* 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.
With hydrogenchloride; iron In ethanol; water at 20℃; for 1 h; Heating / reflux
To a solution of compound 121 (22.00 g, 86.94 mmol) obtained by process 1 in ethanol (1100- ml) were added water (66 ml), concentrated hydrochloric acid (66 ml) and iron powder (24.28 g, 434.8 mmol) at room temperature. The reaction mixture was refluxed for 1 hour and cooled to room temperature, and the insoluble materials were filtered off by passing through Celite pad. To the residue obtained by evaporation under reduced pressure were added 10 percent sodium hydrogen carbonate solution (700 ml) and ethyl acetate (500 ml), and the mixture was stirred for 30 minutes. The insoluble materials . were filtered off by passing through Celite pad, and the organic layer obtained by filtration was washed with brine, dried over magnesium sulfate and decolorized with activated carbon. The solvent was concentrated under reduced pressure to give compound 122 (18.11 g, 81.19 mmol, 93.4percent) as pale yellow crystals.
60%
at 20℃; for 18 h;
Intermediate 2 (0.847 g, 3.3 mmol) was dissolved in 30 mL of acetic acid-water (2:1), followed by the addition of iron powder (0.935 g, 16.7 mmol). The reaction mixture was stirred at ambient temperature for 18 hours. Solvent was removed by rotary evaporation; theproduct mixture was suspended in dichloromethane and filtered through CELITE to remove iron salts. The resultant solid was purified by column chromatography on silica gel (35 g) using dichloromethane as the eluent. Fractions containing the product were combined, evaporated to dryness to yield 4 as a yellow solid 0.45 g (60 percent yield, mp 104 °C, lit mp = 106-107 °C). 1H NMR (400MHz, CDCI3) O 8.72 (1H, d, J= 2.4 Hz), 8.21 (1H, d, J= 2.0 Hz),7.32-7.38 (1H, t, J= 8.0 Hz), 7.06 (1H, d, J= 8.0 Hz), 6.92 (1H, d, J= 7.2 Hz), 4.8-5.2 (3H,5).
Reference：
[1] Organic and Biomolecular Chemistry, 2016, vol. 14, # 34, p. 8092 - 8100
[2] Patent: EP1375486, 2004, A1, . Location in patent: Page 114; 115
[3] Monatshefte fuer Chemie, 1991, vol. 122, # 11, p. 935 - 942
[4] Patent: US2017/29452, 2017, A1, . Location in patent: Paragraph 0093-0095
[5] Asian Journal of Chemistry, 2014, vol. 26, # 13, p. 3779 - 3784
[6] Patent: WO2016/183578, 2016, A1, . Location in patent: Page/Page column 12
[7] Journal of the American Chemical Society, 1946, vol. 68, p. 1544
[8] Journal fuer Praktische Chemie (Leipzig), 1893, vol. <2> 48, p. 158[9] Journal fuer Praktische Chemie (Leipzig), 1894, vol. <2> 50, p. 239
2
[ 607-35-2 ]
[ 139399-67-0 ]
Reference：
[1] Monatshefte fuer Chemie, 1991, vol. 122, # 11, p. 935 - 942
[2] Journal of the American Chemical Society, 1946, vol. 68, p. 1544
[3] Asian Journal of Chemistry, 2014, vol. 26, # 13, p. 3779 - 3784
[4] Patent: WO2016/183578, 2016, A1,
[5] Patent: US2017/29452, 2017, A1,
3
[ 5332-24-1 ]
[ 139399-67-0 ]
Reference：
[1] Journal fuer Praktische Chemie (Leipzig), 1893, vol. <2> 48, p. 158[2] Journal fuer Praktische Chemie (Leipzig), 1894, vol. <2> 50, p. 239
[3] Organic and Biomolecular Chemistry, 2016, vol. 14, # 34, p. 8092 - 8100
4
[ 88-74-4 ]
[ 139399-67-0 ]
Reference：
[1] Patent: US2017/29452, 2017, A1,
5
[ 139399-67-0 ]
[ 56-81-5 ]
[ 66127-01-3 ]
Reference：
[1] Journal of Organic Chemistry, 1951, vol. 16, p. 941,945
6
[ 139399-67-0 ]
[ 408529-03-3 ]
[ 100125-12-0 ]
Reference：
[1] Journal of Organic Chemistry, 1951, vol. 16, p. 941,945
8-Amino-3-bromoquinoline (4) (0.3 g, 1.3 mmol) was dissolved in 10 mL of 70% sulfuric acid and placed in a Q-Tube (Sigma Aldrich). The tube was sealed and heated with stirring at 22000 for 3 days. After cooling to ambient temperature, the reaction solution was brought to pH 8 by addition of NH4OH (16 M), followed by extraction with ethyl acetate (4 x 25 mL). The organic phases were combined, dried over Na2504, filtered, and evaporated todryness. The crude product was purified by column chromatography on silica gel (7 g) using3:1 dichloromethane/hexane as the eluent. Fractions containing the product were combinedand evaporated to dryness to give 5 as a white solid 0.184 g (34% yield, mp 99-101 00, litmp 111.5-1 12.5 00) 1H NMR (400 MHz, ODd3) O 8.77 (1H, d, J= 2.0 Hz), 8.32 (1H, d, J=2.0 Hz), 7.99 (1H, 5), 7.48 (1H, t, J= 8.0 Hz), 7.18 (1H, dd, J= 23.2 Hz, J= 9.6 Hz). LCMSfound 225.90, [M+2H].
With sulfuric acid; In water; at 220℃; for 16h;
To compound 122 (2.67 g, 10.6 mmol) obtained by process 2 was added a solution of 54 wt% sulfuric acid (16 ml), and the mixture was sealed up. The reaction mixture was heated at 220 C for 16 hours and then cooled. This reaction mixture was added to ice water (270 ml) and neutralized (pH=7.9) with 28 wt% aqueous ammonia (20 ml). Water (110 ml) was added to the mixture, and the precipitated crystals were stirred at room temperature for 30 minutes. The crystals were collected by filtration, washed with water (30 ml) and dried at 70 C under reduced pressure for 1 hour to give compound 123 as crude crystals (2.51 g).
With hydrogenchloride; iron; In ethanol; water; at 20℃; for 1h;Heating / reflux;
To a solution of compound 121 (22.00 g, 86.94 mmol) obtained by process 1 in ethanol (1100- ml) were added water (66 ml), concentrated hydrochloric acid (66 ml) and iron powder (24.28 g, 434.8 mmol) at room temperature. The reaction mixture was refluxed for 1 hour and cooled to room temperature, and the insoluble materials were filtered off by passing through Celite pad. To the residue obtained by evaporation under reduced pressure were added 10 % sodium hydrogen carbonate solution (700 ml) and ethyl acetate (500 ml), and the mixture was stirred for 30 minutes. The insoluble materials . were filtered off by passing through Celite pad, and the organic layer obtained by filtration was washed with brine, dried over magnesium sulfate and decolorized with activated carbon. The solvent was concentrated under reduced pressure to give compound 122 (18.11 g, 81.19 mmol, 93.4%) as pale yellow crystals.
60%
With iron; at 20℃; for 18h;
Intermediate 2 (0.847 g, 3.3 mmol) was dissolved in 30 mL of acetic acid-water (2:1), followed by the addition of iron powder (0.935 g, 16.7 mmol). The reaction mixture was stirred at ambient temperature for 18 hours. Solvent was removed by rotary evaporation; theproduct mixture was suspended in dichloromethane and filtered through CELITE to remove iron salts. The resultant solid was purified by column chromatography on silica gel (35 g) using dichloromethane as the eluent. Fractions containing the product were combined, evaporated to dryness to yield 4 as a yellow solid 0.45 g (60 % yield, mp 104 C, lit mp = 106-107 C). 1H NMR (400MHz, CDCI3) O 8.72 (1H, d, J= 2.4 Hz), 8.21 (1H, d, J= 2.0 Hz),7.32-7.38 (1H, t, J= 8.0 Hz), 7.06 (1H, d, J= 8.0 Hz), 6.92 (1H, d, J= 7.2 Hz), 4.8-5.2 (3H,5).
With sodium carbonate; In butan-1-ol; for 72h;Heating / reflux;
bis- (2-Chloro-ethyl)-amine hydrochloride (3.7g, 19.2 MMOL) and sodium carbonate (9. 0g, 85 MMOL) were added to a suspension of <strong>[139399-67-0]3-bromo-quinolin-8-ylamine</strong> (3.9g, 17.5 MMOL) (for synthesis see Gershon et al., Monatsh. Chem., 1991,122, 935) in n-butanol (70 ml). The stirred suspension was heated at reflux for 72h. The reaction mixture was cooled to ambient temperature, diluted with DICHLOROMETHANE (300 ML) and the solution washed with water (300 ML), dried (MGS04) and concentrated in vacuo to an oil. The oil was purified by chromatography over silica gel eluting with a gradient of methanol/dichloromethane to afford the title compound (D1) as an oil (2.6g, 8.5 mmol, 49%); aH (CDOS) 2.43 (3H, s), 2.78 (4H, BRS), 3.44 (4H, br, s), 7.14 (1H, d, J = 6.8Hz), 7.33 (1H, d, J = 7. 4Hz), 7.47 (1H, dd, J = 7. 8Hz), 8.25 (1H, d, J = 2. 3Hz), 8.85 (1H, d, J = 2.3Hz) ; Mass Spectrum: C14H16BRN3 requires 305/307; found 306/308 (MH+).
With triethylamine; In N-methyl-acetamide; 1,3-dimethyl-2-imidazolidinone; dichloromethane;
Example 132 To a solution of 9-fluorenecarboxylic acid (158 mg) and dimethylformamide (1 drop) in dichloromethane (2 ml) was dropwise added oxalyl chloride (191 mg), and the mixture was stirred for 1 hour at ambient temperature. The mixture was concentrated in vacuo, and the residue was added to a solution of <strong>[139399-67-0]8-amino-3-bromoquinoline</strong> (112 mg) and triethylamine (152 mg) in 1,3-dimethyl-2-imidazolidinone (1 ml). The mixture was stirred for 3 hours at ambient temperature. The mixture was partitioned between ethyl acetate and water, and the organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel and crystallized from diethyl ether-diisopropyl ether to give 3-bromo-8-[(fluoren-9-yl)carbonylamino]quinoline (22 mg). mp: 196-198 C. NMR (CDCl3, delta): 5.03 (1H, s), 7.32-7.43 (3H, m), 7.45-7.55 (3H, m), 7.80-7.90 (4H, m), 8.20 (1H, s), 8.50 (1H, s), 8.75 (1H, d, J=7 Hz), 9.65 (1H, br s)
3-Bromo-8-(3-nitrobenzoylamino)quinoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
(1) 3-Bromo-8-(3-nitrobenzoylamino)quinoline was obtained from <strong>[139399-67-0]8-amino-3-bromoquinoline</strong> and 3-nitrobenzoyl chloride according to a similar manner to that of Example 1. mp: 258 C. NMR (DMSO-d6, delta): 7.69-7.84 (2H, m), 7.90 (1H, t, J=8 Hz), 8.43-8.52 (2H, m), 8.60 (1H, d, J=6 Hz), 8.76-8.88 (2H, m), 9.03 (1H, d, J=2 Hz)
Preparation 13 A mixture of <strong>[139399-67-0]8-amino-3-bromoquinoline</strong> (200 mg) and sodium thiomethoxide (109 mg) in N,N-dimethylformamide (2 ml) was stirred at ambient temperature for 2 days. After diluted with ethyl acetate, the resulting mixture was washed with water and brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was purified by chromatography on silica gel (n-hexane-ethyl acetate) to give 8-amino-3-methylthioquinoline (113 mg) as an oil. NMR (CDCl3, delta): 2.60 (3H, s), 4.86-4.99 (2H, m), 6.86 (1H, d, J=8 Hz), 7.05 (1H, d, J=8 Hz), 7.31 (1H, t, J=8 Hz), 7.83 (1H, s), 8.65 (1H, s)
diethyl 8-aminoquinolin-3-yl phosphonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
25%
With palladium diacetate; triethylamine; In ethanol;Inert atmosphere; Reflux;
Compound 4c (4.0 g, 17.9 mmol) was added to EtOH (53 mL) under N2, and then HPO(OEt)2 (3.0 mL, 23.3 mmol), TEA (3.7 mL, 26.9 mmol), Ph3P (1.27 g, 4.8 mmol) and Pd(OAc)2 (0.8 g, 3.58 mmol) was added. The resulting mixture was refluxed for overnight. The reaction mixture was cooled to room temperature and charged with H2O (100 mL), extracted with EA. The organic layers was merged, washed with brine, dried over anhydrous Na2SO4, concentrated, and purified with chromatography (EA:PE=1:1). A yellow oil 5c 1.4 g was given in 25%. (0098) 1H NMR (300 MHz, CDCl3) delta 8.98 (dd, J=1.8 Hz, 4.2 Hz, 1H), 8.59 (dd, J=2.1 Hz, 15.3 Hz, 1H), 7.38 (d, J=7.8 Hz, 1H), 7.21 (d, J=7.5 Hz, 1H), 7.01 (t, J=7.5 Hz, 1H), 4.20-4.07 (m, 4H), 1.35 (t, J=6.9 Hz, 6H)
3-bromo-N-(2-methoxyethyl)quinolin-8-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 110 - 130℃; for 22h;Sealed tube;
Potassium carbonate (92 mg) and 2-chloroethylmethylether (32 mg) were added to a tube containing a DMF (0.5 ml) solution containing 3-bromoquinolin-8-amine (50 mg) and the tube was sealed, followed by stirring at 110C-130C for 22 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resultant was washed with water (x3) and saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 1:0 to 1:1), and light yellow oily matter of 3-bromo-N-(2-methoxyethyl)quinolin-8-amine (15 mg) was thus obtained. MS (ESI m/z): 281, 283 (M+H) RT (min): 1.86
With potassium carbonate; sodium iodide; In N,N-dimethyl-formamide; at 95℃; for 17h;Sealed tube;
A DMF (2 ml) solution containing <strong>[139399-67-0]3-bromoquinolin-8-amine</strong> (223 mg), dimethyl sulfate (189 mg), potassium carbonate (415 mg), and sodium iodide (20 mg) were added to a tube and the tube was sealed, followed by stirring at 95C for 17 hours. The reaction solution was cooled to room temperature, ethyl acetate was added, an insoluble precipitate was removed, and the organic layer was washed with 1M hydrochloric acid, water, and saturated saline. Subsequently, the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane : ethyl acetate = 0:1 to 1:1), and a yellow solid of 3-bromo-N-methylquinolin-8-amine (52 mg) was thus obtained. MS (ESI m/z): 237, 239 (M+H) RT (min): 1.76
3-bromo-N-(2-(2-ethoxyethoxy) ethyl)quinolin-8-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40 mg
With potassium carbonate; sodium iodide; In N,N-dimethyl-formamide; at 130℃; for 7h;Sealed tube;
Potassium carbonate (69 mg), sodium iodide (20 mg), and 2-(2-ethoxyethoxy)ethyl-4-methylbenzenesulfonate () were added to a tube containing a DMF (2 ml) solution containing <strong>[139399-67-0]3-bromoquinolin-8-amine</strong> (223 mg) and the tube was sealed, followed by stirring at 130C for 7 hours. The reaction solution was adjusted to room temperature, and water was added, followed by extraction with ethyl acetate. The resultant was washed with water (x3) and saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane : ethyl acetate = 1:7), and light yellow oily matter of 3-bromo-N-(2-(2-ethoxyethoxy) ethyl)quinolin-8-amine (40 mg) was thus obtained. MS (ESI m/z): 339, 341 (M+H) RT (min): 1.82
With tetrafluoroboric acid; sodium nitrite; In water; at 20℃; for 1h;
A mixture of <strong>[139399-67-0]3-bromoquinolin-8-amine</strong> (38 mg), 48% aqueous fluoroboric acid solution (0.5 ml), and sodium nitrite (16 mg) was stirred at room temperature for 1 hour. Water was poured into the reaction solution and an insoluble precipitate was collected by filtration. Further, the solid collected by filtration was dissolved in 1,2-dichlorobenzene (1 ml) and stirred at 130C for 1 hour and at 190C for 0.5 hour. 1M hydrochloric acid was added to the reaction solution, followed by extraction with ethyl acetate. The resultant was washed with water (x2) and saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane : ethyl acetate = 1:0 to 1:1), and 3-bromo-8-fluoroquinolin-8-amine (32 mg) was thus obtained. MS (ESI m/z): 226, 228 (M+H) RT (min): 1.34
With 2,4,6-trimethyl-pyridine; oxygen; palladium diacetate; trifluoroacetic acid; at 150℃; under 760.051 Torr; for 12h;
22.31 g (100 mmol) of <strong>[139399-67-0]3-bromo-8-aminoquinoline</strong>, 11.05 g (100 mmol) 2-chloro-1,3-propanediol, 1.12 g (5 mmol) palladium acetate, 1.21 g (5 mmol) of 2,4,6-trimethylpyridine, 1.14 g (10 mmol) of trifluoroacetic acid, under an oxygen atmosphere (1 atm),The temperature was raised to 150 C and the reaction was carried out for 12 hours. after completion of the reaction, the mixture was filtered, and the filtrate was concentrated and purified by column chromatography to yield Compound N-1.
General procedure: 3.11 g (10 mmol) of 5-bromo-2-iodobenzaldehyde, 1.44 g (10 mmol) of 8-aminoquinoline, 0.23 g (0.25 mmol) of Pd2(dba)3, 0.28 g (0.5 mmol) of dppf, and 2.76 g (20 mmol) of K2CO3 were dissolved in 250 mL of toluene, and then, the mixture was stirred at a temperature of 80 C. for 24 hours. The reaction solution was cooled to ambient temperature, immediately filtered through silica, and the filtrate was dried under reduced pressure. Then, 2.66 g (20 mmol) of AlCl3 was added thereto and dissolved in 300 mL of toluene, followed by stirring at 80 C. for 24 hours. The reaction solution was cooled to ambient temperature, and then subjected to an extraction process three times by using 60 mL of water and 60 mL of diethyl ether. An organic layer obtained therefrom was dried by using magnesium sulfate and the residual obtained by evaporating a solvent therefrom was separation-purified by silica gel column chromatography to obtain 1.23 g (yield: 40%) of Intermediate 3-1. The obtained compound was identified by LC-MS. C16H9BrN2;M+1 309.16
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