* 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.
a) Synthesis of 3-amino-pyridin-2-ol In a 500 ml flask, 3-nitro-pyridin-2-ol (1 g, 71.4 mmol) was dissolved in methanol (200 ml), and then added 10percent palladium on active carbon (100 mg, 10 w/w percent). The reaction mixture was stirred for 3 hours under hydrogen atmosphere at room temperature. The resulting reaction solution was filtered on celite and then evaporated under reduced pressure to obtain white solid (800 mg, quantitative yield). 1H-NMR (CD3OD, 300 MHz); δ=6.78-6.73 (m, 2H), 6.23 (t, J=6.5 Hz, 1H). MS (ESI); 111.1 (M++1).
84%
With hydrogen In methanol; ethanol; ethyl acetate for 16 h;
3-Aminopyridin-2-ol; To a 500 mL round bottom flask charged with 2-hydroxy-3-nitro pyridine (2 g, 14.2 mmol) was added 2:1 EtOH:MeOH (120 mL). The mixture was stirred for 10 minutes while flushing with N2 gas. 10percent Pd/C (200 mg) was added as a suspension in ethyl acetate (5 mL) and the heterogeneous reaction mixture was stirred under H2 gas for 16 h. The mixture was purged with nitrogen and filtered. The filtrate was evaporated and dried to give 3- aminopyridn-2-ol as a pink solid (1.31 g, 84percent). Mp: 124-1250C. LC/MS m/z 111 (M+1).
Reference：
[1] Patent: US2011/28467, 2011, A1, . Location in patent: Page/Page column 14
[2] Patent: WO2006/51410, 2006, A1, . Location in patent: Page/Page column 46
[3] Heterocycles, 1990, vol. 31, # 12, p. 2201 - 2204
[4] Heterocycles, 1990, vol. 31, # 12, p. 2201 - 2204
[5] Recueil des Travaux Chimiques des Pays-Bas, 1949, vol. 68, p. 1013,1024
[6] Chemical and Pharmaceutical Bulletin, 1959, vol. 7, p. 725,729
[7] Justus Liebigs Annalen der Chemie, 1955, vol. 593, p. 91,109
[8] Journal of the American Chemical Society, 1957, vol. 79, p. 3552
[9] Angewandte Chemie, 1936, vol. 49, p. 486,488
[10] Journal of the Chemical Society, <1952> 4985, 4991,
[11] Journal of Organic Chemistry, 1995, vol. 60, # 17, p. 5721 - 5725
[12] Journal of Medicinal Chemistry, 2002, vol. 45, # 8, p. 1607 - 1623
[13] Patent: US2001/47006, 2001, A1,
[14] Patent: US2001/47006, 2001, A1,
[15] Patent: US2001/47006, 2001, A1,
[16] Patent: WO2017/184589, 2017, A1, . Location in patent: Page/Page column 104; 105
2
[ 98786-86-8 ]
[ 33630-99-8 ]
Reference：
[1] Patent: CN108570001, 2018, A, . Location in patent: Paragraph 0012-0013; 0015; 0019; 0023
3
[ 165547-79-5 ]
[ 33630-99-8 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1949, vol. 68, p. 1013,1024
4
[ 142-08-5 ]
[ 33630-99-8 ]
Reference：
[1] Angewandte Chemie, 1936, vol. 49, p. 486,488
5
[ 33630-99-8 ]
[ 56-81-5 ]
[ 67967-11-7 ]
Reference：
[1] Journal of the Chemical Society, 1952, p. 4985,4990
6
[ 33630-99-8 ]
[ 501-53-1 ]
[ 147269-67-8 ]
Yield
Reaction Conditions
Operation in experiment
84%
With sodium carbonate In tetrahydrofuran; water at 0 - 20℃;
The amine (64.5 g, 586 mmol , 1.0 Eq) was dissolved in THF (1.6 L) and a solution of Na2CO3 (68.3 g, 644 mmol, 1.1 Eq) in water (800 mL) was added. The reaction was cooled to 0 0C with an ice-bath and benzyl chloroformate (92 mL, 644 mmol, 1.1 Eq) was added drop wise over 30 minutes with vigorous stirring. After addition was complete the reaction was allowed to warm to ambient overnight. The mixture was diluted with water (5 L) and stirred for 30 minutes. The resultant precipitate was removed by filtration. This solid was dissolved in DCM (5 L) with gentle warming and the EPO <DP n="41"/>resultant solution washed with water (2 x 1 L) and brine (1 x 1 L) . The organic layer was dried over Na2SO4 and concentrated in vacuo to give the desired product as a pink solid (120.4 g, 423 mmol, 84percent).
80%
With sodium carbonate In tetrahydrofuran at 20 - 25℃; for 24.0833 h;
To a mixture of 3-aminopyridin-2(1H)-one (3.25 g, 29.5 mmol) and sodium carbonate (6.26 g, 59.0 mmol) in tetrahydrofuran (100 mL) at rt was added benzylcarbonochloridate (5.27 mL, 36.9 mmol) over 5 mm. The mixture was stirred at rt for 24diluted with ethyl acetate (150 mL), and filtered through Celite®. The filtrate was concentrated under vacuum to a volume of approximate 200 mL, washed with water (40 mL), and dried over anhydrous Mg504. The solution was concentrated under vacuum to a volume of approximate 50 mL. The precipitating material (the first crop of product) wascollected as a white solid by suction. The filtrate was concentrated under vacuum to almost dryness. The residue was stirred with diethyl ether (50 mL). The insoluble material (the second crop of product) was collected as a white solid by suction. The two crops of product was combined and dried at 50 °C under vacuum to give the desired product, benzyl (2-oxo-1,2-dihydropyridin-3-yl)carbamate (5.77 g, 23.62 mmol, 80 percentyield), as a white solid.
With hydrogen;palladium 10% on activated carbon; In methanol; at 20 - 50℃; for 4.5h;
2-Oxo-l,2-dihydro-pyridin-3-yl) -carbamic acid benzyl ester; [0095] 2-Hydroxy-3-nitropyridone (two batches of 336 g, 2.4 mol, 1.0 Eg.) was charged to a flask followed by MeOH (6 L) . The flask was purged with nitrogen and the yellow mixture was heated to 30 0C. 10% Pd/C (34.5 g, 10 wt%) in MeOH (600 mL) was charged to the flask and washed in with further MeOH (200 mL) . The flask was purged with hydrogen and the reaction left to stir for 2 hours. A gradual exotherm was observed over 30 minutes and the temperature reached 50 C before cooling was applied. The temperature remained at 40 0C for the remainder of the 2 hour period. After this time tic indicated that the reaction had gone to completion, therefore the reaction was filtered through CeIite (40Og) resulting in a dark green solution. At this point, both batches were combined and the solution was concentrated in vacuo to give the crude amine as a brown solid (538.6 g, 102% contains residual MeOH) .
98%
palladium; In ethanol;
a. 3-Aminopyrid-2-one. Ethanol (300 mL) was added to a mixture of 10% (w/w) palladium on carbon catalyst (1 g) and 3-nitropyrid-2-one (10 g). The mixture was hydrogenated at atmospheric pressure and room temperature for 8 h. The catalyst was removed by filtration, washed with ethanol, and the ethanol evaporated to give the amine as a brown crystalline solid (98%).
With H2;palladium-carbon; In methanol;
A. Preparation of 3-amino-2-pyridone 3-Nitro-2-pyridone (2.0 g, 14 mmoles), 10%, Pd/C (0.20 g) and methanol (50 ml) were placed on a Parr shaker under 45 psi of H2. After 18 hours the mixture was filtered and concentrated to give 1.3 g of a pale pink solid. M.P.: 123-125 C.
With hydrogen;palladium 10% on activated carbon; In ethanol; under 2585.81 Torr;
Step A: 3-Aminopyridin-2(1H)-one 3-Nitropyridin-2(1H)-one (1.195 g, 8.53 mmol) and 10% palladium on carbon (0.156 g) were stirred in ethanol (30 ml) overnight under hydrogen atmosphere (50 psi). Catalyst was filtered from the solution and solvent removed in vacuo to produce the title compound (0.930 mg).
5-(2,4-difluorophenoxy)-1-isobutyl-N-(2-oxo-1,2-dihydropyridin-3-yl)-1H-indazole-6-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
32%
With N-ethyl-N,N-diisopropylamine; In dichloromethane; for 48h;
Example 30; 5 -(2.4-difluorophenoxyV 1 -isobutyl-N-(2-oxo- 1.2-dihvdropyridin-3-vD- 1 H-indazole-6- carboxamide fin)[00286] To a solution of 2,5-dioxopyrrolidin-l-yl-5-(2,4-difluorophenoxy)-l- isobutyl-li-indazole-6-carboxylate (Example 16; 100 mg, 0.226 mmol) in dichloromethane (1.1 mL) was added 3-aminopyridin-2(lH)-one (26.1 mg, 0.237 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.039 mL, 0.226 mmol). After 48 h, the reaction was treated with tris-amine resin (silica supported amine 3, 100 mg, loading = 1.76 mmol/g). After 45 minutes, the reaction was filtered though a silica gel plug, washing well with ethyl acetate. The filtrate was washed with 1 N hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride. The organics were dried with sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography, eluting with a gradient of 50% to 100% ethyl acetate/hexanes to yield 5-(2,4-difluorophenoxy)-l -isobutyl-N-(2-oxo-l,2-dihydropyridin-3-yl)-lH- indazole-6-carboxamide (32 mg, 32%). Mass spec: 439 (M+l). 1H NMR (CDCl3) delta 10.8 (s, IH), 8.68 (dd, IH), 8.42 (s, IH), 7.89 (s, IH), 7.28-.6.88 (m, 6 H), 6.36 (dd, IH), 4.25 (d, 2H), 2.38 (m, IH), 0.95 (d, 6 H).
EDCI (0.52 g, 2.70 mmol) was added to a mixture of 4-fluorobenzoic acid (0.25 g, 1.80 mmol) and HOBt (0.37 g, 2.70 mmol) in DMF (5 mL) and was stirred at room temperature for 30 minutes. 3-Aminopyridin-2(lH)-one (0.10 g, 0.91 mmol) was added followed by Et3N (0.38 mL, 2.70 mmol). After stirring 17 hours, the reaction mixture was diluted with EtOAc and washed with saturated aqueous NH4Cl, saturated aqueous NaHCO3, and brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure to give the crude material that was purified by silica gel flash column chromatography (1% MeOH in CH2Cl2) to afford 0.11 g (52%) of the desired product. 1H-NMR (400 MHz, CDCl3) delta 11.62 (br. s, IH), 9.03 (br. s, IH), 8.63 (dd, IH), 7.96 (m, 2H), 7.19 (t, 2H), 7.11 (dd, IH), 6.41 (t, IH); 19F NMR (376 MHz, CD3OD) delta -107.4. LRMS (ESI pos) m/e 233 (M+l).
With trichloromethyl chloroformate; In 1,4-dioxane; at 0 - 20℃; for 2.5h;
Preparation of [3-ISOCYANATO-2 (1H)-PYRIDINONE] : To a solution of 3-amino-pyridone (220 mg, 2 [MMOL)] in 1,4-dioxane (20 mL) was added diphosgene [(0.] 363 mL) at 0 [C.] After addition, the reaction mixture was stirred at rt for 2. 5h, and the precipitate was formed. The solid was filtered, washed with [ET20,] dried in vacuo to afford the isocyanate (192 mg). Preparation of 4-(2-amino-7-chloro-4-quinolinyl)-N-(1,2-dihydro-2-oxo-3-pyridinyl)-1- piperazinecarboxamide : As described example 159, 7-chloro-4-(1-piperazinyl)-2- [QUINOLINAMINE,] 3-isocyanato-2 [(1 H)-PYRIDINONE,] and diisopropylethyl amine, are reacted to give the title product as a white solid. LC-MS: 399 (M++1). 1H NMR (DMSO-d6) 8 7.95 (m, 2H), 7.76 (d, 1H), 7.40 (s, 1H), 7.12 (m, 1H), 7.0 (d, 1H), 6.45 (m, 2H), 6.25 (s, 1H), 6.22 (m, 1H), 3.75 (m, [4H),] 3.10 (m, 4H).
With hydrogenchloride; In water; for 2h;Heating / reflux;
To a solution of 3-Amino-1H-pyridin-2-one (2.0 g, 18.7 mmol) in water (2 mL) was added 15% HCl (10 mL, 18 mmol) followed by ammonium thiocyanate (1.5 g, 18 mmol) and the mixture was heated to reflux for two hours. Upon cooling the intermediate thiourea was found to precipitate as a red-brown solid. The mixture was filtered and the solid washed with water (5 mL). To a solution of the thiourea (1.3 g, 7.7 mmol) in EtOH (20 mL) and water (5 mL) was added chloroacetaldehyde (2.3 mL), 16.4 mmol) and the mixture was heated to reflux for four hours. On cooling, the mixture was diluted with EtOAc (30 mL) and washed with 10% NaHCO3 and brine. The organic phase was dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (100% EtOAc) to afford the title compound as a pale green solid (1.43 g, 40%): 1H NMR (400 MHz, CDCl3) delta 1.6 (1H, s), 6.45 (1H, t), 6.75 (1H, s), 7.05-7.10 (1H, m), 7.40-7.42 (1H, m), 8.35-8.5 (2H, m); M+H 194.1, M-H 192.1.
With sodium carbonate; In tetrahydrofuran; ethyl acetate;
(1) To a mixture of <strong>[33630-99-8]3-aminopyrid-2-one</strong> (24.6 g, 0.223 mol), sodium carbonate (52.1 g, 0.492 mol), THF (250 mL) and 1,4-dioxane (50 mL) was added dropwise benzyloxycarbonyl chloride (35.1 mL, 0.246 mol). The resulting mixture was stirred at room temperature for 15 h. Ethyl acetate (1200 mL) was added and the mixture was washed with water, saturated aqueous sodium hydrogencarbonate solution and saturated brine. After filtering off insolubles, the filtrate was dried over anhydrous magnesium sulfate. The residue obtained by concentration of the extract solution was recrystallized from methanol-ethyl acetate (6:1) to give 21.5 g of 3-benzyloxycarbonylaminopyrid-2-one as colorless crystals. The insolubles obtained were dissolved in chloroformmethanol (10:1), and then washed with saturated brine. The aqueous layer was further extracted with chloroform, and combined with the organic layer obtained earlier. The combined extracts were dried over anhydrous magnesium sulfate. Evaporation of the solvent further afforded 16.7 g (total yield 70%) of the same product as a colorless solid.
b. 3-Benzyloxycarbonylaminopyrid-2-one. Benzyl chloroformate (13.085 g) was added dropwise to a stirred suspension of sodium carbonate (16.26 g) and <strong>[33630-99-8]3-aminopyrid-2-one</strong> (7.67 g) in tetrahydrofuran. The mixture was stirred overnight, poured into ethyl acetate (400 mL), washed (saturated aqueous sodium bicarbonate, brine), dried and evaporated. The resulting residue was purified by crystallization from methanol to give the benzyl carbonate as a white crystalline solid (10.7 g). The benzylcarbamate can alternatively be prepared as follows:
(+/-)-2,6-dichloro-α-[(1,2-dihydro-2-oxo-3-pyridinyl)amino]benzeneacetonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
37.9%
In water; acetic acid;
Example 2 A mixture of 2,6-dichlorobenzaldehyde (0.012 mol) and <strong>[33630-99-8]3-amino-2-pyridinone</strong> (0.01 mol) in acetic acid (50 ml) was stirred for 30 rain at room temperature. Potassium cyanide (0.012 mol) was added and the reaction mixture was stirred for 8 hours at room temperature. The reaction mixture was poured out into water (500 ml). The resulting precipitate was filtered off, washed with water and recrystallized from acetonitrile. The crystals were filtered off and dried, yielding: 1.1 g of (+-)-2,6-dichloro-alpha-[(1,2-dihydro-2-oxo-3-pyridinyl)amino]benzeneacetonitrile (37.9%); mp. 213.3 C. (interm. 4).
Step A Preparation of 3-(2-fluorobenzoylamino)-2-pyridone To a solution of 3.3 g. (0.03 mole) of <strong>[33630-99-8]3-amino-2-pyridone</strong> in 75 ml. of pyridine cooled in ice was added portionwise 6.3 g. (0.04 mole) of 2-fluorobenzoyl chloride over 5 minutes. After stirring for 15 hours at ambient temperature, the mixture was poured into ice-water. The resultant precipitate was collected by filtration, washed with water and recrystallized from ethanol to give 3-(2-fluorobenzoylamino)-2-pyridone, m.p. 223 C.
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