* 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
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