* 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] Helvetica Chimica Acta, 1949, vol. 32, p. 1806,1812
2
[ 15733-89-8 ]
[ 10447-29-7 ]
Reference：
[1] Proceedings of the Royal Society of London, Series B: Biological Sciences, 1938, vol. 125, p. 60,69
[2] Journal of the American Chemical Society, 1946, vol. 68, p. 1837,1838
3
[ 141-82-2 ]
[ 91-56-5 ]
[ 15733-89-8 ]
Yield
Reaction Conditions
Operation in experiment
97.3%
for 6 h; Reflux; Large scale
400 kg of recovered glacial acetic acid was placed in a 1000 L reactor and 100 kg of isatin, 160 kg of malonic acid, and 15 kg of sodium acetate were added under stirring. The mixture was heated to reflux and refluxed for 6 hours. After the reaction is completed, the acetic acid is distilled off under reduced pressure. 300 kg of deionized water are added to stir the crystals. The filtered solids are first washed with cold 30 kg glacial acetic acid and then rinsed with cold 30 kg methanol to obtain 2-hydroxy-. 4-Carboxyquinoline wet product, after filtering and drying at 45-70°C for 24 hours,125 kg of 2-hydroxy-4-carboxyquinoline was obtained with a yield of 97.3percent and a liquid phase purity of 99.6percent.
40%
for 16 h; Reflux
A stirred suspension of isatin, also called 1H-indole-2,3-dione, available from Sigma-Aldrich, (3.80 g, 25 mmol) and malonic acid (8.06 g, 77 mmol) in acetic acid (150 ml) was refluxed for 16 h. Acetic acid was removed under reduced pressure, the residue was suspended in water (150 ml), filtered and washed with water (100 ml) to give a brown solid. The solid was stirred in NaHCO3 saturated aqueous solution (200 ml) and the insoluble material was filtered off. The filtrate was acidified to pH 1-2 withconcentrated HCl and the precipitate was filtered, washed with water and dried to obtainthe desired product as a grey solid (2.2 g, 11.6 mmol, Yield 40percent). 1H NMR (500 MHz; d6-DMSO) δ 6.87 (5, 1H), 7.23 (ddd, 1H, J= 1.2 Hz, J= 7.2 Hz, J=8.3 Hz), 7.41 (dd, 1H, J= 0.7 Hz, J= 8.3 Hz), 7.55 (ddd, 1H, J= 1.4 Hz, J= 7.2 Hz, J=8.4 Hz), 8.15 (dd, 1H, J= 1.2 Hz, J= 8.3 Hz), 12.13 (brs, 1H) ppm. Purity by LCMS (UV Chromatogram, 190-450nm) 90percent, rt = 2.96 min m/z 190 (M+H)+
40%
for 16 h; Reflux
Preparation 10 2-hydroxyquinoline-4-carboxylic acid A stirred suspension of isatin, also called 1H-indole-2,3-dione, available from Sigma-Aldrich, (3.80 g, 25 mmol) and malonic acid (8.06 g, 77 mmol) in acetic acid (150 ml) was refluxed for 16 h. Acetic acid was removed under reduced pressure, the residue was suspended in water (150 ml), filtered and washed with water (100 ml) to give a brown solid. The solid was stirred in NaHCO3 saturated aqueous solution (200 ml) and the insoluble material was filtered off. The filtrate was acidified to pH 1-2 with concentrated HCl and the precipitate was filtered, washed with water and dried to obtain the desired product as a grey solid (2.2 g, 11.6 mmol, Yield 40percent). 1H NMR (500 MHz; d6-DMSO) δ 6.87 (s, 1H), 7.23 (ddd, 1H, J=1.2 Hz, J=7.2 Hz, J=8.3 Hz), 7.41 (dd, 1H, J=0.7 Hz, J=8.3 Hz), 7.55 (ddd, 1H, J=1.4 Hz, J=7.2 Hz, J=8.4 Hz), 8.15 (dd, 1H, J=1.2 Hz, J=8.3 Hz), 12.13 (brs, 1H) ppm. Purity by LCMS (UV Chromatogram, 190-450 nm) 90percent, rt=2.96 min, m/z 190 (M+H)+
Reference：
[1] Patent: CN108101842, 2018, A, . Location in patent: Paragraph 0021; 0023
[2] Synthetic Communications, 2005, vol. 35, # 17, p. 2243 - 2250
[3] Patent: WO2013/153357, 2013, A1, . Location in patent: Page/Page column 44
[4] Patent: US2015/45354, 2015, A1, . Location in patent: Paragraph 0271-0274
[5] Chemische Berichte, 1914, vol. 47, p. 358
[6] Journal of the Chemical Society, 1926, p. 2908
[7] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 15, p. 1727
4
[ 574-17-4 ]
[ 15733-89-8 ]
Reference：
[1] Synthetic Communications, 2005, vol. 35, # 17, p. 2243 - 2250
[2] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2008, vol. 47, # 1, p. 117 - 128
[3] Archiv der Pharmazie (Weinheim, Germany), 1899, vol. 237, p. 687
[4] Journal of the Chemical Society, 1926, p. 2908
[5] Helvetica Chimica Acta, 1957, vol. 40, p. 499
[6] Journal of the Chemical Society, 1926, p. 2908
[7] Journal of the Chemical Society, 1926, p. 2908
5
[ 5467-57-2 ]
[ 157915-68-9 ]
[ 15733-89-8 ]
Reference：
[1] Journal of the American Chemical Society, 1946, vol. 68, p. 2714,2716
6
[ 910035-64-2 ]
[ 15733-89-8 ]
Reference：
[1] Journal of the American Chemical Society, 1953, vol. 75, p. 5301,5303
7
[ 65112-88-1 ]
[ 15733-89-8 ]
Reference：
[1] Journal of the American Chemical Society, 1953, vol. 75, p. 5301,5303
8
[ 67520-95-0 ]
[ 15733-89-8 ]
Reference：
[1] Journal of the American Chemical Society, 1953, vol. 75, p. 5301,5303
9
[ 91-56-5 ]
[ 15733-89-8 ]
Reference：
[1] Helvetica Chimica Acta, 1957, vol. 40, p. 499
[2] Archiv der Pharmazie (Weinheim, Germany), 1899, vol. 237, p. 687
10
[ 32375-61-4 ]
[ 15733-89-8 ]
Reference：
[1] Journal of the Chemical Society, 1926, p. 2908
[2] Journal of the Chemical Society, 1926, p. 2908
Reference：
[1] Chemische Berichte, 1938, vol. 71, p. 387,393
[2] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 25, p. 366
13
[ 486-74-8 ]
[ 15733-89-8 ]
Reference：
[1] Chemische Berichte, 1879, vol. 12, p. 97
[2] Chemische Berichte, 1883, vol. 16, p. 2158
14
[ 118-10-5 ]
[ 15733-89-8 ]
Reference：
[1] Chemische Berichte, 1879, vol. 12, p. 97
15
[ 64-19-7 ]
[ 15733-89-8 ]
Reference：
[1] Journal of the American Chemical Society, 1942, vol. 64, p. 1669,1670
16
[ 7647-01-0 ]
[ 910035-64-2 ]
[ 15733-89-8 ]
Reference：
[1] Journal of the American Chemical Society, 1953, vol. 75, p. 5301,5303
17
[ 15733-89-8 ]
[ 5467-57-2 ]
Yield
Reaction Conditions
Operation in experiment
87%
for 24 h; Heating / reflux
2-Hydroxyquinoline-4- carboxylic acid (34, 2.57 g, 13.6 MMOL) and POCI3 (25 mL) were refluxed for 24 h. The reaction mixture was poured onto crushed-ice (300 g). The solid that separated was filtered, washed with water, and dried well under high vacuum afforded 2.47 g (87percent) white flasks of desired PRODUCT. 1H NMR (CDCI3, 300 MHz): 8 8.67 (d, 1H, J = 8.4 Hz), 7.91 (d, 1H, J = 8.1 Hz), 7.83 (s, 1H), 7.67 (t, 1H, J = 7.2 Hz), 7.54 (t, 1H, J = 7.2 Hz); LCMS (m/z): 208 (MH+).
Reference：
[1] Patent: WO2005/30774, 2005, A1, . Location in patent: Page/Page column 23
[2] Journal of the American Chemical Society, 1946, vol. 68, p. 1837,1838
[3] Proceedings of the Royal Society of London, Series B: Biological Sciences, 1938, vol. 125, p. 60,69
18
[ 15733-89-8 ]
[ 5467-57-2 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1992, vol. 40, # 5, p. 1322 - 1324
[2] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 14, p. 4629 - 4635
[3] Journal of the Korean Chemical Society, 2013, vol. 57, # 2, p. 241 - 245
19
[ 15733-89-8 ]
[ 15733-87-6 ]
Yield
Reaction Conditions
Operation in experiment
56%
With phosphorus(V) oxybromide In toluene at 100℃; for 3 h;
A mixture of 2-hydroxyquinoline-4-carboxylic acid a (4.0 g, 21.2 mmol), POBr3 (25.0 g, 87.2 mmol) in toluene (40 mL) was heated at 100 0C for 3 h. It was cooled ..to RT, carefully poured onto crushed ice, extracted with EtOAc (2 x 250 mL), dried (MgSO4), concentrated in vacuo. The residue was dissolved in 1 N NaOH (150 mL), extracted with EtOAc (2 x 100 mL). The aqueous layer was then acidified with 1 N HCl to pH 3. The white solid was collected by filtration, washed with water, dried to afford 3.0 g (56percent) of bromo acid b as a white solid.
EXAMPLE II Synthesis of 2-quinoline triazole derivatives; Methyl 2-hydroxyquinoline-4-carboxylate, 1: 500 mg of 2-hydroxyquinoline-4- carboxylic acid (2.65 mmol) were suspended in anhydrous methanol and 40 drops of concentrated H2S04 (96percent) were added. Then the reaction was heated to reflux, the solution became clear, it was allowed to stir under reflux for 18 hrs (until no starting material was observed in LC-MS). Then it was cooled to room temperature, a white precipitate was produced. The precipitate was filtrated and washed with diethylether. White solid, 70 percent (0.38 g) yield. 1H NMR (DMSO, INOVA-400): 3.91 (s, 3H), 6.88 (d, 1H, J= 1.6 Hz), 7.22 (td, 1H, Jt= 7.5 Hz, 0.8 Hz ), 7.35 (d, 1H, J= 8.4 Hz),7.55 (td, 1H, Jt = 7.2 Hz, J<r 1.2 Hz), 8.05 (d, 1H, J= 8.4 Hz), 12.15 (s, 1H). I3C NMR (DMSO, INOVA-400): 5 53.64, 116.10, 116.53, 123.05, 124.70, 126.58, 131.78, 140.10, 140.64, 161.45, 166.20; LC-MS (ES+): mlz 203.90, calcd 203.06 (M+).
Reference：
[1] Patent: WO2012/6068, 2012, A2, . Location in patent: Page/Page column 64-65
[2] Patent: WO2006/66584, 2006, A1, . Location in patent: Page/Page column 19
[3] Chemistry - A European Journal, 2009, vol. 15, # 24, p. 5950 - 5955
[4] Patent: WO2007/9250, 2007, A1, . Location in patent: Page/Page column 40
21
[ 15733-89-8 ]
[ 144-55-8 ]
[ 39497-01-3 ]
Reference：
[1] Patent: US5935970, 1999, A,
[2] Patent: US5594140, 1997, A,
22
[ 542-69-8 ]
[ 15733-89-8 ]
[ 10222-61-4 ]
Reference：
[1] Patent: US5319085, 1994, A,
23
[ 15733-89-8 ]
[ 87864-14-0 ]
Reference：
[1] Glasnik Hemijskog Drustva Beograd, 1955, vol. 20, p. 553,554[2] Chem.Abstr., 1958, p. 16395
With phosphorus pentachloride; trichlorophosphate; for 18h;Heating / reflux;
a 2-Choroquinoline4-carboxylic Acid Dimethylamide A slurry of <strong>[15733-89-8]2-hydroxyquinoline4-carboxylic acid</strong> (3.0 g, 15.9 mmol), phosphorus pentachloride (3.5 g, 16.7 mmol), and phosphorus oxychloride (20 ml) was heated at reflux for 18 hours. The reaction was then cooled to ambient temperature and evaporated under reduced pressure to a black tar. Residue was dissolved in diethyl ether (100 ml) and washed with ice-cold water and ice-cold brine. Dried over anhydrous sodium sulfate and activated charcoal. Filtration through Celite, followed by evaporation under reduced pressure gave 2-chloroquinoline-4-carbonyl chloride as a light green-gray powder.
With trichlorophosphate; at 100℃; for 1h;
A mixture of 4-carboxy-2-hydroxyquinoline a (500 mg, 2.64 mmol) and POCI3 (5 mL) was heated at 100 0C for 1 h. The solvent was removed under reduced pressure, and the residue was dissolved in CH2Cl2 (10 mL), and cooled to 0 0C. Morpholine (1.0 mL, 13.2 mmol) was added dropwise, and the mixture was allowed to come to rt. The mixture was then re-cooled to 0 0C and more morpholine (1.0 mL, 13.2 mmol) was added dropwise, and the mixture was allowed to come to rt overnight. The mixture was then diluted with CH2Cl2 (50 mL), and washed with saturated NH4CI (3 x 20 mL). The combined aqueous phases were extracted with CH2Cl2 (1 x 20 mL), and the combined organic phases were dried (Na2SO4), adsorbed onto Celite and purified by chromatography ISCO CombiFlash 12 g column, 5-75% ethyl acetate-hexanes to afford 570 mg (78%) of amide b as a colorless solid.
With phosphorus pentachloride; trichlorophosphate;
(c) 2-Chloro-4-quinolinecarboxylic acid chloride (IX) 23 g (0.122 moles) of compound (VIII) and 55.7 g (0.122*2 moles+10% excess) of PCl5 were heated in oil-bath to 140-150 C. for 1 hour, under stirring. The produced POCl3 was evaporated off, and a brownish residue was obtained which was crystallized from n-hexane, giving an almost colourless residue. M.p. 85-87 C. [Lit. 89]. Yield: 27.8 g (quantitative on the crude product).
With thionyl chloride; N,N-dimethyl-formamide; In dichloromethane; for 3h;Inert atmosphere; Resolution of racemate;
To a stirred suspension of <strong>[15733-89-8]2-hydroxyquinoline-4-carboxylic acid</strong> (preparation 10) (2.20 g, 12 mmol) in anhydrous DCM (60 ml), was added anhydrous DMF (36 drops) and thionyl chloride (3.3 ml, 46 mmol) under argon at room temperature. The mixture was refluxedfor 3 h and then allowed to cool to room temperature. The solvents were removed under reduced pressure and the residue was dissolved in anhydrous THF (37 ml) under argon. 2-Pyrrolidin-1-ylethanamine (4.4 ml, 35 mmol) was added and the reaction was stirred at room temperature for 16 h. Solvents were removed under vacuum and the residue partitioned between NaHCO3 saturated aqueous solution (100 ml) and DCM (2 x 100ml). The organic layers were combined, dried over MgSO4, filtrated and evaporated under reduced pressure. The crude was purified by column chromatography using a 24 g silica gel cartridge. Solvent A: DCM, Solvent B: 10% MeOH-NH3 in DCM. Gradient: 2 mm hold 100% A followed by 18 mm ramp to 40% B and then hold 5 mm at 40% B. The desired fractions were combined and concentrated to dryness under reduced pressureto obtain the desired material as a white solid (2 g, 6.6 mmol, 56%). 1H NMR (500 MHz; CDCl) delta 1.76-1.19 (m, 4H), 2.54-2.57 (m, 4H), 2.73-2.75 (m, 2H),3.64 (dt, 2H, J= 5.2 Hz, J= 11.7 Hz), 6.78 (brs, 1H), 7.45 (5, 1H), 7.60 (ddd, 1H, J= 1.2Hz, J= 6.9 Hz, J= 8.3Hz), 7.76 (ddd, 1H, J = 1.4 Hz, J = 6. 9Hz, J = 8.4 Hz), 8.03 (d,1H, J= 8.5 Hz), 8.22 (d, 1H, J= 8.4Hz) ppm.Purity by LCMS (UV Chromatogram, 190-450nm) 99%, rt = 4.5 min m/z 304 (M+H)+
With thionyl chloride; In N,N-dimethyl-formamide; for 5h;Reflux;
100 g of <strong>[15733-89-8]2-hydroxy-4-carboxyquinoline</strong>, 500 g of thionyl chloride, and 0.8 g of DMF were placed in a reaction flask, and the mixture was stirred and heated to reflux, and refluxed for 5 hours. The TLC dot plate confirmed that the raw material consumption was completed, the heating and cooling were turned off, and then the distillation was carried out under reduced pressure, and the reaction liquid was concentrated under reduced pressure at 80 C to recover thionyl chloride (can be applied). The remaining concentrate is cooled, directly added 400g of dichloromethane, stirred half hour, Add 8g of shirasagi A activated carbon, The temperature was controlled by stirring at 45 C for 30 min, the reaction flask was washed with 200 g of dichloromethane, the filter cake was washed, and the filtrate was directly fed to the next step. 90 g of N,N-diethylethylenediamine, 80 g of triethylamine, and 300 g of dichloromethane were placed in a reaction flask, and the ice water was cooled to 15 C. The filtered solution of 2-chloroquinoline-4-carbonyl chloride and dichloromethane was slowly added dropwise to control the temperature below 20 C, and the addition was completed in about 1.5 hours. After the completion of the dropwise addition, the reaction was stirred. After the TLC plate was completed, 300 g of water was added, and the mixture was stirred for 10 minutes and allowed to stand for 1 hour. The lower organic layer was separated and concentrated under reduced pressure, and evaporated to 60 C. After concentration, the remaining solid was added with 120 g of ethyl acetate, heated to dissolve, and then frozen and crystallized in a refrigerator for 12 hours, suction filtered, and a small amount of cold ethyl acetate was added to wash the filter cake, and filtered to obtain a wet product of 170 g. The mother liquid was evaporated to dryness and added to 20 g of ethyl acetate to freeze and crystallize, and suction-filtered to obtain 18 g of a wet product. The total weight of the wet product was dried in an electric heating circulating blast oven for 12 hours to obtain 153.6 g of an off-white to white solid, the liquid phase purity was 99.95%, and the total yield was 95.02%.
With phosphorus(V) oxybromide; In toluene; at 100℃; for 3h;
A mixture of 2-hydroxyquinoline-4-carboxylic acid a (4.0 g, 21.2 mmol), POBr3 (25.0 g, 87.2 mmol) in toluene (40 mL) was heated at 100 0C for 3 h. It was cooled ..to RT, carefully poured onto crushed ice, extracted with EtOAc (2 x 250 mL), dried (MgSO4), concentrated in vacuo. The residue was dissolved in 1 N NaOH (150 mL), extracted with EtOAc (2 x 100 mL). The aqueous layer was then acidified with 1 N HCl to pH 3. The white solid was collected by filtration, washed with water, dried to afford 3.0 g (56%) of bromo acid b as a white solid.
With phosphorus(V) oxybromide; at 90℃; for 4h;
[Reference Example 2] Synthesis of 2-bromo-4-quinolinecarboxylic acid Phosphorus oxybromide (5.00 g, 17.4 mmol) was added to commercially available 2-hydroxy-4-quinolinecarboxylic acid (1.00 g, 5,29 mmol), and the mixture was heated with stirring at 90C for 4 hours. The reaction solution was added to ice water. To the mixture, sodium chloride was added, and the deposited crystal was collected by filtration, washed with water, and dried to obtain the title compound.
b) The product of the previous step (10.2 g, 53.9 mmol) was dissolved in 20 mL of phosphorus oxychloride and refluxed for 1 h. The phosphorus oxychloride was removed by rotary evaporation, the residue was poured into ice water, the pH was adjusted to 4-5 with a saturated aqueous solution of sodium bicarbonate, suction filtered, washed with water and dried to obtain 9.8 g of 2-chloroquinoline-4-carboxylic acid, the yield was 87.5%;
With trichlorophosphate; for 3h;Inert atmosphere; Reflux; Cooling;
General procedure: To cinconinic acid (1.7 g, 9.0 mmol) was added POCl3 (10 mL) under cooling and then heated to reflux for 3 h under nitrogen. The mixture was cooled to room temp, poured into ice-water and extracted with CHCl3. The combined extracts were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. To the residue was added thionyl chloride (10 mL), and the resulting mixture was heated to reflux under nitrogen for 2 h. The excess of thionyl chloride was then removed under reduced pressure, and ethanol (20 mL) / methanol, triethylamine (6 mL) were added at 0C. The resulting reaction mixture was heated to reflux for 30 min. The excess of alcohol was distilled off completely, and the mixture was extracted with CHCl3. The organic layer was collected, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the desired product (1.4 g, 70% yield).
With potassium carbonate; In N,N-dimethyl-formamide; at 80 - 100℃; for 19h;
A mixture of <strong>[15733-89-8]2-hydroxyquinoline-4-carboxylic acid</strong> a (6.25 g, 33.1 mmol), MeI (10.33 g, 72.7 mmol), and K2CO3 (10.0 g, 72.7 mmol) in DMF (110 mL) was heated at 80 0C for 16 h overnight. LCMS indicated incomplete reaction. Extra MeI (4.69 g, 33.1 mmol) was added to the reaction mixture and heated at 1000C for 3 h. It was cooled, poured into ice water, and 10% K2CO3 (50 mL), extracted with EtOAc (2 x 150 mL). The combined EtOAc were washed with water, dried (MgSO4), concentrated in vacuo. The crude product was adsorbed on to Celite and purified by ISCO CombiFlash 80 g column (2-50% ethyl acetate-hexane) to afford 4.68 g (65%) of dihydroquinoline ester b as an off white solid.
EXAMPLE II Synthesis of 2-quinoline triazole derivatives; Methyl 2-hydroxyquinoline-4-carboxylate, 1: 500 mg of 2-hydroxyquinoline-4- carboxylic acid (2.65 mmol) were suspended in anhydrous methanol and 40 drops of concentrated H2S04 (96%) were added. Then the reaction was heated to reflux, the solution became clear, it was allowed to stir under reflux for 18 hrs (until no starting material was observed in LC-MS). Then it was cooled to room temperature, a white precipitate was produced. The precipitate was filtrated and washed with diethylether. White solid, 70 % (0.38 g) yield. 1H NMR (DMSO, INOVA-400): 3.91 (s, 3H), 6.88 (d, 1H, J= 1.6 Hz), 7.22 (td, 1H, Jt= 7.5 Hz, 0.8 Hz ), 7.35 (d, 1H, J= 8.4 Hz),7.55 (td, 1H, Jt = 7.2 Hz, J<r 1.2 Hz), 8.05 (d, 1H, J= 8.4 Hz), 12.15 (s, 1H). I3C NMR (DMSO, INOVA-400): 5 53.64, 116.10, 116.53, 123.05, 124.70, 126.58, 131.78, 140.10, 140.64, 161.45, 166.20; LC-MS (ES+): mlz 203.90, calcd 203.06 (M+).
With hydrogenchloride; at 20℃;
2-Hydroxyquinoline-4-carboxylic acid (180 mg) was added to methanol saturated with HCI (10 ml). After stirring at room temperature overnight the title compound was isolated by filtration as colourless crystals.13C NMR (DMSO) delta = 165.4, 160.7, 139.9, 139.3, 131.0, 125.8, 123.9, 122.3, 115.8, 115.3, 52.8
Step 1 : Methyl 2-hydroxyquinoline-4-carboxylateTo a solution of 2-hydroxyquinoline-4-carboxylic acid (1 eq.) in methanol (0.1 1 M) was added HCl (4 M dioxane solution, 1 eq.) and the resulting suspension was heated at reflux for 24 h. The reaction was quenched with sat. aq. NaHCO3 and extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4 and filtered. Concentration of the filtrate in vacuo afforded the title compound.
With hydrogenchloride; In methanol;
Step I. Methyl 2-hydroxyquinoline-4-carboxylate (VI) To 2-hydroxyquinoline-4-carboxylic acid (V. 5.52 g) is added a saturated methanol/hydrochloric acid mixture in 50 ml aliquots over 5 days. The methanol/hydrochloric acid is then removed under reduced pressure and the residue is carefully treated with aqueous sodium bicarbonate. When the aqueous layer tests basic, the solid is collected, washed with water, and dried under reduced pressure to give methyl 2-hydroxyquinoline-4-carboxylate (VI), mp 240-241.
With potassium carbonate; In N,N-dimethyl-formamide;
Method D An alternative method of assembling the final framework involves a tin-mediated coupling as indicated below. To a stirred solution of <strong>[15733-89-8]2-hydroxyquinoline-4-carboxylic acid</strong> (Lancaster, Windham, USA) (10 g, 50 mmol), anhydrous potassium carbonate (10.35 g, 75 mmol) and anhydrous DMF (200 mL) at room temperature under nitrogen was added iodomethane (6.14 mL, 100 mmol). The mixture was stirred for 16 h, then poured into saturated aqueous sodium bicarbonate (150 mL). The resulting solid was washed with water (2*50 mL) and dried by suction to afford the desired product xv (9.1 g, 90%). 1H NMR (DMSO-d6) delta 12.14 (br s, 1H), 8.05 (d, J=8 Hz, 1H), 7.55-7.60 (m, 1H), 7.39 (d, J=8 Hz, 1H), 7.21-7.28 (m, 1H), 6.85 (s, 1H), 3.93 (s, 3H); ESI-MS m/z 204.1 (100, M+H+).
Step I. Methyl 2-hydroxyquinoline-4-carboxylate (VI) To 2-hydroxyquinoline-4-carboxylic acid (V, 5.52 g) is added a saturated methanol/hydrochloric acid mixture in 50 ml aliquots over 5 days. The methanol/hydrochloric acid is then removed under reduced pressure and the residue is carefully treated with aqueous sodium bicarbonate. When the aqueous layer tests basic, the solid is collected, washed with water, and dried under reduced pressure to give methyl 2-hydroxyquinoline-4-carboxylate (VI), mp 240-241.
concentrated. cis-2,6-Dimethylpiperazine[ No CAS ]
[ 15733-89-8 ]
3,5-dimethylpiperazino 2-chloroquinoline-4-carboxamide[ No CAS ]
cis-3,5-dimethylpiperazino 2-chloroquinoline-4-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With thionyl chloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; N,N-dimethyl-formamide; toluene;
Step I. cis-3,5-Dimethylpiperazino 2-chloroquinoline-4-carboxamide (X) A mixture of <strong>[15733-89-8]2-hydroxyquinoline-4-carboxylic acid</strong> (V, 1.25 g), thionyl chloride (8.3 ml) and DMF (1 drop) is heated at reflux for 1 hr. The resultant mixture is allowed to cool to 20-25 and is concentrated. Toluene (25 ml) is added and the mixture concentrated. cis-2,6-Dimethylpiperazine (906 mg) is added to a mixture of the crude acid chloride, methylene chloride (35 ml) and diisopropylethylamine (1.66 ml) at 0. The mixture is stirred for 1 hr at 0 and for 16 hrs at 20-25. Partitioning between methylene chloride and sodium bicarbonate, drying of the combined organic phase over magnesium sulfate, filtration, concentration, and crystallization from ether/hexane gives 3,5-dimethylpiperazino 2-chloroquinoline-4-carboxamide (X), mp 305 dec; IR (mineral oil) 1646, 1639, 1556, 1445, 1098, 774 cm-1; NMR (CDCl3) 8.08, 7.55-7.95, 7.2-7.4, 4.7-4.9, 2.4-3.2, 1.5-1.9, 1.15-1.35, 0.93 and 0.87 delta; MS (EI, m/e) 303, 259, 207, 190, 162, 127, 113, 101 and 84.
With sodium hydrogencarbonate; In N-methyl-acetamide;
REFERENCE EXAMPLE 1 1-(n-Butyl)-2-oxo-1,2-dihydro-4-quinolinecarboxylic acid (Compound a) While stirring, 5.00 g (26.4 mmols) of <strong>[15733-89-8]2-hydroxy-4-quinolinecarboxylic acid</strong> was added at 0 C. by small portions to 120 ml of a dimethylformamide solution containing 1.39 g (57.9 mmols) of sodium hydride. Under ice cooling, 70 ml of dimethylformamide solution containing 10.7 g (58.0 mmols) of n-butyl iodide was dropwise added to the mixture with stirring. The mixture was stirred at room temperature for further one day. After completion of the reaction, an aqueous saturated sodium bicarbonate solution was added to the reaction mixture followed by extraction with chloroform. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluding solvent: hexane/ethyl acetate=7/1). From the corresponding fraction, 2.05 g (yield; 26%) of 1-(n-butyl)-4-(n-butyloxycarbonyl)-2-oxo-1,2-dihydro-quinoline (Compound b) was obtained.
endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2-hydroxy-4-quinolinecarboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
23%,, 100%
EXAMPLE 25 Endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2-hydroxy-4-quinolinecarboxamide (Compound 25) Compound 25 was obtained as the fumarate (yield, 23%,, 100%).in a manner similar to Example 6 except for using <strong>[15733-89-8]2-hydroxy-4-quinolinecarboxylic acid</strong> instead of Compound a. Melting point: 231.8 235.2 C. MS (EI) m/e: 311 (M+) IR(KBr) cm-1: 3240(br), 3015, 1668, 1635, 1538, 1431, 1091, 973, 754, 637 NMR (DMSO-d6) delta(ppm): 11.89 (1H, brs), 8.59 (1H, d, J=4.1Hz), 7.68 (1H, d, J=8.1Hz), 7.53(1H, m), 7.36(1H, d, J=7.6Hz), 7.19(1H, m), 6.51(2H, s), 6.46 (1H, s), 4.01(1H, m), 3.54 (2H, m), 2.50 (3H, s), 1.97~2.56 (8H, m)
REFERENCE EXAMPLE 1 2-n-Butoxy-4-quinolinecarboxylic acid (Compound a) While stirring at 0 C., 5.00 g (26.4 mmols) of <strong>[15733-89-8]2-hydroxy-4-quinolinecarboxylic acid</strong> was added by small portions to 120 ml of a dimethylformamide solution containing 1.39 g (57.9 mmols) of sodium hydride. Under ice cooling, 70 ml of a dimethylformamide solution containing 10.7 g (58.0 mmols) of n-butyl iodide was dropwise added to the mixture with stirring. The mixture was stirred at room temperature for further one day. After completion of the reaction, a saturated sodium bicarbonate aqueous solution was added to the reaction mixture. The mixture was extracted with chloroform, and the extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluding solvent: hexane/ethyl acetate=7/1) to give 2.68 g (yield 34%) of 2-n-butoxy-4-n-butoxycarbonylquinoline (Compound b) from the first fraction. NMR (CDCl3) delta(ppm): 8.60 (1H, d, J=8.1 Hz), 7.88 (1H, d, J=8.1 Hz), 7.1-7.8 (3H, m), 4.2-4.8 (4H, m), 0.4-2.2 (14H, m)
With diphenyl phosphoryl azide; triethylamine; In 1,4-dioxane; at 20℃; for 0.5h;
General procedure: To a stirred solution of appropriate benzoic acid (10 mmol) in 50 ml of dioxane, DPPA (10 mmol) and triethylamine (11 mmol) were added. The reaction mixture was stirred at room temperature for 30 min. Then, the solution was poured into 25 ml water and extracted with hexane (3 x 30 ml). The organic layer was combined and washed with water (1 x 10 ml), brine (1 x 10 ml) and dried over Na2SO4 before evaporating in vacuo to give the corresponding acyl azide. After that, 75 ml of dioxane was added to the obtained acyl azide before refluxing for 2 h to give corresponding isocyanate. After cool down the reaction mixture to room temperature, propargylamine (12 mmol) was added and stirred at room temperature for 1 h. Next, solvent was evaporated under reduced pressure to give crude product. The purification was done by column chromatography on silica gel.
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