* 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 the American Chemical Society, 1947, vol. 69, p. 1659,1660
2
[ 23432-39-5 ]
[ 4363-94-4 ]
Reference：
[1] European Journal of Medicinal Chemistry, 2012, vol. 57, p. 259 - 267
[2] Organic Letters, 2018, vol. 20, # 4, p. 1195 - 1199
3
[ 28027-16-9 ]
[ 23432-39-5 ]
Yield
Reaction Conditions
Operation in experiment
100%
at 245 - 250℃; for 2 h; Inert atmosphere
A solution of 4-hydroxy-6-methoxyquinoline-3-carboxylic acid (7, 15.7 g, 72 mmol) in 80 ml of diphenyl ether was heated for 2 h in a metal bath to 245 °C. The reaction mixture was cooled to room temperature and taken up in 200 ml hexane. This mixture was stirred for 3 h, then filtered. The solid was washed with ethyl acetate and dried to deliver 6-methoxyquinolin-4-ol (8, 12.5 g, 72 mmol, 100 percent). 1H-NMR (DMSO): δ = 3.81 (s, 3H), 5.99 (d, 1H), 7.28 (dd, 1H), 7.48 – 7.53 (m, 2H), 7.86 (d, 1H), 11.87 (bs, 1H). LC-MS: Rt = 0.87 min; MS: m/z = 176 [M+1]+.
Reference：
[1] Tetrahedron Letters, 2017, vol. 58, # 8, p. 794 - 796
[2] Journal of the American Chemical Society, 1946, vol. 68, p. 1204,1206[3] Organic Syntheses, 1955, vol. Coll. Vol. III, p. 272
[4] Journal of the American Chemical Society, 1947, vol. 69, p. 1659,1660
[5] Chemical and Pharmaceutical Bulletin, 2007, vol. 55, # 5, p. 821 - 824
[6] Patent: US2002/111492, 2002, A1,
[7] Patent: US2719848, 1955, ,
4
[ 25063-43-8 ]
[ 23432-39-5 ]
Yield
Reaction Conditions
Operation in experiment
96%
at 255℃; for 0.0833333 h;
To a flask with Dowthem (250 mL) at 2550C was added 2,2-dimethyl-5-([4-(methyloxy)phenyl]amino}methylidene)-1 ,3-dioxane-4,6-dione (39.1 g, 141 mmol) in portions. The resulting solution was heated for 5 min., cooled down to room temperature and diluted with diethyl ether. A percipitate was filtered, washed with diethy ether and dried in the vaccume line to generate the title compound as a whitel solid (23,7 g, 96percent): LC/MS (ES) m/e 176 (M+H)+
64%
at 220℃; for 0.166667 h;
5-((4-methoxyphenylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (1 g, 3.61 mmol) was added portion wise to Dowtherm A (10 mL) at 220 °C. After bubbling stopped, the mixture was heated for additional 10 min and then allowed to cool down to room temperature. The mixture was poured into n-heptane (50 mL), the brown solid was collected by filtration and washed with n-heptane (20 mL x 3). It was purified by silica gel column chromatography using n-heptane/ethyl acetate and then ethyl acetate/methanol as eluents. Yield 64percent (off-white solid, 403 mg,2.30 mmol); TLC, Rf 0.4 (ethyl acetate/methanol, 80/20); UPLC-MS(ESI) (A), RT 0.56 min, m/z 176.4 [M+H]+ (>95percent).
Reference：
[1] Patent: WO2007/16610, 2007, A2, . Location in patent: Page/Page column 31
[2] European Journal of Medicinal Chemistry, 2012, vol. 57, p. 259 - 267
[3] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 10, p. 2723 - 2727
[4] European Journal of Medicinal Chemistry, 2017, vol. 125, p. 890 - 901
[5] Tetrahedron Letters, 2012, vol. 53, # 7, p. 738 - 743
Reference：
[1] Chemical and Pharmaceutical Bulletin, 2007, vol. 55, # 5, p. 821 - 824
[2] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 10, p. 2723 - 2727
[3] Journal of the American Chemical Society, 1946, vol. 68, p. 2685
[4] Zhurnal Obshchei Khimii, 1943, vol. 13, p. 697,700[5] Chem.Abstr., 1945, p. 704
[6] Journal of the American Chemical Society, 1946, vol. 68, p. 113,115
[7] Tetrahedron Letters, 2012, vol. 53, # 7, p. 738 - 743
[8] European Journal of Medicinal Chemistry, 2012, vol. 57, p. 259 - 267
[9] European Journal of Medicinal Chemistry, 2017, vol. 125, p. 890 - 901
[10] Tetrahedron Letters, 2017, vol. 58, # 8, p. 794 - 796
Reference：
[1] Chemical and Pharmaceutical Bulletin, 2007, vol. 55, # 5, p. 821 - 824
[2] Journal of the American Chemical Society, 1946, vol. 68, p. 1204,1206[3] Organic Syntheses, 1955, vol. Coll. Vol. III, p. 272
[4] Journal of the American Chemical Society, 1947, vol. 69, p. 1659,1660
[5] Tetrahedron Letters, 2017, vol. 58, # 8, p. 794 - 796
9
[ 66003-25-6 ]
[ 23432-39-5 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1996, vol. 33, # 3, p. 735 - 746
[2] Journal of the American Chemical Society, 1946, vol. 68, p. 2685
[3] Zhurnal Obshchei Khimii, 1943, vol. 13, p. 697,700[4] Chem.Abstr., 1945, p. 704
[5] Journal of the American Chemical Society, 1946, vol. 68, p. 113,115
10
[ 83507-70-4 ]
[ 23432-39-5 ]
Reference：
[1] Journal of the American Chemical Society, 1946, vol. 68, p. 1204,1206[2] Organic Syntheses, 1955, vol. Coll. Vol. III, p. 272
[3] Journal of the American Chemical Society, 1947, vol. 69, p. 1659,1660
[4] Tetrahedron Letters, 2017, vol. 58, # 8, p. 794 - 796
11
[ 91092-95-4 ]
[ 23432-39-5 ]
Reference：
[1] Journal of the American Chemical Society, 1946, vol. 68, p. 2685
[2] Zhurnal Obshchei Khimii, 1943, vol. 13, p. 697,700[3] Chem.Abstr., 1945, p. 704
[4] Journal of the American Chemical Society, 1946, vol. 68, p. 113,115
[5] Justus Liebigs Annalen der Chemie, 1950, vol. 568, p. 73,79
12
[ 2033-24-1 ]
[ 123-11-5 ]
[ 23432-39-5 ]
Reference：
[1] Journal of Organic Chemistry, 2007, vol. 72, # 6, p. 2232 - 2235
13
[ 3835-21-0 ]
[ 23432-39-5 ]
Reference：
[1] Journal of the American Chemical Society, 1949, vol. 71, p. 1906,1910
14
[ 75227-41-7 ]
[ 23432-39-5 ]
Reference：
[1] Journal of the American Chemical Society, 1949, vol. 71, p. 1906,1910
4-Chloro-6-methoxyquinoline A mixture of 12 g of 4-hydroxy-6-methoxyquinoline in 50 cm3 of phosphorus oxychloride was maintained at a temperature in the region of 100° C., with stirring and under an inert atmosphere, for 2 hours. After cooling to about 20° C., the reaction mixture was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. and then hydrolyzed with ice and brought to pH=10 using a 5 N sodium hydroxide solution. The mixture was extracted with ethyl acetate, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue obtained was chromatographed, under atmospheric pressure, on a column of silica gel (particle size 70-200 mu), eluding with a mixture of dichloromethane/methanol (85/15 by volume). The fractions containing the product were combined and then concentrated to dryness according to the above conditions. 12 g of 4-chloro-6-methoxyquinoline were obtained in the form of a white solid melting at 82° C. 1H NMR Spectrum (300 MHz, (CD3)2SO-d6, 6 in ppm) 3.958 (s: 3H); 7.45 (d, J=2.5 Hz: 1H); 7.53 (dd, J=9 and 2.5 Hz: 1H); 7.76 (d, J=4.5 Hz: 1H); 8.04 (d, J=9 Hz: 1H); 8.70 (d, J=4.5 Hz: 1H).
48b) 4-Chloro-6-methoxy-qniinolineA solution of phenol (48a) (1.35 g) in phosphorous oxychloride(3 ml) was heated at 80°C for 2 hours. After cooling, water wasadded and the resulting solution was made alkaline by adding 6Nsodium hydroxide solution. The precipitated solid was filteredoff and washed with water. The precipitate was taken up indiethyl ether and filtered. The diethyl ether layer was driedover magnesium sulfate, filtered and evaporated to give thedesired product (1 g).XH NMR (300MHz, CDC13) : 5: 8.66 (d, 1H) , 8.06 (d, 1H) , 7.51-7.43(m, 3H), 4.01 (s, 3H)
In diphenylether; at 245 - 250℃; for 2.0h;Inert atmosphere;
A solution of <strong>[28027-16-9]4-hydroxy-6-methoxyquinoline-3-carboxylic acid</strong> (7, 15.7 g, 72 mmol) in 80 ml of diphenyl ether was heated for 2 h in a metal bath to 245 C. The reaction mixture was cooled to room temperature and taken up in 200 ml hexane. This mixture was stirred for 3 h, then filtered. The solid was washed with ethyl acetate and dried to deliver 6-methoxyquinolin-4-ol (8, 12.5 g, 72 mmol, 100 %). 1H-NMR (DMSO): delta = 3.81 (s, 3H), 5.99 (d, 1H), 7.28 (dd, 1H), 7.48 - 7.53 (m, 2H), 7.86 (d, 1H), 11.87 (bs, 1H). LC-MS: Rt = 0.87 min; MS: m/z = 176 [M+1]+.
In diphenylether; di-isopropyl ether; pentane;
4-Hydroxy-6-methoxyquinoline. A suspension of 53.5 g of <strong>[28027-16-9]4-hydroxy-6-methoxyquinoline-3-carboxylic acid</strong> in 1000 cm3 of diphenyl ether was heated with stirring, at a temperature of between 250 C. and 260 C., for 2 hours 45 minutes. The reaction mixture was cooled to about 20 C. After stirring for 16 hours at this temperature, the mixture was poured with stirring into 1 liter of pentane and then filtered. The cake obtained was washed with 3 times 100 cm3 of pentane and then with 3 times 100 cm3 of diisopropyl ether. After drying in air, 37 g of 4-hydroxy-6-methoxyquinoline were obtained in the form of a beige-colored solid. Mass spectrum: DCI m/z=176 MH+base peak 4-Hydroxy-6-methoxyquinoline-3-carboxylic acid can be prepared according to B. R. Baker and Ray R. Bramhall, J. Med. Chem. 15, 230 (1972).
With phosphorus tribromide; In water; N,N-dimethyl-formamide; at 0℃;
To a solution of 6-(methyloxy)-4-quinolinol (23.6 g, 135 mmol) in DNF (100 mL) was added PBr3 (16 mL, 169 mmol) in portions. The flask was filled with a bubbler. When bubbling ceased, the suspension was dumped into icy water with stirring. The resulting mixture was diluted with a large volume of water (-600 mL). The percipitate was filtered, washed with water and dried under vaccume line to afford the title compound as an off-white solid (31.4 g, 97%): LC/MS (ES) m/e 239 (M+H)+
95%
With phosphorus tribromide; sodium hydroxide; In water; N,N-dimethyl-formamide; at 75℃;
A three-necked round bottom flask vented to a 1M NaOH (aq) gas trap was charged with 4-hydroxy-6-methoxyquinoline (12.07 g, 68.90 mmol, 1.0 equiv) and anhydrous N,Ndimethylformamide(75 mL) and stirred magnetically. To the heterogeneous mixture was addedPBr3 (8.0 mL, 85 mmol, 1.2 equiv) drop/portionwise over several minutes by syringe. During theaddition, the internal temperature rose to 75 C, and gas was evolved. A copious precipitate formedtoward the end of the addition. The vent to the gas trap was removed 15 min after the completionof addition, and the reaction was stirred vigorously for an additional 1h 45 min, then quenched bypouring onto 150 g ice in 150 mL water. After brief stirring, Na2CO3 (20 g) was added in smallportions (bubbling), and the mixture was stirred for 15 min, whereupon the pH was approximately7. The taupe-colored product was isolated by vacuum filtration on a Buchner funnel, washingextensively with water. After drying for several days in a vacuum desiccator, the title compoundwas obtained in ca. 95% purity as a light tan, powdery solid (15.58 g, 65.44 mmol, 95%).
95%
With phosphorus tribromide; sodium hydroxide; In N,N-dimethyl-formamide; at 75℃; for 1.75h;
A threenecked round bottom flask vented to a 1MNaOH (aq) gas trap was charged with 14 (12.07 g, 68.9() rnmol, 10 equiv) and anhydious NN-dimethy1forrnainide (75 mL)and stirred magnetically. To the heterogeneous mixture was added PBr3 (8.0 mL, 85 mmol,1.2 equiv) drop/porlionwise over several minutes by syringe. Duiing the addition, the internal temperature rose to 75 C, and gas was evolved. A copious precipitate formed toward the end of the addition. The vent to the gas trap was 15 mm after the completion of addition, and the reaction was stirred vigorously for an additional lh 45 mm, then quenchedby pouring onto 150 g ice in 150 mL water. Aer brief stirring, Na2CO3 (20 g) was added in small portions (bubbling), and the mixture was stirred for 15 mm, whereupon the pH was approximately 7. The taupecoiored product was isolated by vacuum filtration on a Buchner finnel. washing extensively with water. After drying for several days in a vacuum desiccator, the title compound was obtained in ca. 95% purity as a light tan, powdery solid (1558 g, 6544 mmol, 95%). ?H NMR (300 MHz, DMSOd6) oe: 857 (d, J= 4.7, 1H); 8.00(d, J= 9.2, 111); 7.89 (d. ,J= 4.7, 1H); 7.51 (dd, J= 2.8, ). 2, IH); 7.39 (d, J= 2.8, 1H); 3.96 (S. 3H). (See W02006/0002047, which is incorporated by reference herein in its entirety.)
87%
With phosphorus tribromide; In N,N-dimethyl-formamide; at 20℃; for 2h;
Preparation of 4-ethenyl-6-(methyloxy)quinoline; a) 4-bromo-6-methoxy quinoline; To a stirred solution of 4-hydroxy-6-methoxyquinoline (1.20 g, 70.5 mmole) in DMF (60 ml_) at RT was added PBr3 (8.0 mL, 84.6 mmole) dropwise. After 2h, the reaction contents were poured onto H2O (300 mL) and the product filtered and washed with H2O to give, after drying under high vacuum, the title compound (14.3 g, 87%) as a light yellow solid: LC-MS (ES) m/e 233 (M+H)+.
tert-butyl (S)-3-((6-methoxyquinolin-4-yl)oxy)pyrrolidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 12.25h;
tert-Butyl (R)-3-hydroxypyrrolidine-1-carboxylate (187 mg, 1.0 mmol) was dissolved in tetrahydrofuran (5.0 mL). To the resulting solution, 4-hydroxy-6-methoxyquinoline (175 mg, 1.0 mmol) and triphenylphosphine (393 mg, 1.5 mmol) were added. The mixture solution was cooled to 0 C. And then, DIAD (diisopropyl azodicarboxylate) (0.29 mL, 1.5 mmol) was slowly added dropwise for 15 minutes. The reaction mixture was stirred for 12 hours at room temperature. After the completion of the reaction, the reaction mixture was evaporated in vacuo and then purified with silica gel column chromatography (ethyl acetate/methanol= 10/1, v/v) to give a title compound (275 mg, 80%). MS (ESI) m/z= 345.2 (M + H)+
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