* 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, 1986, vol. 108, # 16, p. 4754 - 4760
9
[ 611-35-8 ]
[ 590371-90-7 ]
Reference：
[1] Journal of Organic Chemistry, 2018, vol. 83, # 2, p. 871 - 880
10
[ 611-35-8 ]
[ 40106-98-7 ]
[ 23833-99-0 ]
Yield
Reaction Conditions
Operation in experiment
59%
at -15 - 20℃; for 3 h;
a. 4-Chloro-8-nitroquinoline (6a) and 4-chloro-5-nitroquinoline (6d). 4-Chloroquinoline (10.0 g, 61.3 mmol) was added in small portions to sulfuric acid (45 mL) taking care to maintain the temperature at or below [15 °C.] Then the solution was cooled and maintained at-5 °C during the addition of fuming nitric acid (9 mL). The mixture was allowed to warm to room temperature and stirred for an additional 3 h. The reaction mix was poured on ice and basified (pH 9) with NH40H. The resulting precipitate was filtered, washed well with water, dried, and recrystallized from methanol to provide 7.5 g (59percent) [OF 6A] as golden-brown needles; mp [128-129 °C] (lit. 32 mp [129-130 °C) ; IH NMR (CDC13)] [6] 7.67 (d, 1H, [J=4.] 5), 7.75 (dd, 1H, [J=8.] 6,. [J=7.] 6), 8.10 (dd, 1H, [J=7.] 6, [J=1.] 3), 8. 48 (dd, 1H, [J=8.] 6, J=1. 3), 8.94 (d, 1H, J=4. 5); [13C] NMR (CDC13) [6] 123.0, 124.4, 126.5, 127.5, 128.3, 140.6, 143.2, 148.7, 152.1. The mother liquor was evaporated and chromatographed in 19: 1 hexanes-ethyl acetate, to provide 2.05 g (16percent) of the 5-nitro isomer 6d as a very light yellow solid; mp [144-146 °C] (lit. 31 mp [150 °C) ; IH] NMR (CDCl3) [6] 7.65 (d, 1H, J=4. 7), 7. 82 [(M,] 2H), 8.35 (dd, [1H,] [J=2.] 5, J=7. 3), 8.90 (d, 1H, J=4. 7); [13C] NMR [(CDC13)] 8 118.2, 123.4, 125.1, 128.8, 134.2, 135.6, 139.1, 149.7, 151.2.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 13, p. 3731 - 3742
[2] Patent: WO2004/14906, 2004, A2, . Location in patent: Page 31
[3] Journal of the American Chemical Society, 1946, vol. 68, p. 1532,1534
[4] Journal of the Chemical Society, 1948, p. 1707
[5] Journal of the American Chemical Society, 1947, vol. 69, p. 303,306
11
[ 611-35-8 ]
[ 7664-93-9 ]
[ 7697-37-2 ]
[ 40106-98-7 ]
[ 23833-99-0 ]
Reference：
[1] Journal of the American Chemical Society, 1947, vol. 69, p. 303,306
12
[ 611-35-8 ]
[ 23833-99-0 ]
Yield
Reaction Conditions
Operation in experiment
59%
at -15 - 20℃; for 3 h;
a. 4-Chloro-8-nitroquinoline (6a). This intermediate was prepared from 4-chloroquinoline (obtained by treating 4-hydroxyquinoline with [POC13] as [
DESCRIBED BY GOULEY, R. W., ET AL. , J. AMER. CHEM. SOC., 1947, 69, 303-306.4-] Chloroquinoline (10.0 g, 61.3 mmol) was added in small portions to sulfuric acid (45 mL) taking care to maintain the temperature at or below 15° C. Then the solution was cooled and maintained at-15° C during the addition of fuming nitric acid (9 mL). The mixture was allowed to warm to room temperature and stirred for an additional 3 hours. The reaction mix was poured on ice and basified (pH 9) with NH40H. The resulting precipitate was filtered, washed well with water, dried, and recrystallized from methanol to provide 7.5 g of 6a, in 59 percent yield; m. p. = [128-129° C] (lit. m. p. = [129-130° C) ; IH] NMR [(CDC13)] [8] 7.67 (d, [1H,] J=4. 5), 7.75 (dd, 1H, J=8. 6 [HZ,] J=7. 6), 8.10 (dd, 1H, J=7. 6, J=1. 3), 8. 48 (dd, 1H,. [J=8.] [6,] J=1.3), 8.94 (d, 1H, J=4. 5); [13C] NMR [(CDC13)] [8] 123.0, 124.4, 126.5, 127.5, 128.3, 140.6, 143.2, 148.7, 152.1.
55.7%
Stage #1: at 20℃; Stage #2: With ammonium hydroxide In water at 0℃;
4-Chloroquinoline (5 g, 31 mmol) was dissolved in sulfuric acid (23 mL, 0.42 mol), to which nitric acid (4.5 mL, 0.11 mol) was slowly added dropwise, which was then stirred at room temperature for four hours. When the reaction was completed, the resultant was cooled to 0° C., and neutralized with 1M ammonium hydroxide. The generated solid was dissolved in ethyl acetate, dried with anhydrous sodium sulfate, and then filtered. The solvent was removed by vacuum distillation, and the residue was purified by a column chromatography (ethyl acetate/n-hexane=) to obtain 3.55 g of the desired compound as a white solid (yield 55.7percent).1H NMR (400 MHz, CDCl3): δ 7.59 (d, J=6.76 Hz, 1H), 7.74 (t, J=8.02 Hz, 1H), 8.08 (d, J=7.33 Hz, 1H), 8.47 (d, J=8.44 Hz, 1H), 8.93 (d, J=4.59 Hz, 1H).13C NMR (75 MHz, CDCl3): δ 122.94, 124.33, 126.34, 127.41, 128.19, 140.81, 143.23, 148.96, 152.00.
900 mg
at 0 - 15℃; for 3 h;
To a solution of 4-chloroquinoline (1.0 g, 6.13 mmol) in conc. H2SO4 (4.5 mL) was drop wise added conc. HNO3 (1.8 mL) at 0° C. and the reaction mixture was stirred at 0-15° C. for 3 h. Then the reaction mixture was quenched by addition of aq. NH4OH at 0° C. and the pH of the reaction mixture was adjusted to 8. The solid precipitate was filtered and the filter cake was further purified by column chromatography to afford 900 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.98 (d, J=5.1 Hz, 1H), 8.50-8.47 (d, J=9.0 Hz, 1H), 8.41 (d, J=7.8 Hz, 1H), 8.02-7.99 (d, J=4.8 Hz, 1H), 7.96-7.90 (t, J=7.8 Hz, 1H).
Reference：
[1] Chemical and Pharmaceutical Bulletin, 2013, vol. 61, # 7, p. 747 - 756
[2] Patent: WO2004/14906, 2004, A2, . Location in patent: Page 19
[3] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 13, p. 3517 - 3520
[4] Journal of Enzyme Inhibition and Medicinal Chemistry, 2015, vol. 30, # 4, p. 607 - 614
[5] Patent: US2010/249182, 2010, A1, . Location in patent: Page/Page column 3; 5
[6] Patent: US2013/210844, 2013, A1, . Location in patent: Paragraph 0330; 0331
[7] Chemistry of Heterocyclic Compounds, 2013, vol. 49, # 9, p. 1308 - 1322[8] Khim. Geterotsikl. Soedin., 2013, vol. 49, # 9, p. 1404 - 1419,15
13
[ 611-35-8 ]
[ 40106-98-7 ]
[ 23833-99-0 ]
Yield
Reaction Conditions
Operation in experiment
59%
at -15 - 20℃; for 3 h;
a. 4-Chloro-8-nitroquinoline (6a) and 4-chloro-5-nitroquinoline (6d). 4-Chloroquinoline (10.0 g, 61.3 mmol) was added in small portions to sulfuric acid (45 mL) taking care to maintain the temperature at or below [15 °C.] Then the solution was cooled and maintained at-5 °C during the addition of fuming nitric acid (9 mL). The mixture was allowed to warm to room temperature and stirred for an additional 3 h. The reaction mix was poured on ice and basified (pH 9) with NH40H. The resulting precipitate was filtered, washed well with water, dried, and recrystallized from methanol to provide 7.5 g (59percent) [OF 6A] as golden-brown needles; mp [128-129 °C] (lit. 32 mp [129-130 °C) ; IH NMR (CDC13)] [6] 7.67 (d, 1H, [J=4.] 5), 7.75 (dd, 1H, [J=8.] 6,. [J=7.] 6), 8.10 (dd, 1H, [J=7.] 6, [J=1.] 3), 8. 48 (dd, 1H, [J=8.] 6, J=1. 3), 8.94 (d, 1H, J=4. 5); [13C] NMR (CDC13) [6] 123.0, 124.4, 126.5, 127.5, 128.3, 140.6, 143.2, 148.7, 152.1. The mother liquor was evaporated and chromatographed in 19: 1 hexanes-ethyl acetate, to provide 2.05 g (16percent) of the 5-nitro isomer 6d as a very light yellow solid; mp [144-146 °C] (lit. 31 mp [150 °C) ; IH] NMR (CDCl3) [6] 7.65 (d, 1H, J=4. 7), 7. 82 [(M,] 2H), 8.35 (dd, [1H,] [J=2.] 5, J=7. 3), 8.90 (d, 1H, J=4. 7); [13C] NMR [(CDC13)] 8 118.2, 123.4, 125.1, 128.8, 134.2, 135.6, 139.1, 149.7, 151.2.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 13, p. 3731 - 3742
[2] Patent: WO2004/14906, 2004, A2, . Location in patent: Page 31
[3] Journal of the American Chemical Society, 1946, vol. 68, p. 1532,1534
[4] Journal of the Chemical Society, 1948, p. 1707
[5] Journal of the American Chemical Society, 1947, vol. 69, p. 303,306
14
[ 611-35-8 ]
[ 7664-93-9 ]
[ 7697-37-2 ]
[ 40106-98-7 ]
[ 23833-99-0 ]
Reference：
[1] Journal of the American Chemical Society, 1947, vol. 69, p. 303,306
Reference：
[1] Patent: US4412076, 1983, A,
[2] Patent: US4412076, 1983, A,
17
[ 56-23-5 ]
[ 72812-97-6 ]
[ 7719-12-2 ]
[ 611-35-8 ]
[ 611-36-9 ]
Reference：
[1] Yakugaku Zasshi, 1955, vol. 75, p. 127[2] Chem.Abstr., 1956, p. 1817
18
[ 72812-97-6 ]
[ 67-66-3 ]
[ 7719-12-2 ]
[ 611-35-8 ]
[ 611-36-9 ]
Reference：
[1] Yakugaku Zasshi, 1951, vol. 71, p. 263,265[2] Yakugaku Zasshi, 1955, vol. 75, p. 130,133[3] Chem.Abstr., 1956, p. 1817
19
[ 72812-97-6 ]
[ 141-78-6 ]
[ 7719-12-2 ]
[ 611-35-8 ]
[ 611-36-9 ]
Reference：
[1] Yakugaku Zasshi, 1955, vol. 75, p. 127[2] Chem.Abstr., 1956, p. 1817
20
[ 611-35-8 ]
[ 1020150-22-4 ]
[ 1020149-73-8 ]
Yield
Reaction Conditions
Operation in experiment
0.045 g
With palladium diacetate; potassium carbonate; XPhos In water; N,N-dimethyl-formamide; <i>tert</i>-butyl alcohol at 110℃; for 24 h; Sealed tube; Inert atmosphere
A sealed tube was charged with Pd(OAc)2 (1 mg, 1.32 mmol) and XPhos (2 mg, 3.97 mmol) and degassed t-BuOH/water (1 mL, 2:1 v/v) was added. The resulting solution was heated for 1 min at 80 ºC and then cannulated into another sealed tube charged with 4-amino-N-[4-(2-amino-6-methylpyrimidine-4-ylamino)phenyl]benzamide 12 (0.07g, 0.20 mmol), 4-chloroquinoline 13 (22.0 mg, 0.13 mmol) and potassium carbonate (0.03 g, 0.18 mmol) in DMF (1 mL). The resulting mixture was stirred for 24 h at 110 ºC. When the reaction was complete the solvent was concentrated in vacuo and the residue was purified by column chromatography (silica gel, 85:13:2 CH2Cl2/MeOH/Et3N) to afford 0.045 g (73percent by 1H-NMR) of the titled compound as an amorphous yellow solid. 1H-NMR (400.13 MHz, DMSO-d6): d 10.22 (s, 1H, CONH), 9.98 (s, 1H, NH), 8.59 (d, J = 5.6 Hz, 1H), 8.48 (d, J = 8.4 Hz, 1H), 8.05 (d, J = 8.7 Hz, 2H), 8.00-7.94 (m, 2H), 7.86 – 7.75 (m, 3H), 7.74 – 7.61 (m, 4H), 7.57 – 7.50 (m, 3H), 7.44 – 7.37 (m, 1H), 7.15 (d, J = 5.6 Hz, 1H), 6.04 (s, 1H, H5’’), 2.22 (s, 3H, CH3) ppm. 13C-NMR (100.62 MHz, DMSO-d6): d 164.7 (s, CONH), 161.4 (s), 157.1 (s), 154.9 (s), 149.5 (s), 147.8 (d), 145.0 (s), 142.9 (s), 135.4 (s), 134.2 (s), 131.3 (d), 130.2 (s), 129.3 (d, 2x), 125.9 (d, 2x), 123.0 (d, 2x), 121.7 (d), 121.6 (d, 2x), 120.8 (d, 2x), 119.4 (s), 102.5 (d), 96.4 (d), 19.4 (q, CH3) ppm. HRMS (ESI+): Calcd for C27H24N7O ([M + H]+), 462.20368; found, 462.20330. IR (neat): n 3400-3000 (br, N-H), 2976 (w, C-H), 2891 (w, C-H), 1584 (m), 1510 (m), 1444 (m), 1380 (m), 1318 (m), 1228 (w), 1180 (w), 1095 (w) cm-1. UV (DMSO): lmax 258, 355 nm.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 6, p. 1631 - 1635
21
[ 611-35-8 ]
[ 1020149-73-8 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 6, p. 1631 - 1635
[2] Journal of Medicinal Chemistry, 2014, vol. 57, # 3, p. 701 - 713
With sulfuric acid; nitric acid; at -15 - 20℃; for 3.0h;
a. 4-Chloro-8-nitroquinoline (6a) and 4-chloro-5-nitroquinoline (6d). 4-Chloroquinoline (10.0 g, 61.3 mmol) was added in small portions to sulfuric acid (45 mL) taking care to maintain the temperature at or below [15 C.] Then the solution was cooled and maintained at-5 C during the addition of fuming nitric acid (9 mL). The mixture was allowed to warm to room temperature and stirred for an additional 3 h. The reaction mix was poured on ice and basified (pH 9) with NH40H. The resulting precipitate was filtered, washed well with water, dried, and recrystallized from methanol to provide 7.5 g (59%) [OF 6A] as golden-brown needles; mp [128-129 C] (lit. 32 mp [129-130 C) ; IH NMR (CDC13)] [6] 7.67 (d, 1H, [J=4.] 5), 7.75 (dd, 1H, [J=8.] 6,. [J=7.] 6), 8.10 (dd, 1H, [J=7.] 6, [J=1.] 3), 8. 48 (dd, 1H, [J=8.] 6, J=1. 3), 8.94 (d, 1H, J=4. 5); [13C] NMR (CDC13) [6] 123.0, 124.4, 126.5, 127.5, 128.3, 140.6, 143.2, 148.7, 152.1. The mother liquor was evaporated and chromatographed in 19: 1 hexanes-ethyl acetate, to provide 2.05 g (16%) of the 5-nitro isomer 6d as a very light yellow solid; mp [144-146 C] (lit. 31 mp [150 C) ; IH] NMR (CDCl3) [6] 7.65 (d, 1H, J=4. 7), 7. 82 [(M,] 2H), 8.35 (dd, [1H,] [J=2.] 5, J=7. 3), 8.90 (d, 1H, J=4. 7); [13C] NMR [(CDC13)] 8 118.2, 123.4, 125.1, 128.8, 134.2, 135.6, 139.1, 149.7, 151.2.
With trichlorophosphate; for 0.333333h;Heating / reflux;
a. Synthesis of 4-Chloroquinoline (6d). 4-Quinolone (10.0 g, 69.0 mmol) was added to phosphorus oxychloride [(82.] 3 g, 0.537 mol), and the stirred mixture was heated to reflux, and maintained at this temperature for 20 minutes. The reaction mixture was then cooled, and ice was slowly added to the crude residue until the evolution of HCl gas was no longer observed. The mixture was then neutralized by addition of 10% [NAOH] (pH 7.0) and then extracted into [CHC13] (3 x 100 mL), washed with water (3 x 100 mL), dried [(MGS04),] and evaporated to give 10.34 g of the chloroquinoline, in 92 % yield; mp [28-29 C] (lit mp [29-32 C) ; IH NMR (CDC13) 6] 7.50 (d, 1H, J=4. 6), 7.65 (ddd, 1H, J=8. 4, J=7. 0, J=1. 2), 7.78 (ddd, [1H,] J=8. 4, J=7. 0, J=1. 4), 8.14 (dd, 1H, J=8. 4, J=1. 4), 8.24 (dd, 1H, J=8. 4, J=1. 2), 8.79 (d, 1H, J=4. 6); [13C] NMR [(CDC13)] [6] 121.4, 124.3, 126.7, 127.7, [130.] 0, [130.] 5,142. 7,129. 3,149. 9.
87%
With trichlorophosphate; at 120℃; for 3h;Sealed tube;
Add 4-hydroxyquinoline (2.90 g, 0.020 mol) to a dry sealed 100 mL reaction vial.Phosphorus oxychloride (30mL),Stir the reaction, seal and heat to 120 C to continue the reaction for 3 h,The reaction was completed by TLC and the reaction was stopped. The reaction solution was cooled to room temperature.The solvent was concentrated under reduced pressure, and 50 mL of ice water was added, and the activated carbon was decolorized, suction filtered, and the filtrate was collected.The pH was adjusted to 8 to 9 with 10% NaOH, and distilled to obtain 2.80 g of <strong>[611-36-9]4-chloroquinoline</strong> as a colorless liquid, yield 87%.
87%
With trichlorophosphate; at 120℃; for 12h;
A mixture of 4-hydroxyquinoline 1 (2.90g, 0.020mol) and phosphorus oxychloride (30mL) was stirred at 120C for 12h. Then, the mixture was cooled to room temperature and the solvent was removed by reduced pressure distillation. The residue was dissolved in 50mL of code water, the aqueous was adjusted pH to 8-9 with 10% NaOH under cooling in an ice-water bath, and extracted with dichloromethane (DCM, 3×30mL). The combined organic layer was dried over anhydrous MgSO4, filtered, and concentrated in vacuo to get the colorless liquid (2.80g, 87%). 1H NMR (600MHz, DMSO-d6): delta 8.87-8.92 (m, 1H), 8.22-8.25 (m, 1H), 8.13-8.17 (m, 1H), 7.91-7.94 (m, 1H), 7.80-7.84 (m, 2H); ESI-MS: positive mode m/z 164.3 [M+H]+.
86%
With trichlorophosphate; at 80℃;
General procedure: Compounds 5a-c was added in POCl3, and the resulting mixture was refluxed for 12 h. The POCl3 was evaporated under reduced pressure, and the residue codisted once with CHCl3, and twice with toluene. The resulting solid was dissolved in CH2Cl2 and treated with triethylamine until aqueous washings of aliquots had pH >10. The solution was then filtered to yield the title compounds 6a-c.
78%
With trichlorophosphate; for 2h;Reflux;
Compound 1a (4-hydroxyquinoline) (2g, 13.79mmol) was placed in a 25mL flask, 6.5ml (70mmol) of phosphorus oxychloride was added, and refluxed for 2 hours under stirring;After the reaction was completed, the reaction liquid was added to ice water, and the mixture was neutralized with solid NaHCO3, and extracted with ethyl acetate (30 mL×3), and the organic phase was combined and washed with saturated sodium hydrogen carbonate solution (10 mL×3).Then washed with saturated brine (10 mL × 3),Dry with anhydrous Na2SO4, and finally concentrate under reduced pressure.Column chromatography gave 2a pale yellow liquid (1.75 g, 10.74 mmol).The yield was 78%.
78%
With trichlorophosphate; for 5h;Reflux;
General procedure: POCl3 (7 mL) was added to 4-hydroxyquinoline (2.00 g, 13.79 mmol) in a dryround bottom flask. After refluxed for 5 h, the reaction mixture was cooled to roomtemperature and then slowly added into ice. The solution was neutralized with solidsodium bicarbonate in ice bath, and then extracted with DCM (30 mL × 3). Thecombined organic layers were washed with brine (10 mL × 3). The organic phase wasseparated and dried over anhydrous Na2SO4. Then the solvent was evaporated in vacuo andthe crude product was purified by flash column chromatography to give the title compound16 as yellow liquid (1.75 g, 78%).
77%
With trichlorophosphate; at 100℃; for 4h;
A suspension of <strong>[611-36-9]quinolin-4-ol</strong> (5) (2g) in POCl3 (30mL) was heated at 100C for 4h. After cooling, the mixture was concentrated under reduced pressure and the ice was added to the residue. The pH was adjusted to 6 with ammonia to allow precipitation. The filter cake was washed with water and dried to give <strong>[611-36-9]4-chloroquinoline</strong> (6). White powder, yield: 77%, mp: 28-31C. 1H NMR (300MHz; CDCl3): 7.41 (d, J=4.7Hz, 1H); 7.54-7.60 (m, 1H); 7.69-7.74 (m, 1H); 8.09-8.17 (m, 2H); 8.73 (d, J=4.7Hz, 1H). MS (ESI+) m/z 164.0 (M+H)+. Anal. Calcd for C9H6ClN: C, 66.07; H, 3.70; N, 8.56; Found: C, 66.18; H, 3.68; N, 8.52.
N-formyldiethylamine; N,N-dimethyl-formamide;
f) reacting the 4-hydroxyquinoline of formula (11) with thionyl chloride in the presence of N,N-dimethylformamide or N,N-diethylformamide under anhydrous conditions to obtain a <strong>[611-36-9]4-chloroquinoline</strong> of formula (12), the excess thionyl chloride and the sulfur dioxide are stripped from the mixture by distillation under reduced pressure at a temperature of 60-95 C,
General Procedure X: <strong>[611-36-9]4-chloroquinoline</strong> (Intermediate 462)POCl3 (50 ml) was added to <strong>[611-36-9]quinolin-4-ol</strong> (5.0 g, 34.9 mmol) and the mixture was heated at 90 C. for 0.5 h. After cooling, the mixture was concentrated in vacuo. The residue was quenched with cold sat. NaHCO3 solution under cooling and the resulting aqueous phase was extracted with chloroform. The combined organic phases were washed with water, dried (Na2SO4) and concentrated in vacuo to give the title compound (5.0 g, 89%) which was used in the next step without further purification.MW: 163.61HPLCMS (Method C): [m/z]: 163.95
1.1 g
With trichlorophosphate; for 2h;Reflux;
A solution of 4-quinolinol (1.0 g, 6.88 mmol) in POCl3 (3 mL) was heated at reflux for 2 h. Then the reaction mixture was concentrated and the concentrate was dissolved in EtOAc. The organic layer was washed with a saturated solution of NaHCO3 and water. The organic layer was separated, dried, filtered and concentrated to afford 1.1 g of the title product. 1H NMR (300 MHz, DMSO d6): delta 8.87 (d, J=4.5 Hz, 1H), 8.23 (d, J=7.8 Hz, 1H), 8.14-8.11 (d, J=8.7 Hz, 1H), 7.93-7.88 (t, J=7.5 Hz, 1H), 7.82-7.77 (m, 2H).
With trichlorophosphate; at 120℃;
A mixture of 15 (1.0 g,6.89 mmol) and POCl3 (12 mL) was heated at 120 C for 4 h. Thereaction was monitored by using TLC. After completion of the reaction,excess of POCl3 was distilled off. The residue was stirred with ice waterfor 10 min, and then the pH value was adjusted to 7 with aqueousNaOH. The compound was collected by filtration and washed withwater. The crude product was purified by using flash columnchromatography with CH2Cl2/methanol (100: 1) elution to afford awhite solid compound 16. 1H NMR (300 MHz, DMSO-d6): delta 8.85 (d,J=4.6 Hz, 1H), 8.20 (d, J=8.4 Hz, 1H), 8.11 (d, J=8.4 Hz, 1H), 7.88(t, J=7.6 Hz, 1H), 7.81-7.72 (m, 2H).
A mixture of 4-chloroquinoline (486 mg, 3 mmol), acetamide (2.13 g, 36 mmol) and K2CO3 (2.9 g, 21 mmol) was thoroughly vortexed on a mixer and subjected to microwave irradiation at 175 C. for 1 h. The reaction mixture was cooled to room temperature and partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with water and brine and dried over anhydrous Na2SO4. The solvent was removed in vacuo to yield 4-aminoquinoline as a brown solid (260 mg, 60%). EIMS m/z: 145 ([M+1]+).
With sulfuric acid; nitric acid; at -15 - 20℃; for 3.0h;
a. 4-Chloro-8-nitroquinoline (6a). This intermediate was prepared from 4-chloroquinoline (obtained by treating 4-hydroxyquinoline with [POC13] as [ DESCRIBED BY GOULEY, R. W., ET AL. , J. AMER. CHEM. SOC., 1947, 69, 303-306.4-] Chloroquinoline (10.0 g, 61.3 mmol) was added in small portions to sulfuric acid (45 mL) taking care to maintain the temperature at or below 15 C. Then the solution was cooled and maintained at-15 C during the addition of fuming nitric acid (9 mL). The mixture was allowed to warm to room temperature and stirred for an additional 3 hours. The reaction mix was poured on ice and basified (pH 9) with NH40H. The resulting precipitate was filtered, washed well with water, dried, and recrystallized from methanol to provide 7.5 g of 6a, in 59 % yield; m. p. = [128-129 C] (lit. m. p. = [129-130 C) ; IH] NMR [(CDC13)] [8] 7.67 (d, [1H,] J=4. 5), 7.75 (dd, 1H, J=8. 6 [HZ,] J=7. 6), 8.10 (dd, 1H, J=7. 6, J=1. 3), 8. 48 (dd, 1H,. [J=8.] [6,] J=1.3), 8.94 (d, 1H, J=4. 5); [13C] NMR [(CDC13)] [8] 123.0, 124.4, 126.5, 127.5, 128.3, 140.6, 143.2, 148.7, 152.1.
55.7%
4-Chloroquinoline (5 g, 31 mmol) was dissolved in sulfuric acid (23 mL, 0.42 mol), to which nitric acid (4.5 mL, 0.11 mol) was slowly added dropwise, which was then stirred at room temperature for four hours. When the reaction was completed, the resultant was cooled to 0 C., and neutralized with 1M ammonium hydroxide. The generated solid was dissolved in ethyl acetate, dried with anhydrous sodium sulfate, and then filtered. The solvent was removed by vacuum distillation, and the residue was purified by a column chromatography (ethyl acetate/n-hexane=) to obtain 3.55 g of the desired compound as a white solid (yield 55.7%).1H NMR (400 MHz, CDCl3): delta 7.59 (d, J=6.76 Hz, 1H), 7.74 (t, J=8.02 Hz, 1H), 8.08 (d, J=7.33 Hz, 1H), 8.47 (d, J=8.44 Hz, 1H), 8.93 (d, J=4.59 Hz, 1H).13C NMR (75 MHz, CDCl3): delta 122.94, 124.33, 126.34, 127.41, 128.19, 140.81, 143.23, 148.96, 152.00.
900 mg
With sulfuric acid; nitric acid; at 0 - 15℃; for 3.0h;
To a solution of 4-chloroquinoline (1.0 g, 6.13 mmol) in conc. H2SO4 (4.5 mL) was drop wise added conc. HNO3 (1.8 mL) at 0 C. and the reaction mixture was stirred at 0-15 C. for 3 h. Then the reaction mixture was quenched by addition of aq. NH4OH at 0 C. and the pH of the reaction mixture was adjusted to 8. The solid precipitate was filtered and the filter cake was further purified by column chromatography to afford 900 mg of the title product. 1H NMR (300 MHz, DMSO d6): delta 8.98 (d, J=5.1 Hz, 1H), 8.50-8.47 (d, J=9.0 Hz, 1H), 8.41 (d, J=7.8 Hz, 1H), 8.02-7.99 (d, J=4.8 Hz, 1H), 7.96-7.90 (t, J=7.8 Hz, 1H).
a. 4-Chloro-8-nitroquinoline (6a). This intermediate was prepared from 4-chloroquinoline (obtained by treating 4-hydroxyquinoline with [POC13] as [ DESCRIBED BY GOULEY, R. W., ET AL. , J. AMER. CHEM. SOC., 1947, 69, 303-306.4-] Chloroquinoline (10.0 g, 61.3 mmol) was added in small portions to sulfuric acid (45 mL) taking care to maintain the temperature at or below 15 C. Then the solution was cooled and maintained at-15 C during the addition of fuming nitric acid (9 mL). The mixture was allowed to warm to room temperature and stirred for an additional 3 hours. The reaction mix was poured on ice and basified (pH 9) with NH40H. The resulting precipitate was filtered, washed well with water, dried, and recrystallized from methanol to provide 7.5 g of 6a, in 59 % yield; m. p. = [128-129 C] (lit. m. p. = [129-130 C) ; IH] NMR [(CDC13)] [8] 7.67 (d, [1H,] J=4. 5), 7.75 (dd, 1H, J=8. 6 [HZ,] J=7. 6), 8.10 (dd, 1H, J=7. 6, J=1. 3), 8. 48 (dd, 1H,. [J=8.] [6,] J=1.3), 8.94 (d, 1H, J=4. 5); [13C] NMR [(CDC13)] [8] 123.0, 124.4, 126.5, 127.5, 128.3, 140.6, 143.2, 148.7, 152.1.
With trifluoroacetic acid; In isopropyl alcohol; at 20 - 130℃; for 2h;
TFA (0.57 mL) was added to a suspension of 4- chloroquinoline (0.48 mg, 2.9 mmol) and 4-amino-2- nitrophenol (0.45 g, 2.9 mmol) in I-PROH (4 mL) was added at RT. The reaction was heated to 130 C in a sealed tube for 2 h. A solid precipitated upon cooling. The solid was filtered out and washed with i-PrOH to give 2-nitro-4- (quinolin-4-ylamino) -phenol.
EXAMPLE 19A 4-iodoquinoline A solution of 4-chloroquinoline (5.0 g, 30.56 mmol) in 2-butanone (40 mL) at room temperature was treated with sodium iodide (23 g, 153 mmol) and 47% hydriodic acid (20 mL), heated to reflux for 8 hours, cooled to room temperature, adjusted to pH 7 with saturated NaHCO3, and extracted with ethyl acetate. The extract was concentrated, and the concentrate was purified by flash column chromatography on silica gel with 4:1/hexanes:ethyl acetate to provide the desired product. MS (ESI(+)) m/z 256 (M+H)+; 1H NMR (300 MHz, CDCl3) delta 8.46 (d, 1H), 8.06-8.00 (m, 3H), 7.79-7.73 (m, 1H), 7.66-7.61 (m, 1H).
EXAMPLE 1 N-(1H-Pyrrol-1-yl)-4-quinolinamine hydrochloride A solution of 4-chloroquinoline (10 g) and <strong>[765-39-9]1-aminopyrrole</strong> (6 g) in 100 ml isopropanol containing 1 ml saturated ether/HCl was stirred at 80 for thirty minutes, and thereafter cooled, stirred with water, basified with sodium carbonate and extracted with dichloromethane. The organic extract was washed successively with water and saturated sodium chloride solution, dried (anhy. MgSO4), filtered and concentrated to 12 g of solid, m.p. 165-168. Four grams were converted to the hydrochloride salt and recrystallized twice from methanol/ether to give 2.9 g crystals, m.p. 233-234.
N-(1H-Indol-1-yl)-4-quinolinamine maleate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; In methanol; dichloromethane; water; ethyl acetate; isopropyl alcohol;
EXAMPLE 8 N-(1H-Indol-1-yl)-4-quinolinamine maleate A solution prepared from 4-chloro-quinoline (5 g), <strong>[53406-38-5]1H-indol-1-amine</strong> (5 g), 100 ml isopropanol and 1 ml saturated ether/HCl was stirred for three hours at reflux, and thereafter cooled, stirred with water, basified with sodium carbonate and extracted with dichloromethane. The organic extract was washed successively with water and saturated sodium chloride solution, dried (anhy. MgSO4), filtered and concentrated to a solid. This was purified by flash chromatography (silica, 10% ethyl acetate in dichloromethane) to give 6.5 g solid, m.p. 128 C. This was converted to the maleate salt in methanol to give 7.4 g of crystals, m.p. 207-208 C. dec. Three grams were recrystallized from methanol/ether to give 2.6 g crystals, m.p. 209-210 dec.
(1-quinolin-4-yl-pyrrolidin-3-yl)-carbamic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
In isopropyl alcohol; at 100℃;
To a mixture of racemic pyrrolidin-3-yl-carbamic acid tert-butyl ester (102 mg, 0.55 mmol), 4-chloroquinoline (Sigma-Aldrich, Inc) (82 mg, 0.5 mmol), was added isopropanol (2.5 mL), and the mixture was stirred overnight at 100 C. After cooling to rt, it was concentrated in vacuo. The residue was partitioned between aqueous K2CO3 and DCM. The organic layer was drawn off, washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to obtain 155 mg (100%) of crude (1-quinolin-4-yl-pyrrolidin-3-yl)-carbamic acid tert-butyl ester (27a) which was used as such for the next step. LC/MS (ESI): 314 (MH)+. The crude 27a (78 mg, 0.25 mmol) was suspended in 5 mL of 50% TFA/DCM and stirred at RT for 1 h. The mixture was then concentrated in vacuo and the residue was washed with anhydrous ether and the washings were discarded. This was repeated twice more and the residual solid was dried in vacuo to obtain 97 mg (90%) of the crude 1-quinolin-4-yl-pyrrolidin-3-ylamine (27b) as a yellow semi-solid which was used as such for the next step. LC/MS (ESI): 214 (MH)+. The crude 27b (22 mg, 0.05 mmol) was dissolved in anhydrous THF and triethylamine (20 mg, 0.2 mmol) was added followed by (4-isopropyl-phenyl)-carbamic acid 4-nitro-phenyl ester (30 mg, 0.1 mmol), prepared as described in Example 2a, and the mixture was stirred at 70 C. for 1 h. The mixture was then concentrated in vacuo and the residue was partitioned between aqueous K2CO3 and EtOAc. The organic layer was drawn off, washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to obtain the crude product which was purified by flash column chromatography (silica gel; 1-2% MeOH/DCM followed by 90:9:1 DCM:MeOH:NH3) to yield 10 mg (54%) of pure (4-isopropyl-phenyl)-3-(1-quinolin-4-yl)-pyrrolidin-3-yl-urea. 1H NMR (300 MHz, CDCl3): delta 8.07-7.97 (m, 2H), 7.94-7.84 (m, 2H), 7.62-7.5 (m, 2H), 7.31-7.23 (m, 3H), 7.11-7.05 (m, 2H), 5.81 (d, 1H), 4.74-4.64 (m, 1H), 4.09-4.00 (dd, 1H), 3.66-3.38 (m, 3H), 2.88-2.74 (heptet, 1H), 2.34-1.90 (m, 2H), 1.18 (d, 6H). LC/MS (ESI): calcd mass 374.2, found 375.2 (MH)+.
100%
EXAMPLE 27; (4-Isopropyl-phenyl)-3-(1-quinolin-4-yl)-pyrrolidin-3-yl-urea (Compound No. 27); To a mixture of racemic pyrrolidin-3-yl-carbamic acid tert-butyl ester (102 mg, 0.55 mmol), 4-chloroquinoline (Sigma-Aldrich, Inc) (82 mg, 0.5 mmol), was added isopropanol (2.5 mL), and the mixture was stirred overnight at 100 C. After cooling to rt, it was concentrated in vacuo. The residue was partitioned between aqueous K2CO3 and DCM. The organic layer was drawn off, washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to obtain 155 mg (100 %) of crude (1-quinolin-4-yl-pyrrolidin-3-yl)-carbamic acid tert-butyl ester (27a) which was used as such for the next step. LC/MS (ESI) : 314 (MH)+. The crude 27a (78 mg, 0.25 mmol) was suspended in 5 mL of 50 % TFA/DCM and stirred at RT for 1 h. The mixture was then concentrated in vacuo and the residue was washed with anhydrous ether and the washings were discarded. This was repeated twice more and the residual solid was dried in vacuo to obtain 97 mg (90%) of the crude 1-quinolin-4-yl-pyrrolidin-3-ylamine (27b) as a yellow semi-solid which was used as such for the next step. LC/MS (ESI): 214 (MH)-. The crude 27b (22 mg, 0.05 mmol) was dissolved in anhydrous THF and triethylamine (20 mg, 0.2 mmol) was added followed by (4-isopropyl-phenyl)-carbamic acid 4-nitro-phenyl ester (30 mg, 0.1 mmol), prepared as described in Example 2a, and the mixture was stirred at 70 C. for 1 h. The mixture was then concentrated in vacuo and the residue was partitioned between aqueous K2CO3 and EtOAc. The organic layer was drawn off, washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to obtain the crude product which was purified by flash column chromatography (silica gel; 1-2% MeOH/DCM followed by 90:9:1 DCM:MeOH:NH3) to yield 10 mg (54%) of pure (4-isopropyl-phenyl)-3-(1-quinolin-4-yl)-pyrrolidin-3-yl-urea. 1H NMR (300 MHz, CDCl3): delta 8.07-7.97 (m, 2H), 7.94-7.84 (m, 2H), 7.62-7.5 (m, 2H), 7.31-7.23 (m, 3H), 7.11-7.05 (m, 2H), 5.81 (d, 1H), 4.74-4.64 (m, 1H), 4.09-4.00 (dd, 1H), 3.66-3.38 (m, 3H), 2.88-2.74 (heptet, 1H), 2.34-1.90 (m, 2H), 1.18 (d, 6H). LC/MS (ESI): calcd mass 374.2, found 375.2 (MH)+.
To a mixture of racemic 3-pyrrolidinol (48 mg, 0.55 mmol) and 4-chloroquinoline (82 mg, 0.5 mmol), was added isopropanol (2.5 mL), and the mixture was stirred overnight at 100 C. After cooling to rt, it was concentrated in vacuo. The residue was partitioned between aqueous K2CO3 and DCM. The organic layer was drawn off, washed with water and brine. It was then dried over anhydrous MgSO4, filtered and concentrated in vacuo to obtain 105 mg (100%) of crude 1-quinolin-4-yl-<strong>[40499-83-0]pyrrolidin-3-ol</strong> (34a) which was used as such for the next step. The crude 34a (11 mg, 0.05 mmol) was dissolved in anhydrous THF and stirred at RT while a 1.0 M solution of NaHMDS in THF (0.1 mL, 0.1 mmol) was added to it followed by (4-isopropyl-phenyl)-carbamic acid 4-nitro-phenyl ester (30 mg, 0.1 mmol), prepared as described in Example 2a. The mixture was stirred at RT for 30 min and then at 80 C. for 30 min. The mixture was then concentrated in vacuo and the residue was partitioned between aqueous K2CO3 and EtOAc. The organic layer was drawn off, washed with water and brine. It was then dried over anhydrous MgSO4, filtered and concentrated in vacuo to obtain the crude product which was purified by Preparative TLC (silica gel; 5% MeOH/DCM) to yield 6.9 mg (37%) of pure (4-isopropyl-phenyl)-carbamic acid 1-quinolin-4-yl)-pyrrolidin-3-yl ester. 1H NMR (300 MHz, CDCl3): delta 8.49 (d, 1H), 8.18 (d, 1H), 8.07 (d, 1H), 7.63 (m, 1H), 7.39 (m, 1H), 7.31-7.24 (m, 2H), 7.16 (m, 2H), 6.82 (bs, 1H), 6.48 (d, 1H), 5.53 (m, 1H), 4.16-4.08 (m, 1H), 4.02-3.90 (m, 1H), 3.86-3.70 (m, 2H), 2.92-2.80 (m, 1H), 2.40-2.2 (m, 2H), 1.21 (d, 6H). LC/MS (ESI): calcd mass 375.2, found 376.2 (MH)+.
100%
EXAMPLE 34; (4-Isopropyl-phenyl)-carbamic acid 1-quinolin-4-yl)-pyrrolidin-3-yl ester (Compound No. 34); To a mixture of racemic 3-pyrrolidinol (48 mg, 0.55 mmol) and 4-chloroquinoline (82 mg, 0.5 mmol), was added isopropanol (2.5 mL), and the mixture was stirred overnight at 100 C. After cooling to rt, it was concentrated in vacuo. The residue was partitioned between aqueous K2CO3 and DCM. The organic layer was drawn off, washed with water and brine. It was then dried over anhydrous MgSO4, filtered and concentrated in vacuo to obtain 105 mg (100%) of crude 1-quinolin-4-yl-<strong>[40499-83-0]pyrrolidin-3-ol</strong> (34a) which was used as such for the next step. The crude 34a (11 mg, 0.05 mmol) was dissolved in anhydrous THF and stirred at RT while a 1.0 M solution of NaHMDS in THF (0.1 mL, 0.1 mmol) was added to it followed by (4-isopropyl-phenyl)-carbamic acid 4-nitro-phenyl ester (30 mg, 0.1 mmol), prepared as described in Example 2a. The mixture was stirred at RT for 30 min and then at 80 C. for 30 min. The mixture was then concentrated in vacuo and the residue was partitioned between aqueous K2CO3 and EtOAc. The organic layer was drawn off, washed with water and brine. It was then dried over anhydrous MgSO4, filtered and concentrated in vacuo to obtain the crude product which was purified by Preparative TLC (silica gel; 5% MeOH/DCM) to yield 6.9 mg (37%) of pure (4-isopropyl-phenyl)-carbamic acid 1-quinolin-4-yl)-pyrrolidin-3-yl ester. 1H NMR (300 MHz, CDCl3): delta 8.49 (d, 1H), 8.18 (d, 1H), 8.07 (d, 1H), 7.63 (m, 1H), 7.39 (m, 1H), 7.31-7.24 (m, 2H), 7.16 (m, 2H), 6.82 (bs, 1H), 6.48 (d, 1H), 5.53 (m, 1H), 4.16-4.08 (m, 1H), 4.02-3.90 (m, 1H), 3.86-3.70 (m, 2H), 2.92-2.80 (m, 1H), 2.40-2.2 (m, 2H), 1.21 (d, 6H). LC/MS (ESI): calcd mass 375.2, found 376.2 (MH)+.
3-ethoxycarbonyl-2-methyl-1-(quinol-4-yl)-1H-pyrrole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2.75 g (17.9 [MMOL)] of [3-ETHOXYCARBONYL-2-METHYL-1 H-PYRROLE ARE] added at [20C] under an argon atmosphere to 0.756 g (18.9 [MMOL)] of sodium hydride, at 60% by weight in liquid petroleum jelly, suspended in 12 cm3 of dimethylformamide. After stirring at [20C] for 0.2 hour, 0.114 g (1.79 [MMOL)] of copper powder and 2.35 cm3 (17.9 [MMOL)] of 4-chloroquinoline are added. After stirring at [140C] for 48 hours, the reaction mixture is filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 100 cm3 of water and then extracted with [3] times 70 cm3 of ethyl acetate. The organic phases are combined, dried over anhydrous magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) to give 5.2 g of a brown oil which is purified by flash chromatography [eluent : dichloromethane/ethyl acetate (97/3 by volume)]. After concentrating the fractions under reduced pressure (2.7 kPa), 3 g of 3-ethoxycarbonyl- 2-methyl-1-(quinol-4-yl)-1 H-pyrrole are obtained in the form of an orange-coloured oil. Mass spectrum [(EL)] : m/e 280 (M+.), [M/E] [251,] m/e 235.
3-methoxycarbonyl-4-methyl-1-(quinol-4-yl)-1H-pyrrole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.208 g (6.5 [MMOL)] of sodium hydride, at 75% by weight in liquid petroleum jelly, is added at a temperature in the region of [20C] under an argon atmosphere to a solution of 0.903 g (6.5 [MMOL)] of 3 methoxycarbonyl-4-methyl-1 H-pyrrole in 20 cm3 of dimethylformamide. After stirring at a temperature in the region [OF 40C] for 0.3 hour,- 1.07 g (6.5 mmol) of 4-chloroquinoline and 10 cm3 of [DIMETHYLFORMAMIDE] are added. After stirring at a temperature in the region of [120C] for 4 hours, the reaction mixture is poured into 200 cm3 of salt water and then extracted with 100 cm3 of ethyl acetate. The organic phase is partially concentrated under reduced pressure. 100 cm3 of salt water are added to the residue, which is then extracted with 50 cm3 of ethyl acetate. The organic phase is dried over anhydrous magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) to give 1.8 g of a solid which is purified by silica gel chromatography [eluent : dichloromethane/ethyl acetate (75/25 by volume)]. After concentrating the fractions under reduced pressure (2.7 kPa), 1.23 g of [3-METHOXYCARBONYL-4-METHYL-1-(QUINOL-4-YL)-1 H-PYRROLE] are obtained in the [FORM OF A WHITE SOLID. MASS SPECTRUM (EL) : M/E 266 (M+. ), M/E 235.]
5-chloro-3-methoxycarbonyl-1-(quinol-4-yl)-1H-indole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.771 g (24 [MMOL)] of sodium hydride at 75% by weight in liquid petroleum jelly is added to a solution of 5.03 g (24 [MMOL)] of 5-chloro-3-methoxycarbonyl-1 H-indole in 120 cm3 of dimethylformamide at a temperature in the region of [20C] under an argon atmosphere. After the reaction mixture has been stirred for 0.5 hour at a temperature in the region of 40C, 3.94 g (24 [MMOL)] of 4-chloroquinoline are added. After stirring for 6 hours at a temperature in the region of [120C,] the reaction mixture is cooled to a temperature in the region of [20C] and then poured into 400 cm3 of water and extracted with 500 cm3 of ethyl acetate. The organic phase is washed three times with 250 cm3 of water, dried over anhydrous magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by chromatography on silica gel (eluent : dichloromethane). After the fractions containing the expected product have been concentrated to dryness under reduced pressure, 2.5 g of [5-CHLORO-3-METHOXYCARBONYL-1-(QUINOLIN-4-YL)-1 H-INDOLE] are obtained in the form of a sticky beige-colored solid, which is used in the following step without further purification
6-fluoro-3-methoxycarbonyl-1-(quinol-4-yl)-1H-indole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.25 g (7.8 [MMOL)] of sodium hydride, at 75% by mass in liquid petroleum jelly, is added at a temperature in the region [OF 20C] under an argon atmosphere to a solution of 1.5 g (7.76 [MMOL)] of 6-fluoro-3-methoxycarbonyl-1 H-indole in 40 cm3 of [DIMETHYLFORMAMIDE.] After stirring at a temperature in the region [OF 40C] for 0.5 hour, 1.29 g (7.8 [MMOL)] of 4-chloroquinoline are added. After stirring at a temperature in the region of [120C] for 6 hours, the reaction mixture is poured into 150 cm3 of water and extracted with 150 cm3 of ethyl acetate. The organic phase is washed with 3 times 100 cm3 of water and is then dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give a brown solid which is purified by silica gel chromatography [eluent : [DICHLOROMETHANE] and then [DICHLOROMETHANE/ETHYL ACETATE (90/10 BY VOLUME) ]. AFTER CONCENTRATING THE FRACTIONS] under reduced pressure, 1.5 g of [6-FLUORO-3-METHOXYCARBONYL-1-(QUINOL-4-YL)-1 H-INDOLE] are obtained in the form of a beige-coloured solid. melting at [186C.]
5-fluoro-3-methoxycarbonyl-1-(quinol-4-yl)-1H-indole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.384 g (12 [MMOL)] of sodium hydride, at 75% by mass in liquid petroleum jelly, is added at a temperature in the region of [20C] under an argon atmosphere to a solution of 2.26 g [(11.] 7 [MMOL)] of [5-FLUORO-3-METHOXYCARBONYL-1] [H-INDOLE] in 60 cm3 of dimethylformamide. After stirring at a temperature in the region [OF 40C] for 0.5 hour, 1.98 g (12 [MMOL)] of 4-chloroquinoline are added. After stirring at a temperature in the region of [120C] for 6 hours, the reaction mixture is poured into 200 cm3 of water and extracted with 200 cm3 of ethyl acetate. The organic phase is washed with 3 times 100 cm3 of water and is then dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 3. 5 g of a brown solid which is purified by silica gel chromatography (eluent : dichloromethane). After concentrating the fractions under reduced pressure, 1. 6 g of [5-FLUORO-3-] [METHOXYCARBONYL-1-(QUINOL-4-YL)-1 H-INDOLE] are obtained in the form of a beige-coloured solid [MELTING AT 172C.]
With palladium diacetate; potassium carbonate; XPhos; In water; N,N-dimethyl-formamide; tert-butyl alcohol; at 110.0℃; for 24.0h;Sealed tube; Inert atmosphere;
A sealed tube was charged with Pd(OAc)2 (1 mg, 1.32 mmol) and XPhos (2 mg, 3.97 mmol) and degassed t-BuOH/water (1 mL, 2:1 v/v) was added. The resulting solution was heated for 1 min at 80 ºC and then cannulated into another sealed tube charged with 4-amino-N-[4-(2-amino-6-methylpyrimidine-4-ylamino)phenyl]benzamide 12 (0.07g, 0.20 mmol), 4-chloroquinoline 13 (22.0 mg, 0.13 mmol) and potassium carbonate (0.03 g, 0.18 mmol) in DMF (1 mL). The resulting mixture was stirred for 24 h at 110 ºC. When the reaction was complete the solvent was concentrated in vacuo and the residue was purified by column chromatography (silica gel, 85:13:2 CH2Cl2/MeOH/Et3N) to afford 0.045 g (73% by 1H-NMR) of the titled compound as an amorphous yellow solid. 1H-NMR (400.13 MHz, DMSO-d6): d 10.22 (s, 1H, CONH), 9.98 (s, 1H, NH), 8.59 (d, J = 5.6 Hz, 1H), 8.48 (d, J = 8.4 Hz, 1H), 8.05 (d, J = 8.7 Hz, 2H), 8.00-7.94 (m, 2H), 7.86 - 7.75 (m, 3H), 7.74 - 7.61 (m, 4H), 7.57 - 7.50 (m, 3H), 7.44 - 7.37 (m, 1H), 7.15 (d, J = 5.6 Hz, 1H), 6.04 (s, 1H, H5??), 2.22 (s, 3H, CH3) ppm. 13C-NMR (100.62 MHz, DMSO-d6): d 164.7 (s, CONH), 161.4 (s), 157.1 (s), 154.9 (s), 149.5 (s), 147.8 (d), 145.0 (s), 142.9 (s), 135.4 (s), 134.2 (s), 131.3 (d), 130.2 (s), 129.3 (d, 2x), 125.9 (d, 2x), 123.0 (d, 2x), 121.7 (d), 121.6 (d, 2x), 120.8 (d, 2x), 119.4 (s), 102.5 (d), 96.4 (d), 19.4 (q, CH3) ppm. HRMS (ESI+): Calcd for C27H24N7O ([M + H]+), 462.20368; found, 462.20330. IR (neat): n 3400-3000 (br, N-H), 2976 (w, C-H), 2891 (w, C-H), 1584 (m), 1510 (m), 1444 (m), 1380 (m), 1318 (m), 1228 (w), 1180 (w), 1095 (w) cm-1. UV (DMSO): lmax 258, 355 nm.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; at 90℃; for 12h;Inert atmosphere;
General procedure for the synthesis of 4-Butylquinoline (Compound 26a): To a stirred solution of substrate Compound 25 (187 mg, 1.14 mmol) in 1,4-dioxane were added the <strong>[4426-47-5]butylboronic acid</strong> (234 mg, 2.28 mmol), Pd(PPh3)4 (37 mg, 0.032 mmol) and K2C03 (472 mg, 3.42 mmol). The resulting reaction mixture was stirred at 90 C under nitrogen atmosphere for 12 h. After completion of reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with ethyl acetate (3 x 10 mL). The combined organic layer was dried over Na2S04 and concentrated under reduced pressure, crude material was purified by flash chromatography using CH2Cl2:MeOH as an eluent to obtain Compound 26a as a colorless liquid (100 mg, 73%). Colorless liquid (170 mg, 80%>).
With 4-methyl-morpholine; In 1-methyl-pyrrolidin-2-one; at 130℃; for 20h;Sealed tube;
A mixture of 2- (benzyloxy) aniline (301 mg, 1.51 mmol), 4-chloroquinoline (268 mg, 1.64 mmol), and 4-methylmorpholine (0.18 mL, 1.64 mmol) in 0.5 mL of NMP was heated in a heavy walled sealed tube at 130 C for 20 hr. The mixture was cooled and partitioned between EA and 5% Na2C03 and brine. The organic phases were dried over Na2S04 and concentrated. FC (7.5% MeOH/DCM) gave a dark oil that contained residual 4-methylmorpholine. The oil was filtered through a pad of silica gel using 30% EA/Hex + 2% TEA to give 268 mg of tan solid. R/0.12 (5% MeOH/DCM); 1H NMR (CDC13) delta 8.60 (d, 1H, J=5.4 Hz), 8.05 (dd, 1H, 1.0, 8.4 Hz), 7.88 (dd, 1H, J=0.8, 8.4 Hz), 7.66 (ddd, 1H, J=1.2, 6.9, 8.4 Hz), 7.53-7.40 (m, 2H), 7.37-7.29 (m, 5H), 7.15 (d, 1H, J=5.2 Hz), 7.07-6.98 (m, 3H), 5.17-5.10 (m, 2H, AB).
With tri-n-propylamine; In pentan-1-ol; for 66h;Reflux;
(3-Phenoxyphenyl)methanamine (2.02 g, 10.2 mmol) was taken up in 60 mL of 1-pentanol, and then 15 mL of volatile material was removed by distillation. The mixture was cooled below boiling, and tripropylamine (3.80 mL, 19.9 mmol) and 4-chloroquinoline (1.65 g, 10.2 mmol) were added. Heating at reflux was resumed. After 66 hr, volatile material was removed by evaporation. The mixture was partitioned between DCM (150, 100 mL) and 5% Na2C03 (80 mL). The combined organic phases were dried over Na2S04, filtered, and concentrated to give a solid. Recrystallization from EA/Hex gave 2.08 g of colorless solid. R 0.34 (10% MeOH/DCM); mp 163.0-164.0 C; 1H NMR (CDC13) delta 8.54 (d, 1H, J=5.5 Hz), 8.00 (m, 1H), 7.76 (d, 1H, J=8.1 Hz), 7.64 (m, 1H), 7.43 (m, 1H), 7.34-7.29 (m, 3H), 7.11 (m, 1H), 7.05 (s, 1H), 7.02-6.99 (m, 2H), 6.94 (dd, 1H, J=2.2, 8.0 Hz), 6.42 (d, 1H, J=5.5 Hz), 5.46 (br s, 1H, NH) 4.51 (m, 2H, AB); 13C NMR (CDC13) delta 158.2, 156.9, 151.3, 149.5, 148.7, 139.9, 130.5, 130.3, 130.0, 129.3, 125.0, 123.8, 122.2, 119.5, 119.3, 118.9, 118.0, 117.8, 99.7, 47.4.
ethyl 4-(quinolin-4-ylamino)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With phenol; at 90℃; for 192h;Sealed tube;
4-Chloroquinoline (2.00 g, 12 mmol), ethyl 4-amino-1-piperidine carboxylate (3.16 g, 32mmol), and phenol (6.90 g, 73 mmol) were heated at 90C in a sealed Carius vessel for 6days. TLC indicated that unreacted 4,7-dichloroquinoline remained, and thereforeadditional ethyl 4-amino-1-piperidine carboxylate (1.00 g, 1.0 mmol) was added. Thevessel was again sealed and heated for a further 2 days, whereupon TLC indicated thatreaction was complete. The reaction mixture was diluted with chloroform (50 mL) andrinsed with 10% caustic soda (5 x 10 mL), followed by further rinsing with water (3 x 10mL). The organic layer was dried over MgSO4 and concentrated under reducedpressure with warming to yield a brown semisolid. This material was taken up inboiling ethyl acetate (70 mL) and allowed to cool and concentrate at room temperature(to approximately 15 mL). Vacuum filtration provided the desired product as asparkling, tan, crystalline solid (2.81 g, 77%, mp = 209-210C).
4-chloro-quinoline (440 mg, 2.7 mmol, 1.0 eq.) was added to a solution of <strong>[121219-03-2]4-bromo-3-fluorophenol</strong> (2.04 g, 10.8 mmol, 4.0 eq.) in chlorobenzene (5 mL). The reaction was stirred at 100 C. for 12 hours and then sodium hydroxide solution (1 N, 10 mL) was added. The resulting mixture was extracted with ethyl acetate (10 mL*3). The combined organic phase with anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the crude product (800 mg, yield: 93%), which was used directly in the next step.
ethyl 1-(quinolin-4-ylthio)cyclobutanecarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
4-Chloroquinoline 1a (300 mg, 1.83 mmol) and sodium sulfide (143 mg, 1.83 mmol) were added to 4 mL of N, N-dimethylformamide. Upon completion of the addition, the reaction solution was heated to 70 and stirred for 4 hours. The reaction was monitored by TLC until completion of the reaction and a DMF solution of sodium 4-quinolylthiol was obtained, which was used directly in the next step. Ethyl 1-bromocyclobutanecarboxylate (154 mg, 0.72 mmol) was added directly to the pre-prepared DMF solution of sodium 4-quinolylthiol. The reaction solution was heated to 70 & lt; 0 & gt; C and stirred for 16 hours until TLC indicated completion of the reaction. 100 mL of saturated brine was added and the reaction solution was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title compound ethyl 1- (quinolin-4-ylthio) cyclobutanecarboxylate 1b, which was used directly in the next step.
1-(4'-quinolyl)-4-(N-Boc-N-methyl)aminopiperidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With potassium tert-butylate; palladium diacetate; DavePhos; In toluene; at 120℃; for 12h;Inert atmosphere;
General procedure: An oven-dried reaction flask, equipped with a reflux condenser was charged with heteroaryl chloride (1.0 mmol), 4-(N-Boc-N-methyl)aminopiperidine (1.3 equiv.), Pd(OAc)2 (3 mol%), DavePhos (3 mol%), t-BuONa (1.2 equiv.). The flask was sealed, and was evacuated and backfilled with argon for three times. Then 3 mL toluene was added to the system with a syringe. The reaction mixture was stirred at 120 C for 12 h. After cooling to the room temperature, the resulting residue was filtered through a plug of silica gel and washed with ethyl acetate. The mixture was then poured into water and extracted. The combined organic layers were washed with brine, dried over MgSO4, and filtered. The solvent was removed under vacuum. The residue was purified by flash column chromatography to afford the desired product.
N-(4-methoxy-3-nitrophenyl)quinolin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With hydrogenchloride; In isopropyl alcohol; at 80℃; for 2h;
General procedure: To a solution of 8a-c (1.0 equiv) in isopropanol was added 7a (1.2 equiv) with catalytic amount of HCl (conc) refluxed at 80 C for 2 h, then cooled to room temperature, and filtered to obtain solid. The resulting solid was dissolved in CH2Cl2 and treated with triethylamine until aqueous washings of aliquots had pH >10. The mixture washed with saturated NaHCO3 aq, brine, dried over Na2SO4, filtered and concentrated by vacuum to give compounds 8a-c. Compound 8d was prepared from 6b and 7b followig the same route. Compounds 11a-d were obtained by conducting the same method with 10a as the starting material.
With triethylamine; In 1-methyl-pyrrolidin-2-one; at 100℃; for 1h;Microwave irradiation;
4-Chloroquinoline (300.0 mg, 1.83 mmol), <strong>[29968-78-3]2-(4-nitrophenyl)ethan-1-amine hydrochloride</strong> (371.0 mg, 1.83 mmol) and Et3N (760.0 muL, 5.49 mmol) were added to NMP (6.0 mL). The reaction mixture was reacted in a microwaver (50W, 100) for 1 hour and cooled to room temperature. After addition of ice water, the reaction mixture was extracted with CH2Cl2. The organic layer was washed with brine, dried with Na2SO4and filtered. The residue obtained under reduced pressure was purified by column chromatography (CH2Cl2) on silica. The fractions containing the product were collected and evaporated to obtain the white solid compound,N-(4-nitrophenethyl)quinolin-4-amine (5.0 mg, 1%).[320][321]1H NMR (300 MHz, DMSO-d6) delta = 8.45 - 8.37 (m, 1H), 8.22 - 8.12 (m, 3H), 7.77 (dd,J= 0.8, 8.4 Hz, 1H), 7.65 - 7.56 (m, 3H), 7.41 (ddd,J= 1.1, 7.0, 8.3 Hz, 1H), 7.25 (t,J= 5.5 Hz, 1H), 6.55 (d,J= 5.3 Hz, 1H), 3.58 (q,J= 6.9 Hz, 2H), 3.13 (t,J= 7.2 Hz, 2H)[322]LC/MS ESI (+): 294 (M+1)
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