* 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 Chemical Society, 1950, p. 384,389
[2] Patent: WO2012/116237, 2012, A2,
[3] Patent: WO2014/151147, 2014, A1,
[4] Patent: US2015/30588, 2015, A1,
[5] ChemMedChem, 2015, vol. 10, # 5, p. 836 - 849
[6] European Journal of Medicinal Chemistry, 2015, vol. 99, p. 36 - 50
[7] Patent: US2015/320727, 2015, A1,
[8] Patent: US9295673, 2016, B2,
[9] Patent: WO2006/132739, 2006, A2,
2
[ 122794-99-4 ]
[ 65340-70-7 ]
Reference：
[1] Journal of the Chemical Society, 1950, p. 384,389
[2] Patent: WO2012/116237, 2012, A2,
[3] Patent: WO2014/151147, 2014, A1,
[4] Patent: US2015/30588, 2015, A1,
[5] ChemMedChem, 2015, vol. 10, # 5, p. 836 - 849
[6] European Journal of Medicinal Chemistry, 2015, vol. 99, p. 36 - 50
[7] Patent: US2015/320727, 2015, A1,
[8] Patent: US9295673, 2016, B2,
[9] Patent: CN106432073, 2017, A,
[10] Patent: WO2006/132739, 2006, A2,
3
[ 122794-99-4 ]
[ 98948-95-9 ]
Yield
Reaction Conditions
Operation in experiment
98%
Stage #1: for 5 h; Heating / reflux Stage #2: With hydrogenchloride In water
A suspension of 6-bromo-4-hydroxy-quinoline-3-carboxylic acid ethyl ester (102.59 g, 337.7 mmol) in 10percent potassium hydroxide in water (689 mL) was heated to reflux for 5 h to afford a light brown solution. After cooling to room temperature, the undissolved solid particles were removed by filtration and the filtrate was extracted with dichloromethane to remove any neutral impurities. The aqueous layer was neutralized with 3.0N hydrochloric acid to afford a white precipitate. Then, the solids were collected by filtration and washed with water. After drying in air, 91 g (98percent yield) of 6-bromo-4-hydroxy-quinoline-3-carboxylic acid was isolated as a white solid: EI-HRMS m/e calcd for C10H6BrNO3 (M+) 266.9531, found 266.9521.
96%
for 1 h; Reflux
Ethyl 6-bromo-4-hydroxy-3-quinolinecarboxylate (3.0 g, 10 mmol) was added to NaOH 10percent (40 mL)Should be heated to reflux for 1 hour. The reaction solution was cooled to ° C and adjusted to pH 1 with hydrochloric acid (10 N). Filtration, filter residue washed with water, dried 2.6g(96percent) of a white solid.
94%
at 100℃; for 1 h;
4.1.6 6-Bromo-4-hydroxyquinoline-3-carboxylic acid (9) Ethyl 6-bromo-4-hydroxyquinoline-3-carboxylate (8) (6.0 g, 20.34 mmol) and 2.5 N NaOH (50 mL) were charged in a 100 mL round-bottomed flask. The mixture was stirred at reflux for 1 h. After cooling to room temperature, the pH of the mixture was adjusted to 5 using 2 N HCl and the resulting solid was filtered and washed with water. The filter cake was then dried under reduced pressure to afford the title compound (5.15 g, 19.22 mmol, 94percent yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 12.51 (s, 1H), 8.63 (s, 1H, Ar-), 8.23 (d, J = 2.5 Hz, 1H, Ar-H), 7.87 (dd, J = 8.5, 2.5 Hz, 1H, Ar-H), 7.61 (d, J = 8.5 Hz, 1H, Ar-H). ESI-MS: m/z = 268 [M+H]+.
80%
With sodium hydroxide In water for 1.5 h; Reflux
10558] The bicyclic compound 3-2 is prepared from bromoaniline 3-1 using diethyl 2-(ethoxymethylene)malonate or a similar reagent. Deprotection and removal of the carboxylic acid, followed by halogenation using a reagent such as phosphorus oxychloride yields compound 3-5. Derivatization with pyridine boronate in Suzuki coupling conditions yields 3-6, which is reacted in a second Suzuki reaction with a benzothiazolyl boronate to yield compound 3-7. Subsequent heating in hydrochloric acid in a solvent such as methanol results in removal of an acetyl group.
Reference：
[1] Patent: US2006/63805, 2006, A1, . Location in patent: Page/Page column 9
[2] ChemMedChem, 2015, vol. 10, # 5, p. 836 - 849
[3] Patent: CN106432073, 2017, A, . Location in patent: Paragraph 0061; 0062; 0067; 0068
[4] European Journal of Medicinal Chemistry, 2015, vol. 99, p. 36 - 50
[5] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1995, vol. 31, # 2, p. 167 - 175[6] Khimiya Geterotsiklicheskikh Soedinenii, 1995, # 2, p. 195 - 203
[7] Patent: WO2012/116237, 2012, A2, . Location in patent: Page/Page column 120
[8] Patent: US2015/320727, 2015, A1, . Location in patent: Paragraph 0557; 0558
[9] Journal of the Chemical Society, 1950, p. 384,389
[10] Tetrahedron Letters, 2008, vol. 49, # 19, p. 3137 - 3141
[11] Patent: WO2014/151147, 2014, A1, . Location in patent: Paragraph 00641
[12] Patent: US2015/30588, 2015, A1, . Location in patent: Page/Page column 77
[13] Patent: US9295673, 2016, B2, . Location in patent: Page/Page column 365
[14] Patent: WO2006/132739, 2006, A2, . Location in patent: Page/Page column 44-45
4
[ 122794-99-4 ]
[ 206257-39-8 ]
Yield
Reaction Conditions
Operation in experiment
94%
With trichlorophosphate In N,N-dimethyl-formamide at 20℃; for 3 h; Inert atmosphere
Suspend 6-bromo-4-hydroxyquinoline-3-carboxylic acid ethyl ester (11 g, 37 mmol) in anhydrous dimethylformamide (148.6 mL) under nitrogen atmosphere. Add phosphoryl chloride (20.7 mL, 222 mmol, 6 eq.) via syringe over 5 minutes and stir vigorously at room temperature for 3 hours. Quench the reaction by pouring the mixture into ice water (1.5 L) and continue stirring until all the ice has melted. Obtain the solid formed by filtration, rinse with water and allow complete drying to afford the titled compound (11.4 g, 94percent). MS (ESI) m/z (M+H)+314.0, 316.0
94.1%
at 120℃; for 3 h;
6-Bromo-4-hydroxyquinoline-3-carboxylic acid ethyl ester (10 g) in phosphorus oxychloride(100 mL) was stirred at 120 ° C under reflux for 3 hours.The reaction mixture was evaporated in vacuo to remove phosphorous oxychloride.The residue was poured into ice-water and the pH was adjusted to 6 with saturated aqueous sodium bicarbonate.The resulting mixture was extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated.The residue was purified by flash column chromatography (silica gel, petroleum ether / ethyl acetate = 80: 1) to give the product as a white solid (10 g, 94.1percent yield).
93%
for 4 h; Reflux
To a suspension of 5 (4.00 g, 13.6 mmol) in POCl3 (15.0 mL) was added catalytic amount of N,N-dimethylformamide (DMF) and the mixture was heated to reflux for 4 h. It was then cooled to room temperature and carefully poured onto ice. After vigorous agitation, the precipitate was filtered, washed with water and dissolved in DCM. The solution was subsequently washed with saturated NaHCO3 solution, brine, dried with anhydrous Na2SO4 and concentrated in vacuo to provide the title intermediate as a light yellow solid. Yield: 93percent; 1H NMR (500 MHz, CDCl3): δ 9.21 (s, 1H, Ar-H), 8.47 (d, 1.5 Hz, 1H, Ar-H), 8.02 (d, 9.0 Hz, 1H, Ar-H), 7.95 (dd, 1.5 Hz, 9.0 Hz, 1H, Ar-H), 4.40 (q, 7.0 Hz, 2H, CH2), 1.60 (t, 7.0 Hz, 3H, CH3). ESI-MS: m/z = 314 [M+H]+.
83%
With trichlorophosphate In N,N-dimethyl-formamide for 6 h; Reflux
To a 100 mL round-bottomed flask was added ethyl 6-bromo-4-hydroxyquinoline-3- carboxylate (6) (10.0 g, 33.90 mmol), POCl3(100 mL) and DMF (2 mL). The mixture was stirred at reflux for 6 h.After cooling to room temperature, the reaction mixture waspoured into ice water (100 mL) and stirred for 1 h. Then the pH ofthe mixture was adjusted to 8 using saturated aqueous NaHCO3. The mixture was extracted with EtOAc and the organic phase wasdried over sodium sulfate and concentrated in vacuo to give thetitle compound (8.82 g, 28.18 mmol, 83percent yield) as a brown solid.ESI-MS: m/z = 314 [M+H]+.
72%
Stage #1: Heating / reflux
Ethyl 6-bromo-4-chloro-3-quinolinecarboxylate. The mixture of the compound from Example 17 a) (2.0 g, 6.8 mmol) in POCI3 (20 ml_) was ref luxed overnight. The product was cooled, quenched with ice water, diluted with ethyl acetate, washed with NaHCO3 and brine. The organic layer was separated, dried over magnesium sulfate, filtered, concentrated under vacuo and purified via flash chromatography (0-100percent ethyl acetate in hexane) to afford the title compound as a white solid (1.5 g, 72percent). 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.22 (s, 1 H) 8.59 (d, J=2.02 Hz, 1 H) 8.03 (d, J=8.84 Hz, 1 H) 7.93 (dd, J=8.97, 2.15 Hz, 1 H) 4.53 (q, J=7.24 Hz, 2 H) 1.49 (t, J=7.20 Hz, 3 H).
Reference：
[1] Patent: US2012/184577, 2012, A1, . Location in patent: Page/Page column 2; 3
[2] Patent: CN105859684, 2016, A, . Location in patent: Paragraph 0148; 0149; 0150
[3] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 24, p. 7585 - 7596
[4] RSC Advances, 2017, vol. 7, # 4, p. 2342 - 2350
[5] European Journal of Medicinal Chemistry, 2017, vol. 127, p. 509 - 520
[6] Patent: WO2006/132739, 2006, A2, . Location in patent: Page/Page column 47
[7] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 8, p. 1487 - 1490
(1S,4S)-N-(4-(1-(2-methoxyethyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl)phenyl)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide[ No CAS ]
N-(3-chloro-2-fluoro-4-(1-(2-methoxyethyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl)phenyl)-4-methylpiperazine-1-carboxamide[ No CAS ]
N-(3-fluoro-4-(1-(2-methoxyethyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl)-2-methylphenyl)-4-methylpiperazine-1-carboxamide[ No CAS ]
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