* 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.
The solid 6-bromo-4-hydroxy-quinoline-3-carboxylic acid (102.59 g, 337.7 mmol) was added to hot diphenyl ether (508 g) and then the mixture was heated to reflux for 9 h to afford a light brown suspension. After cooling to room temperature, the mixture was diluted with methanol (20 mL) and diethyl ether (300 mL). Then, the solids were collected by filtration and washed with diethyl ether. After drying in air, 72.43 g (95percent yield) of 6-bromo-quinolin-4-ol was isolated as a white solid: EI-HRMS m/e calcd for C9H6BrNO (M+) 222.9633, found 222.9630.
90%
for 0.5 h; Reflux
. Deprotection and removal of the carboxylic acid
90%
for 0.5 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.
77%
at 260℃; for 2 h;
4.1.7 6-Bromoquinolin-4-ol (10) 6-Bromo-4-hydroxyquinoline-3-carboxylic acid (9) (5.0 g, 18.73 mmol) was added to a 100 mL round-bottomed flask in Ph2O (30 mL) and then stirred at 260 °C for 2 h. After cooling to 60 °C, 30 mL petroleum ether was added and the suspended solid was filtered, washed with petroleum ether, EtOAc and dried under reduced pressure to give the title compound (3.21 g, 14.39 mmol, 77percent yield) as a brown solid. ESI-MS: m/z = 224 [M+H]+.
Reference：
[1] ChemMedChem, 2015, vol. 10, # 5, p. 836 - 849
[2] Patent: US2006/63805, 2006, A1, . Location in patent: Page/Page column 9
[3] Patent: WO2012/116237, 2012, A2, . Location in patent: Page/Page column 120
[4] Patent: US2015/320727, 2015, A1, . Location in patent: Paragraph 0557; 0558
[5] European Journal of Medicinal Chemistry, 2015, vol. 99, p. 36 - 50
[6] Journal of the Chemical Society, 1950, p. 384,389
[7] Tetrahedron Letters, 2008, vol. 49, # 19, p. 3137 - 3141
[8] Patent: WO2014/151147, 2014, A1, . Location in patent: Paragraph 00641
[9] Patent: US2015/30588, 2015, A1, . Location in patent: Page/Page column 77
[10] Patent: US9295673, 2016, B2, . Location in patent: Page/Page column 365; 366
[11] Patent: WO2006/132739, 2006, A2, . Location in patent: Page/Page column 44-45
2
[ 98948-95-9 ]
[ 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] Patent: US2015/320727, 2015, A1,
[6] Patent: US9295673, 2016, B2,
[7] ChemMedChem, 2015, vol. 10, # 5, p. 836 - 849
[8] European Journal of Medicinal Chemistry, 2015, vol. 99, p. 36 - 50
[9] Patent: CN106432073, 2017, A,
[10] Patent: WO2006/132739, 2006, A2,
3
[ 98948-95-9 ]
[ 65340-70-7 ]
Reference：
[1] Journal of Medicinal Chemistry, 2015, vol. 58, # 14, p. 5522 - 5537
4
[ 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
5
[ 106-40-1 ]
[ 98948-95-9 ]
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,
6
[ 101937-44-4 ]
[ 98948-95-9 ]
Reference：
[1] Journal of the Chemical Society, 1950, p. 384,389
[2] ChemMedChem, 2015, vol. 10, # 5, p. 836 - 849
[3] Patent: CN106432073, 2017, A,
The solid 6-bromo-4-hydroxy-quinoline-3-carboxylic acid (102.59 g, 337.7 mmol) was added to hot diphenyl ether (508 g) and then the mixture was heated to reflux for 9 h to afford a light brown suspension. After cooling to room temperature, the mixture was diluted with methanol (20 mL) and diethyl ether (300 mL). Then, the solids were collected by filtration and washed with diethyl ether. After drying in air, 72.43 g (95% yield) of 6-bromo-quinolin-4-ol was isolated as a white solid: EI-HRMS m/e calcd for C9H6BrNO (M+) 222.9633, found 222.9630.
90%
for 0.5h;Reflux;
. Deprotection and removal of the carboxylic acid
90%
for 0.5h;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.
77%
In diphenylether; at 260℃; for 2h;
4.1.7 6-Bromoquinolin-4-ol (10) 6-Bromo-4-hydroxyquinoline-3-carboxylic acid (9) (5.0 g, 18.73 mmol) was added to a 100 mL round-bottomed flask in Ph2O (30 mL) and then stirred at 260 C for 2 h. After cooling to 60 C, 30 mL petroleum ether was added and the suspended solid was filtered, washed with petroleum ether, EtOAc and dried under reduced pressure to give the title compound (3.21 g, 14.39 mmol, 77% yield) as a brown solid. ESI-MS: m/z = 224 [M+H]+.
In diphenylether; for 2h;Heating / reflux;
6-Bromo-4-quinolinol. The mixture of the compound from Example 17a) (2 g, 6.8 mmol) in NaOH ( 6 N, 100 mL) was refluxed overnight, cooled and filtered. The filtrate was acidified. The precipitate was collected and refluxed in phenyl ether EPO <DP n="46"/>for two hours. The product was cooled, then petroleum ether was added until precipitate appeared. The precipitate was collected, washed with petroleum ether and dried over vacuo to afford the title compound as a white solid (1.2 g, 85%). 1 H NMR (400 MHz, DMSOd6) delta ppm 12.06 (br. s., 1 H) 8.16 (d, J=2.27 Hz, 1 H) 7.90 - 8.02 (m, 1 H) 7.79 (dd, J=8.84, 2.53 Hz, 1 H) 7.55 (d, J=8.84 Hz,1 H) 6.08 (d, J=7.33 Hz, 1 H).
With water; sodium hydroxide; In ethanol; at 75℃; for 1.5h;
2N Sodium hydroxide (506mL, 1011.43mmol) was added to a stirred suspension of ethyl 6-bromo-4-oxo-lH-quinoline-3-carboxylate (59.9g, 202.29mmol) in EtOH (590mL) and the resulting solution stirred at 75C for 1.5 h. Water was added and the mixture cooled to 0C. The pH of the solution was adjusted to 3 using hydrochloric acid and the precipitate collected by filtration. The solid was washed with water, EtOH/water (1 : 1) then Et20 before being dried to afford the desired material (51.9g, 96%) as a beige solid. NMR Spectrum: 1H MR (500MHz, DMSO-d6) delta 7.80 (1H, d), 8.05 (1H, d), 8.37 (1H, s), 8.93 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+ = 270.
6-bromo-4-hydroxy-3-quinolinecarboxylic acid (2.5 g, 9.3 mmol) was added to diphenyl ether (30 mL) and the reaction was heated at reflux for 1 hour. The reaction solution was cooled, poured into n-hexane (200 mL), filtered, washed with n-hexane and dried to give 2.0 g (96%) of whiteColor solid.
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