reached and a brown precipitate was formed. Then thesolid was filtrated, washed with ice water (50 mL), acetone/Et2O (1:1; 3x 50 mL) and Et2O (2x 50 mL). Thesolid was dried under vacuum affording 22.9 g (77 %) of 8 as brown solid. 1H NMR (DMSO-d6) delta: 11.33 (s,2H), 6.85 (s, 4H, NH2), 5.38 (s, 2H, Py). 13C{1H} NMR (DMSO-d6) delta: 170.3 (Py), 152.8 (Py), 82.9 (Py).
70%
A mixture of 1 (10.0 g, 105.1 mmol), sodium amide (16.4 g, 420.6 mmol), and liquid paraffin (52 mL) was heated stepwise from 180 to 250 C under nitrogen atmosphere for 12 h. Subsequent color change from orange to brown to black was observed. The mixture was cooled in an ice bath. Water (100 mL) was added carefully to quench the excess of sodium amide and it was stirred for 10 min. The paraffin layer was separated and washed by water. The combined aqueous solutions were acidified with concd HNO3. The black precipitate obtained was filtered off and dried. Finally it was crystallized from hot water to give 2 as a deep brown solid (13.72 g, 70% yield). 1H NMR (500 MHz, DMSO-d6): delta = 11.34 (br, 1H), 11.22 (s, 1H), 6.84 (br, 4H), 5.40 ppm (s, 2H); 13C NMR (125 MHz, DMSO-d6): delta = 170.8, 153.2, 83.6 ppm.
With potassium carbonate; In N,N-dimethyl-formamide; at 95℃;
4-Hydroxypyridine 1.88g (0.02 mol) and 4,6-dimethoxypyrimidine-2-yl methyl sulfone 4.36g (0.02 mol) were dissolved in DMF 100 ml, and K2CO3 3.3g (1.2 eq) was added thereto. Then, the temperature was maintained at 95C while the mixture was stirred over night. The reacted solution was added to water 100 ml, extracted with diethyl ether, dried with MgSO4, and distilled under reduced pressure to obtain residue. Through purification with silica gel column chromatography, a solid material 3.73g (80%) was obtained: 1H NMR (CDCl3); 3.73 (s, 6H), 5.49 (s, 1H), 6.85-8.42 (m, 4H).
Example 106 2-Chloro-N-(1 -hydroxy-cyclohexylmethyl)-5-(pyridin-4-yloxy)- benzamide106.1 Sodium 2-chloro-5-(Dyridin-4-yloxy)benzoateA microwave vial was charged with copper (I) bromide (23 mg), Cs2C03 (2055 mg), 4- hydroxypyridine (300 mg) and <strong>[620621-48-9]methyl-2-chloro-5-iodobenzoate</strong> (1 122 mg) and flushed with argon. DMSO (4.7 mL) was added followed by 2-pyridyl acetone (0.043 mL) and the reaction mixture was heated to 100C for 3h in the microwave. It was diluted with EtOAc, filtered and the filtrate was washed with H20. The aqueous phase was basified with a 1 M solution of NaOH and extracted with EtOAc. The crude was purified by CC (RP C18, H20/CH3CN 1/0 to 8/2) to give 1 .2 g of the titled compound as a white powder.LC-MS (B): tR = 0.34 min; [M+H]+: 249.98
1.2 g
With 2-acetonylpyridine; caesium carbonate; copper(I) bromide; In dimethyl sulfoxide; at 100℃; for 3h;Microwave irradiation; Inert atmosphere;
106.1 Sodium 2-chloro-5-(pyridin-4-yloxy)benzoate A microwave vial was charged with copper (I) bromide (23 mg), Cs2CO3 (2055 mg), 4-hydroxypyridine (300 mg) and <strong>[620621-48-9]methyl-2-chloro-5-iodobenzoate</strong> (1122 mg) and flushed with argon. DMSO (4.7 mL) was added followed by 2-pyridyl acetone (0.043 mL) and the reaction mixture was heated to 100 C. for 3 h in the microwave. It was diluted with EtOAc, filtered and the filtrate was washed with H2O. The aqueous phase was basified with a 1M solution of NaOH and extracted with EtOAc. The crude was purified by CC(RP C18, H2O/CH3CN 1/0 to 8/2) to give 1.2 g of the titled compound as a white powder. LC-MS (B): tR=0.34 min; [M+H]+: 249.98
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide; at 66℃; for 4h;
To a mixture of <strong>[626-64-2]4-hydroxypyridine</strong> (0.953 g, 10 mmol) and DBU (2.3 mL, 15 mmol, 1.5 equiv) in DMF (20 mL) was added p-methoxybenzyl chloride (2.0 mL, 15 mmol, 1.5 equiv). The reaction mixture was stirred at 66 C for 4 h. After cooling to the room temperature, the solvent was removed under reduced pressure. The residue was partitioned between CHCl3 and H2O. The organic layer was washed with saturated aqueous NaCl solution, dried over anhydrous MgSO4, and then concentrated under reduced pressure. The residue was purified by flash column chromatography (CHCl3/MeOH=9:1, Rf=0.30) to give the white solid (11, 1.89 g, 8.8 mmol, 88%). Mp 166-168 C (from column); 1H NMR (CDCl3, 400 MHz) delta 7.35 (d, 2H, J=7.6 Hz, CH), 7.12 (d, 2H, J=8.8 Hz, CH), 6.88 (d, 2H, J=8.8 Hz, CH), 6.31 (d, 2H, J=7.6 Hz, CH), 4.87 (s, 2H, CH2), 3.77 (s, 3H, CH3); 13C NMR (CDCl3, 100 MHz) delta 178.8, 159.9, 139.9 (CH), 129.1 (CH), 126.7, 118.5 (CH), 114.5 (CH), 59.5 (CH2), 55.3 (CH3).
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 16h;
Example 56Compound 68Compound 318 (Example 48; 98 mg, 0.34 mmol, 1 eq.) and PPh3 (138 mg, 0.53 mmol, 1 .5 eq.) were dissolved in dry THF (2 ml). Next DIAD (104 muIota, 0.53 mmol, 1 .5 eq.) and 4- hydroxypyridine (50 mg, 0.53 mmol, 1 .5 eq.) were added. The reaction mixture was stirred at RT for approximately 16 hrs, after which the solvent was removed and the crude mixture purified by flash column chromatography (silica, DCM/MeOH 1 :0 to 8:2) to afford compound 68 as a white foam (73 mg; 59%).
59%
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 16h;
Compound 318 (Example 48; 98 mg, 0.34 mmol, 1 eq.) and PPh3 (138 mg, 0.53 mmol, 1.5 eq.) were dissolved in dry THF (2 ml). Next DIAD (104 mul, 0.53 mmol, 1.5 eq.) and <strong>[626-64-2]4-hydroxypyridine</strong> (50 mg, 0.53 mmol, 1.5 eq.) were added. The reaction mixture was stirred at RT for approximately 16 hrs, after which the solvent was removed and the crude mixture purified by flash column chromatography (silica, DCM/MeOH 1:0 to 8:2) to afford compound 68 as a white foam (73 mg; 59%).
methyl 4-(1-(pyridin-4-yloxy)ethyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
35%
Methyl 4-(l-(pyridin-4-yloxy)ethyl)benzoate. To a solution of 4-(l- hydroxyethyl)benzoate (300 mg.1.67 mmol) in tetrahydrofuran (80 mL) were added triphenylphosphine (570 mg, 2.2 mmol) and pyridin-4-ol (159 mg,1.67 mmol). The mixture was stirred for 30 minutes at room temperature, and then cooled to 0C. And diisopropylazodicarboxylate (568.3 mg, 2.8 mmol) was added dropwise to the solution at 0C. The resultant mixture was stirred at room temperature for 12 hours. Then the mixture was concentrated to give a residue and the residue was purified by column chromatography (silica gel, ethyl acetate/petroleum ether = 1 :10) to give methyl 4-(l-(pyridin-4-yloxy)ethyl)benzoate as an oil (151 mg, 35%). LRMS (M + H+) m/z: calcd 257.1; found 257.
35%
To a solution of 4-(1-hydroxyethyl)benzoate (300 mg. 1.67 mmol) in tetrahydrofuran (80 mL) were added triphenylphosphine (570 mg, 2.2 mmol) and pyridin-4-ol (159 mg, 1.67 mmol). The mixture was stirred for 30 minutes at room temperature, and then cooled to 0 C. And diisopropylazodicarboxylate (568.3 mg, 2.8 mmol) was added dropwise to the solution at 0 C. The resultant mixture was stirred at room temperature for 12 hours. Then the mixture was concentrated to give a residue and the residue was purified by column chromatography (silica gel, ethyl acetate/petroleum ether=1:10) to give methyl 4-(1-(pyridin-4-yloxy)ethyl)benzoate as an oil (151 mg, 35%). LRMS (M+H) m/z: calcd 257.1. found 257.
With copper(ll) sulfate pentahydrate; ellagic acid; In methanol; at 60℃; under 760.051 Torr; for 8h;Green chemistry;
General procedure: In a typical reaction, 10 mol% CuSO4·5H2O, (0.049 g, 0.2 mmol)and 6.7 mol% EA (20 mg) were mixed in methanol followed by2 mmol of phenylboronic acid. This reaction mixture was kept ina preheated oil bath by maintaining the temperature at 60 C andstirred under atmospheric pressure. After completion of the reac-tion, modified by TLC, the mixture was washed twice with hot ethylacetate to remove the reactant and product. The hot ethyl acetatewas removed from the reaction mixture and the resulting crudeproduct was purified by a column chromatography using silicagel 260 mesh (pet ether:ethyl acetate) ratio (25:75). The recov-ered catalyst was reused for the next run. All the products werecharacterized by1H and13C NMR spectra.
With choline chloride; urea; potassium hydroxide; at 80℃; for 2h;Green chemistry;
General procedure: Phenol (0.5 mmol), benzyl bromide(1.2 mmol) and KOH (2.0 mmol) was added to the DES (1 mL) and heated at temperature (80C) for 2 h. After cooling to room temperature water was added and the product was extracted with ethyl acetate (1 3 mL) andanalyzed by GC-MS after the addition of hexamethylbenzene as an internal standard. The product was purified using column chromatography on silica gel(hexane/EtOAc::99:1). The pure product was characterized by 1H NMR and 13CNMR.Table 4 Comparison of different methodologies for benzylation of phenols with benzyl bromide
With potassium carbonate; In acetonitrile; at 83℃; for 24h;
Example 31,1'-(dodecane-1,12-diyl)bis(pyridin-4(1H)-one) (3): Before the reaction, <strong>[626-64-2]4-hydroxypyridine</strong> was recrystallized from chloroform and the solvent was distilled. A 100 ml three-necked round bottom flask equipped with a magnetic stirrer, additional condenser and thermometer were charged with <strong>[626-64-2]4-hydroxypyridine</strong> (1.2 g, 12 mmol), K2CO3 (2.1 g, 15 mmol), 1,12-dibromododecane (1.6 g, 5 mmol) and CH3CN (30 ml). The reaction suspension was heated to reflux at 83C for 24 hours. After the reaction was complete, the mixture was separated by hot filtration through a filter paper, and the filtrate was evaporated at 40C under vacuum (45mmHg) to give the crude product as a light yellow solid. The residue on the filter was the carbonate salt and was discarded. 1H NMR confirmed that the crude product contained three different compounds, unreacted <strong>[626-64-2]4-hydroxypyridine</strong> (6.3%), the desired symmetrical main product (3) of general type Ib (84%), and the unsymmetrical by-product of type Ic (9.7%). The crude product was washed by cold water three times to remove unreacted <strong>[626-64-2]4-hydroxypyridine</strong> and washed with acetone two times to remove the by-products. After that, the symmetrical product (Ib) was recrystallized from a solution in hot acetonitrile on cooling. The purity was increased to 99.7% (as judged by 1H-NMR integration). It was obtained as a pale yellow colored powdery solid and was dried overnight under vacuum. Yield: 76%. Melting point: 106.9 C. 1H-NMR (400 MHz, DMSO-d6, 25 C):delta 1.24 (s, 16H, He), delta 1.66 (m, 4H, Hd), 3.83 (t, 4H, Hc), 6.07 (d, 4H, Hb), 7.67 (d, 4H, Ha). 13C-NMR (100 MHz, DMSO-d6, 25 C):delta = 177.6, 141.3, 117.8, 55.7, 30.7, 29.3, 28.9, 25.9. MS (ESI+, MeOH, m/z): calcd for [M + H]+, 357.24; found, 357.31.
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.
9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-6-(4-oxopyridin-1-yl)purine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
Step a (Method 2): A mixture of <strong>[626-64-2]4-hydroxypyridine</strong> (0.21 g, 2.2 mmol) and sodium hydride (60% dispersion in mineral oils, 107 mg, 2.66 mmol) in DMF (5 mL) was stirred at rt under nitrogen for 17 min. The resulting mixture was added to cold 9-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)-6-chloropurine (0.82 g, 2.0 mmol) in DMF (5 mL) stirred at 0 C. under nitrogen. The reaction was stirred at 0 C. for 2 h, TLC analysis showed complete reaction). After removal of volatiles, the residue was chromatographed (CH2Cl2 then MeOH/CH2Cl2, 1:13) to give 9-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)-6-(4-pyridin-1-yl)purine (0.766 g, 82%).
4-hydroxy-1-methyl-2-oxo-7-(pyridin-4-yloxy)-1,2-dihydroquinoline-3-carboxylic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
With copper(l) iodide; dimethylaminoacetic acid; caesium carbonate; In N,N-dimethyl-formamide; at 140℃; for 12h;Inert atmosphere;
Under nitrogen, 7-bromo-4-hydroxy-1-methyl-2-oxo -1,2-dihydro-quinoline-3-carboxylic acid methyl ester (1.00g, 3 . 2mmol), <strong>[626-64-2]pyridin-4-ol</strong> (0.432g, 4 . 54mmol), N, N-dimethyl glycine (0.088g, 0 . 85mmol), cuprous iodide (0.082g, 0 . 43mmol), cesium carbonate (2.50g, 7 . 67mmol) and N, N-dimethylformamide (20 ml) were added in the flask. The reaction mixture is heated to 140 C for 12 hours. Cooling to room temperature, adding ice water (40 ml), using 1M pH=6 dilute hydrochloric acid is adjusted to, filtration, filters the filtrate, dry to give a white solid (1.05g, 100%).
3-(3-N,N-dimethylaminomethyl)phenyl-2-chloro-6-bromoquinoline[ No CAS ]
6-bromo-3-(3-((dimethylamino)methyl)phenyl)-2-(pyridin-4-yloxy)quinoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75.82%
With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 8h;
3-(3-N,N-Dimethylaminomethyl)phenyl-2-chloro-6-bromoquinoline (50 mg, 0.13 mmol) was dissolved in 1 mL dry N,N-dimethylformamide, Followed by the addition of 4-pyridinol(19 mg, 0.20 mmol),Cesium carbonate (65 mg, 0.20 mmol) was added and the reaction was stirred at 80 C for 8 hours.Filtered and the filter cake washed with 10 mL of dichloromethane, column chromatography (dichloromethane / methanol 15: 1)Yielding 44 mg of a yellow solid in a yield of 75.82%
3-(4-oxopyridin-1(4H)-yl)-N-(quinolin-8-yl)butanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With palladium diacetate; acetic acid; In acetonitrile; at 120℃; for 4h;Sealed tube;
General procedure: Unless otherwise stated, the procedure was as follows. To a 1-dram (4 mL) vial equipped with a magnetic stir bar were added Pd(OAc)2 (4.4 mg, 0.02 mmol), alkene (0.2 mmol), acetic acid (6.0 mg, 0.1 mmol), nucleophile (0.3 mmol), and MeCN (0.1 mL). The vial was sealed with an unpunctured TFE septum-covered screw cap, and placed in a heating block that was pre-heated to 120 C. After the designated reaction time, the dark black reaction was purified either by flash column chromatography only or by flash column chromatography followed by an aqueous workup to produce the desired product.
1,1-dimethylethyl (S)-2,2-dimethyl-4-[[(4-pyridyl)oxy]methyl]-3-oxazolidinecarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 80℃; for 3h;
General procedure: To a stirred solution of 35 (0.300g, 1.30mmol), appropriate hydroxypyridine (0.247g, 2.60mmol) and PPh3 (0.681g, 2.60mmol) in anhydrous THF (15mL) was added DIAD 95% (0.54mL, 2.60mmol) at 80C. After 3h, the mixture was concentrated under reduced pressure and EtOAc (100mL) was added. The organic layer was extracted with cold 0.1M aqueous HCl (2×40mL). 1 M aqueous NaOH (60mL) was added to the aqueous layer and the resulting mixture was extracted with EtOAc (2×100mL). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash silica gel column chromatography eluting with Hexanes/EtOAc (7:3).
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 12h;
To a mixture of <strong>[26272-83-3]oxetan-3-yl 4-methylbenzenesulfonate</strong> (800 mg, 3.50 mmol) and pyridin- 4-ol (367 mg, 3.86 mmol) in N,N-dimethylformamide (10 mL) was added K2CO3 (1453 mg, 10.51 mmol). The mixture was heated to 80 C and stirred for 12 hours. The mixture was poured onto water (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were concentrated to give crude 4-(oxetan-3-yloxy) pyridine which was combined with a batch of material that was prepared in a similar manner and purified by column chromatography (PE/EA = 2/1) to give 4-(oxetan-3-yloxy)-pyridine.
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 4-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 0.24 g of yellow solid IV-2c was obtained.Yield: 22.2%.
4-((1r,3r)-3-(benzyloxy)cyclobutoxy)pyridine[ No CAS ]
4-(3-benzyloxycyclobutoxy) pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
With diisopropyl (E)-azodicarboxylate; triphenylphosphine;
Step 1: 4-((1r,3r)-3-(benzyloxy)cyclobutoxy)pyridine To a solution of pyridin-4-ol (3.20 g, 33.66 mmol, 1.5 eq) and <strong>[100058-61-5]3-benzyloxycyclobutanol</strong> (4 g, 22.44 mmol, 1 eq) in tetrahydrofuran (200 mL) was added triphenylphosphine (7.06 g, 26.93 mmol, 1.2 eq) and diisopropyl azodicarboxylate (5.45 g, 26.93 mmol, 1.2 eq) in one portion at 10 C. under nitrogen. The mixture was stirred at 50 C. for 12 hours. The reaction mixture was concentrated under reduced pressure to remove tetrahydrofuran. Water (50 mL) was poured into the mixture and stirred for 1 minute. The aqueous phase was extracted with dichloromethane (50 mL*3). The combined organic phase was washed with brine (50 mL*2), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by silica gel column chromatography (petroleum ether: tetrahydrofuran from 20:1 to 5:1). HPLC showed 41% of the product in 254 mm. The residue was purified by flash C18 column chromatography [acetonitrile: water (0.5% ammonium hydroxide)=5%-50%]. Compound 4-(3-benzyloxycyclobutoxy) pyridine (3.2 g, 12.53 mmol, 55% yield) was obtained as a white solid.
With N-chloro-succinamide; In water; acetonitrile; at 40 - 55℃;
A stirred solution of 4-pyridinol (1.0 eq.) in acetonitrile (15.0 vol.) and water(0.1 vol.) was heated to 40 C and then added N-chloro succinamide (2.2 eq.) in portions at 40-55 C. The reaction mixture was stirred for 6-8h at 45-55C, the progress of reaction was monitored by H PLC. After completion of the reaction the reaction were cooled and stirred for 3-4h. The solid was filtered and washed with acetonitrile (1x2.0 vol.) and water (5.0 vol + 2.0 vol). The product was dried in oven up to constant weight.
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