* 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-quinolin-4-ol (52 g, 232.1 mmol) was added to phosphorus oxychloride (213.5 mL) and then the mixture was heated to reflux for 6 h to afford a light brown solution. After cooling to room temperature, the excess phosphorus oxychloride was removed under the vacuum. The remaining residue was poured into an ice-containing beaker (2 L). Then, it was slowly neutralized with solid potassium carbonate and the resulting solids were collected by filtration and washed with water. After drying in air, 55.46 g (98.5percent yield) of 6-bromo-4-chloro-quinoline was isolated as a light yellow solid: EI-HRMS m/e calcd for C9H5BrClN (M+) 240.9294, found 240.9297.
93%
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.
84%
With trichlorophosphate In N,N-dimethyl-formamide at 120℃; for 5 h;
4.1.8 6-Bromo-4-chloroquinoline (11) To a 100 mL round-bottomed flask was added 6-bromoquinolin-4-ol (10) (3.0 g, 13.45 mmol), POCl3 (20 mL) and DMF (0.5 mL). The mixture was stirred at reflux for 6 h. After cooling to room temperature, the reaction mixture was poured into ice water (100 mL) and stirred for 1 h. Then the pH of the mixture was adjusted to 8 using saturated aqueous NaHCO3. The mixture was extracted with EtOAc and the organic phase was dried over sodium sulfate and concentrated in vacuo to give the title compound (2.75 g, 11.36 mmol, 84percent yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 8.87 (d, J = 4.5 Hz, 1H, Ar-H), 8.32 (d, J = 2.0 Hz, 1H, Ar-H), 8.03 (d, J = 9.0 Hz, 1H, Ar-H), 7.99 (dd, J = 9.0, 2.0 Hz, 1H, Ar-H), 7.82 (d, J = 4.5 Hz, 1H, Ar-H). ESI-MS: m/z = 242 [M+H]+.
84%
Stage #1: Heating / reflux
6-Bromo-4-chloroquinoline. The solution of the compound from Example 17b (2 g, 8.9 mmol) in POCI3 (10 mL) was refluxed overnight, cooled and quenched by ice water. The precipitate was collected, washed with H2O and dried in vacuo to afford the title compound as a grey solid (1.8 g, 84percent). 1 H NMR (400 MHz, DMSO-CZ6) δ ppm 8.90 (d, J=4.80 Hz, 1 H) 8.37 (d, J=2.02 Hz, 1 H) 8.07 (d, J=8.59 Hz, 1 H) 8.03 (dd, J=8.84, 2.02 Hz, 1 H) 7.86 (d, J=4.55 Hz, 1 H).
32%
With trichlorophosphate In toluene at 115℃; for 4 h;
To a suspension of 6-bromo-4-hydroxyquinolin (14.55 g, 64.9 mmol) in toluene (20mL) was added POCh (6.05 mL, 64.9 mmol) slowly. The reaction was stirred at 115°C for 4 h,then cooled down to 0°C and diluted with DCM (400 mL). The mixture was washed with 4MNaOH (70 mL) followed by brine (100 mL), dried over anhydrous Na2S04 and concentrated invacuo. The residue was recrystallized in n-heptane (150 mL) to give the title compound as ayellow solid (5.5 g, 32percent). The title compound was characterized by LC-MS and 1H NMR asshown below:LC-MS (ESI, pos. ion) m/z: 242 [M+Ht;1H NMR (400 MHz, CDCh) 8 (ppm): 7.50 (d, J= 4.72 Hz, 1H), 7.82 (dd, J= 8.96 Hz, 2.16 Hz,1H), 7.98 (d, J= 8.92 Hz, 1H), 7.95 (d, J= 2.16 Hz, 1H), 8.34 (d, J= 4.68 Hz, 1H).
32%
With trichlorophosphate In toluene at 115℃; for 4 h;
To 6-bromo-4-hydroxyquinoline (14.55g, 64 . 9mmol) toluene (20 ml) is slowly added in solution POCl 3 (6.05 ml, 64 . 9mmol). responds the fluid in 115 °C stirring 4 hours, cooling to 0 °C, and added DCM (400 ml) dilution. The resulting mixed solution for sequentially 4MNaOH aqueous solution (70 ml) and the brine (100 ml) washing, anhydrous Na 2 SO 4 drying, and concentrated under reduced pressure. In normal heptane of the residue (150 ml) is recrystallized in, to obtain the title compound as yellow solid (5.5g, 32percent).
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: US2015/320727, 2015, A1, . Location in patent: Paragraph 0557; 0558
[4] European Journal of Medicinal Chemistry, 2015, vol. 99, p. 36 - 50
[5] Patent: WO2006/132739, 2006, A2, . Location in patent: Page/Page column 48
[6] Patent: WO2014/22128, 2014, A1, . Location in patent: Paragraph 0144; 0145; 0155
[7] Patent: CN103539777, 2016, B, . Location in patent: Paragraph 0276; 0323; 0324
[8] Journal of the Chemical Society, 1950, p. 384,389
[9] Patent: WO2012/116237, 2012, A2, . Location in patent: Page/Page column 120
[10] Patent: WO2011/84402, 2011, A1, . Location in patent: Page/Page column 144-145
[11] European Journal of Medicinal Chemistry, 2014, vol. 75, p. 96 - 105
[12] Journal of the Brazilian Chemical Society, 2014, vol. 25, # 5, p. 980 - 986
[13] Patent: WO2014/151147, 2014, A1, . Location in patent: Paragraph 00641
[14] Patent: US2015/30588, 2015, A1, . Location in patent: Page/Page column 77; 78
[15] Patent: US9295673, 2016, B2, . Location in patent: Page/Page column 366
2
[ 145369-94-4 ]
[ 65340-70-7 ]
Yield
Reaction Conditions
Operation in experiment
92.6%
With phosphorus trichloride In toluene for 2 h; Reflux
willL0g (44.63 mol) of 6-bromoquinolin-4 (1H) -one, 100 ml of toluene and 12.25 g (89.26 mol) of phosphorus trichloride were added to a 250 ml three-necked flask and heated to reflux for 2 hours. , Dried and dried. The solid was beaten with ether (100 ml), filtered and dried to give a yellow powder (yield 92.6percent).
85%
for 3 h; Heating / reflux
Diphenyl ether (80 ml) was added to 4-bromoaniline (4.5 g) and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxan-4,6-dione (5.4 g), and the mixture was stirred at 80°C for one hr. Biphenyl (24.2 g) was added thereto, and the mixture was stirred at 220°C for 3 hr. The reaction mixture was cooled to room temperature, and diethyl ether was added to the cooled mixture. The precipitated crystal was collected by filtration and was washed with diethyl ether. The residue was purified by column chromatography with a hexane-acetone system to give 6-bromoquinolone (1.57 g, yield 27percent). Thionyl chloride (5 ml) and a minor amount of dimethylformamide were added to 6-bromoquinolone (1.6 g), and the mixture was stirred under reflux for 3 hr. The reaction mixture was added to a saturated aqueous sodium bicarbonate solution under ice cooling, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography with a hexane-ethyl acetate system to give 6-bromo-4-chloroquinoline (1.43 g, yield 85percent).
70%
With trichlorophosphate In N,N-dimethyl-formamide for 2 h; Reflux
A mixture of 4 (17.0 g, 131.5 mmol), POCl3 (180 mL) and anhydrous DMF (18 mL) was stirred and heated at reflux for 2 h. After removal of POCl3, the residue was poured into ice water and extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (4:1 hexanes/EtOAc) to afford 5 (12.8 g, 70percent) as a white solid, mp 111-112 °C (lit31 111-112 °C). 1H NMR (CDCl3) δ 8.79 (d, J = 5.0 Hz, 1H, Ar-H), 8.40 (d, J = 2.5 Hz, 1H, Ar-H), 8.00 (d, J = 9.0 Hz, 1H, Ar-H), 7.84 (dd, J = 9.0, 2.0 Hz, 1H, Ar-H), 7.52 (d, J = 5.0 Hz, 1H, Ar-H).
Reference：
[1] Journal of Medicinal Chemistry, 2015, vol. 58, # 14, p. 5522 - 5537
[2] Patent: CN106432073, 2017, A, . Location in patent: Paragraph 0026; 0027; 0036; 0037; 0045; 0046; 0056; 0057
[3] Patent: EP1724268, 2006, A1, . Location in patent: Page/Page column 41-42
[4] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 4, p. 1569 - 1574
3
[ 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,
4
[ 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,
5
[ 106-40-1 ]
[ 65340-70-7 ]
Reference：
[1] Journal of the Chemical Society, 1950, p. 384,389
[2] Patent: WO2012/116237, 2012, A2,
[3] Patent: WO2014/22128, 2014, A1,
[4] Patent: WO2014/151147, 2014, A1,
[5] Patent: US2015/30588, 2015, A1,
[6] ChemMedChem, 2015, vol. 10, # 5, p. 836 - 849
[7] European Journal of Medicinal Chemistry, 2015, vol. 99, p. 36 - 50
[8] Journal of Medicinal Chemistry, 2015, vol. 58, # 14, p. 5522 - 5537
[9] Patent: US2015/320727, 2015, A1,
[10] Patent: US9295673, 2016, B2,
[11] Patent: CN103539777, 2016, B,
[12] Patent: CN106432073, 2017, A,
[13] Patent: CN106432073, 2017, A,
[14] Patent: CN106432073, 2017, A,
[15] Patent: WO2006/132739, 2006, A2,
6
[ 29124-64-9 ]
[ 68-12-2 ]
[ 65340-70-7 ]
Reference：
[1] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 1997, vol. 36, # 7, p. 541 - 544
7
[ 101937-44-4 ]
[ 65340-70-7 ]
Reference：
[1] Journal of the Chemical Society, 1950, p. 384,389
[2] ChemMedChem, 2015, vol. 10, # 5, p. 836 - 849
[3] European Journal of Medicinal Chemistry, 2015, vol. 99, p. 36 - 50
[4] Patent: CN106432073, 2017, A,
Reference：
[1] Journal of Medicinal Chemistry, 2015, vol. 58, # 14, p. 5522 - 5537
10
[ 79607-23-1 ]
[ 65340-70-7 ]
Reference：
[1] Journal of Medicinal Chemistry, 2015, vol. 58, # 14, p. 5522 - 5537
11
[ 98948-95-9 ]
[ 65340-70-7 ]
Reference：
[1] Journal of Medicinal Chemistry, 2015, vol. 58, # 14, p. 5522 - 5537
12
[ 1320361-74-7 ]
[ 65340-70-7 ]
Reference：
[1] Patent: CN106432073, 2017, A,
13
[ 65340-70-7 ]
[ 65340-73-0 ]
Yield
Reaction Conditions
Operation in experiment
43%
at 180℃; for 5 h;
A reaction flask with a stir bar was charged with 6-bromo-4-chloroquinoline 17 (500mg, 2.1mmol), acetamide (2.438g, 41.3mmol), and K2CO3 (1.449g, 10.5mmol). The mixture was heated to 180 °C for 5 h and was allowed to cool to ambient temperature followed by adding water (50ml). The solution was extracted with ethyl acetate (20ml × 3), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (DCM:MeOH=20:1) to provide 6-bromoquinolin-4-amine 18 (198mg, yield = 43percent).1H NMR (400 MHz, DMSO-d6) δ 8.46 (d, J = 2.2 Hz, 1H), 8.25 (d, J = 7.2 Hz, 1H), 7.95 (dd, J = 8.9, 2.3 Hz, 1H), 7.69 (d, J = 8.9 Hz, 1H), 7.12 (d, J = 7.2 Hz, 1H), 5.64 (s, 2H). LC-MS (ESI) m/z = 223.1, 225.1 (M+H, M+2+H).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 9, p. 1919 - 1922
14
[ 65340-70-7 ]
[ 124-41-4 ]
[ 874792-20-8 ]
Yield
Reaction Conditions
Operation in experiment
90.8%
at 20 - 120℃; for 15 h;
To a solution of 6-bromo-4-chloro-quinoline (12.12 g, 50 mmol) in methanol (200 mL) was added sodium methoxide (13.50 g, 250 mmol) at room temperature. Then, the reaction mixture was heated to 120° C. for 15 h in a sealed reaction flask. After cooling to room temperature, the methanol was removed under the vacuum and the residue was diluted with water. Then, the solids were collected by filtration and washed with water. After drying in air, 10.8 g (90.8percent yield) of 6-bromo-4-methoxy-quinoline was isolated as a white solid which can be crystallized from acetonitrile: EI-HRMS m/e calcd for C10H8BrNO (M+) 236.9789, found 236.9784.
36%
at 120℃; for 1 h; Microwave irradiation
300 mg (1.24 mmol) of 6-bromo-4-chloroquinoline [Lin et al., J. Med. Chem. 1978, 21, 268] was taken up in 4 ml methanol and 1.15 ml (6.19 mmol) methanolic sodium methylate solution (30 wt.percent) was added. Then it was reacted in a single mode microwave for 1 h at 1200C. The solvent was removed in a rotary evaporator and the residue was partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate and the combined organic phases were dried over magnesium sulfate. The solvent was removed by distillation at reduced pressure. In this way we obtained 150 mg (36percent of theor.) of the target compound.LC-MS (method 2): R, = 1.24 min; MS (EIpos): m/z = 238 [M]+.
6-Bromo-N-methyl-4-quinolinamine. The mixture of the compound fromExample 22 a) (100 mg, 0.41 mmol) and methylamine (2.0 M in methanol, 2 mL, 4 mmol) was heated to 120 0C for 3 hours in a Biotage Initiator microwave synthesizer. The product was cooled, concentrated and purified via flash chromatography (0-10percent methanol in methylene chloride) to afford the title compound as a white solid (40 mg, 41 percent). 1 H NMR (400 MHz, CHLOROFORM-o) δ ppm 8.39 (d, J=5.81 Hz, 1 H) 8.04 (d, J=1.77 Hz, 1 H) 7.80 (d, J=9.09 Hz, 1 H) 7.67 (dd, J=8.84, 2.02 Hz, 1 H) 6.37 (d, J=5.81 Hz, 1 H) 3.02(s, 3 H).
The solid <strong>[145369-94-4]6-bromo-quinolin-4-ol</strong> (52 g, 232.1 mmol) was added to phosphorus oxychloride (213.5 mL) and then the mixture was heated to reflux for 6 h to afford a light brown solution. After cooling to room temperature, the excess phosphorus oxychloride was removed under the vacuum. The remaining residue was poured into an ice-containing beaker (2 L). Then, it was slowly neutralized with solid potassium carbonate and the resulting solids were collected by filtration and washed with water. After drying in air, 55.46 g (98.5% yield) of 6-bromo-4-chloro-quinoline was isolated as a light yellow solid: EI-HRMS m/e calcd for C9H5BrClN (M+) 240.9294, found 240.9297.
93%
With trichlorophosphate; for 1.5h;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.
84%
With trichlorophosphate; In N,N-dimethyl-formamide; at 120℃; for 5h;
4.1.8 6-Bromo-4-chloroquinoline (11) To a 100 mL round-bottomed flask was added <strong>[145369-94-4]6-bromoquinolin-4-ol</strong> (10) (3.0 g, 13.45 mmol), POCl3 (20 mL) and DMF (0.5 mL). The mixture was stirred at reflux for 6 h. After cooling to room temperature, the reaction mixture was poured into ice water (100 mL) and stirred for 1 h. Then the pH of the mixture was adjusted to 8 using saturated aqueous NaHCO3. The mixture was extracted with EtOAc and the organic phase was dried over sodium sulfate and concentrated in vacuo to give the title compound (2.75 g, 11.36 mmol, 84% yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) delta 8.87 (d, J = 4.5 Hz, 1H, Ar-H), 8.32 (d, J = 2.0 Hz, 1H, Ar-H), 8.03 (d, J = 9.0 Hz, 1H, Ar-H), 7.99 (dd, J = 9.0, 2.0 Hz, 1H, Ar-H), 7.82 (d, J = 4.5 Hz, 1H, Ar-H). ESI-MS: m/z = 242 [M+H]+.
84%
6-Bromo-4-chloroquinoline. The solution of the compound from Example 17b (2 g, 8.9 mmol) in POCI3 (10 mL) was refluxed overnight, cooled and quenched by ice water. The precipitate was collected, washed with H2O and dried in vacuo to afford the title compound as a grey solid (1.8 g, 84%). 1 H NMR (400 MHz, DMSO-CZ6) delta ppm 8.90 (d, J=4.80 Hz, 1 H) 8.37 (d, J=2.02 Hz, 1 H) 8.07 (d, J=8.59 Hz, 1 H) 8.03 (dd, J=8.84, 2.02 Hz, 1 H) 7.86 (d, J=4.55 Hz, 1 H).
32%
With trichlorophosphate; In toluene; at 115℃; for 4h;
To a suspension of <strong>[145369-94-4]6-bromo-4-hydroxyquinolin</strong> (14.55 g, 64.9 mmol) in toluene (20mL) was added POCh (6.05 mL, 64.9 mmol) slowly. The reaction was stirred at 115C for 4 h,then cooled down to 0C and diluted with DCM (400 mL). The mixture was washed with 4MNaOH (70 mL) followed by brine (100 mL), dried over anhydrous Na2S04 and concentrated invacuo. The residue was recrystallized in n-heptane (150 mL) to give the title compound as ayellow solid (5.5 g, 32%). The title compound was characterized by LC-MS and 1H NMR asshown below:LC-MS (ESI, pos. ion) m/z: 242 [M+Ht;1H NMR (400 MHz, CDCh) 8 (ppm): 7.50 (d, J= 4.72 Hz, 1H), 7.82 (dd, J= 8.96 Hz, 2.16 Hz,1H), 7.98 (d, J= 8.92 Hz, 1H), 7.95 (d, J= 2.16 Hz, 1H), 8.34 (d, J= 4.68 Hz, 1H).
32%
With trichlorophosphate; In toluene; at 115℃; for 4h;
To <strong>[145369-94-4]<strong>[145369-94-4]6-bromo-4-hydroxyquinolin</strong>e</strong> (14.55g, 64 . 9mmol) toluene (20 ml) is slowly added in solution POCl 3 (6.05 ml, 64 . 9mmol). responds the fluid in 115 C stirring 4 hours, cooling to 0 C, and added DCM (400 ml) dilution. The resulting mixed solution for sequentially 4MNaOH aqueous solution (70 ml) and the brine (100 ml) washing, anhydrous Na 2 SO 4 drying, and concentrated under reduced pressure. In normal heptane of the residue (150 ml) is recrystallized in, to obtain the title compound as yellow solid (5.5g, 32%).
With trichlorophosphate; for 1.5h;Reflux;
followed by halogenation using a reagent such as phosphorus oxychloride yields compound 3-5
With trichlorophosphate; at 20℃; for 19h;
A 20 mL scintillation vial was charged with <strong>[145369-94-4]6-bromoquinolin-4-ol</strong> (0.98 g, 4.4 mmol) and phosphorus (V) oxychloride (10 mL). The reaction mixture was stirred for 19 hours at ambient temperature and carefully poured into a mixture of saturated aqueous sodium bicarbonate solution and ice, extracted into ethyl acetate (3x), washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (MPLC, 0-50% EtOAc-hexanes) to give 4-chloro-5-bromoquinoline.LRMS (ESI) calc'd for C9H6BrClN [M+H : 242, Found: 242.
With trichlorophosphate; In N,N-dimethyl-formamide; for 6h;Reflux; Inert atmosphere;
General procedure: To a mixture of 6-bromo-4-hydroxyquinazoline (7.9 g,35.1 mmol) in POCl3 (60 ml) was added DMF (1 ml). Then themixture was heated to reflux under N2 for 6 h. The dark clear solutionwas cooled to room temperature and concentrated in vacuumto produce a brown solid. To the mixture of above brown solidin 2-propanol (150 ml) was added morpholine (12.2 ml,140.5 mmol). Then the mixture was heated to reflux under N2 for1 h, concentrated in vacuum to give a residue which was dissolvedin ethyl acetate (200 ml). The ethyl acetate solution was washedwith brine (80 ml 5), dried over Na2SO4 and concentrated to give abrown oil, which was solidified on keeping to produce 6a (8.9 g).
With triethylamine; In DMF (N,N-dimethyl-formamide); at 130℃; for 8h;
Production Example 82 1-(6-Bromo-4-quinolyl)-4-piperidyl methyl ether A mixture of 500 mg 6-bromo-4-chloroquinoline, 330 mg <strong>[4045-25-4]4-methoxypiperidine monohydrochloride</strong>, 0.57 ML triethylamine and 10 ML N,N-dimethylformamide was stirred at 130C for 8 hours.. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated.. The organic layer was washed with water and brine and dried over sodium sulfate, and the solvent was evaporated.. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 516mg of the title compound as a pale yellow oil.1H-NMR (CDCl3) delta: 1.85-1.98(m, 2H), 2.08-2.20(m, 2H), 2.97-3.08(m, 2H), 3.38-3.55(m, 6H), 6.85(d, J=5.0Hz, 1H), 7.70(d, J=8.6Hz, 1H), 7.90(d, J=8.6Hz, 1H), 8.12(s, 1H), 8.69(d, J=5.0Hz, 1H)
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 130℃; for 8h;
Production Example 74 6-Bromo-4-(4-methylpiperazin-1-yl)quinoline A mixture of 485 mg <strong>[65340-70-7]<strong>[65340-70-7]6-bromo-4-chloroquinolin</strong>e</strong>, 1.1 ML N-methyl piperazine, 415 mg potassium carbonate and 10 ML N,N-dimethylformamide was stirred at 130C for 8 hours.. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated.. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate.. The drying agent was filtered off, and the filtrate was evaporated.. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 502 mg of the title compound as pale yellow crystals.1H-NMR (CDCl3) delta: 2.44(s, 3H), 2.73(m, 4H), 3.25(m, 4H), 6.88(d, J=5.2Hz, 1H), 7.71(dd, J=8.8, 2.0Hz, 1H), 7.91(d, J=8.8Hz, 1H), 8.14 (d, J=2.0Hz, 1H), 8.72(d, J=5.2Hz, 1H)
Step B; Synthesis of (103); [0178] A mixture of <strong>[65340-70-7]<strong>[65340-70-7]6-bromo-4-chloroquinolin</strong>e</strong> (242 mg, 1 mmol) (prepared according to J. Med. Chem. 1978, 21, 268-272) and 102 (598 mg, 2 mmol) was dissolved in DMSO (3 mL), followed by addition of N,N-diisopropylethylamine (1,218 muL, 7 mmol). The reaction mixture was irradiated in a microwave oven (max. power 250W, 180 C) for 5 min, cooled to room temperature, and concentrated in vacuo. The resulting residue was subjected to HPLC purification (Method A). Fractions containing the desired product were combined and concentrated in vacuo. A solution of 1M aqueous HCI was added to the residue and the mixture was concentrated in vacuo. The resulting residue was dissolved in a mixture of acetonitrile/water (1: 4) and lyophilized to provide the dihydrochloride salt of 103 (342 mg, 73%) as a yellow powder.
A mixture of <strong>[65340-70-7]6-bromo-4-chloro-quinoline</strong> (1.0 g, 4.12 mmol) and morpholine (9.98 g, 114.6 mmol) was heated to 150 C. in a sealed tube and stirred for 2 days. Then, the brown suspension was diluted with water and extracted with ethyl acetate (3*50 mL). The combined extracts were washed with brine solution and dried over anhydrous magnesium sulfate. After filtration of the drying agent, the filtrate was removed under the vacuum and the residue was purified by using a Biotage silica gel column chromatography to afford 1.06 g (87.7% yield) of 6-bromo-4-morpholin-4-yl-quinoline as a light brown solid: EI-LRMS m/e calcd for C13H13BrN2O (M+) 293.1, found 293.1.
81.3%
In 1,4-dioxane; at 90℃; for 4h;
General procedure: To a stirred solution of 1-bromo-4-chloro-quinoline 4a (0.5g, 2.06mmol) in 1,4-dioxane (10mL) was added pyrrolidine (1.02mL, 12.36mmol) at 90C for 4h. The solvent was evaporated in vacuo then dissolved in CH2Cl2 (50mL) and washed with water (20mL×3), organic layers were washed with brine, dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to provide 4b (0.33g, 60% yield) as a pale white powder.
72%
In 1,4-dioxane; at 110℃; for 48h;
6-Bromo-4-chloro-quinoline (243 mg, 1.0 mmol) and morpholine(523 mg, 6.0 mmol, 6 eq) in dioxane (3 mL)And the mixture was stirred at 110 C for 48 hours.The reaction mixture was concentrated in vacuo and cooled to room temperature, diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3).The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, dichloromethane / methanol = 100: 1)To give the product as a light yellow oil (211 mg, 72% yield).
8.9 g
In isopropyl alcohol; for 1h;Reflux; Inert atmosphere;
General procedure: To a mixture of 6-bromo-4-hydroxyquinazoline (7.9 g,35.1 mmol) in POCl3 (60 ml) was added DMF (1 ml). Then themixture was heated to reflux under N2 for 6 h. The dark clear solutionwas cooled to room temperature and concentrated in vacuumto produce a brown solid. To the mixture of above brown solidin 2-propanol (150 ml) was added morpholine (12.2 ml,140.5 mmol). Then the mixture was heated to reflux under N2 for1 h, concentrated in vacuum to give a residue which was dissolvedin ethyl acetate (200 ml). The ethyl acetate solution was washedwith brine (80 ml 5), dried over Na2SO4 and concentrated to give abrown oil, which was solidified on keeping to produce 6a (8.9 g).
700 mg
With 4-methyl-morpholine; potassium carbonate; at 100℃; for 12h;
6-Bromo-4-chloroquinoline (1.0 G, 4.1 mmol), morpholine (0.468 g, 5.3 mmol) and K2C03 (1.OG, 7.2 mmol) in NMP (5 mL) were heated at 100 C for 12h. The reaction mixture was cooled to room temperature, diluted with water (20 mL) and the product was extracted into EtOAc/hexanes (140 mL/60 mL). The organic layer was washed with water (75 mL) and brine (20 mL) successively, dried over Mg504 and filtered. The filtrate was concentrated and purified by flash column chromatography (Combiflash companion system with RediSep silica gel column 40 g and 30-70% EtOAC/hexanes as an eluting solvent]. The product fractions were concentrated to provide 4-(6-bromoquinolin-4-yl)morpholine (700 mg) as a white solid. ?H NMR (300 MHz, DMSO-d6) oe 8.73 (d, J= 5.0 Hz, 1H), 8.13 (d, J= 2.2 Hz, 1H), 7.90 (d, J 8.9 Hz, 1H), 7.81 (dd, J= 9.0, 2.2 Hz, 1H), 7.06 (d, J= 5.0 Hz, 1H), 3.87-3.84 (m, 4H), 3.18-3.02 (m, 4H).
With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 80 - 100℃;
General procedure: A solution of 4-chloro-6-[1-(4-methylbenzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]quinoline (Intermediate 4) (0.15 g, 0.35 mmol, 1.0 eq.), (S)-3-(Boc-amino)piperidine (0.14 g, 0.7 mmol, 2.0 eq.), DIPEA (0.09 g, 0.7 mmol, 2.0 eq.) in i-PrOH (3 mL) was heated at 140 C. under microwave irradiation for 1.5 h. After cooling to rt, solvent was evaporated and the crude reaction mixture was used in consecutive step without further purification (UPLC purity: 71%).
In N,N-dimethyl-formamide; at 90℃; for 1.5h;
(2) 6-bromo-4-morpholinoquinoline:; A suspension of 6-bromo-4- chloroquinoline (725 mg, 2990 mumol) and morpholine (651 muL, 7474 mumol) in DMF (4 mL) was heated to 90 0C for 90 minutes. The reaction was then partitioned between EtOAc (30 mL) and water (30 mL). The separated organic was then dried over MgSO4 and concentrated to an oil under reduced pressure. MS (ESI pos. ion) m/z calc'd for Ci3H13BrN2O: 292.0/294.0; found 293.0/295.0. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 3.17 - 3.25 (m, 4 H) 3.95 - 4.02 (m, 4 H) 6.87 (d, J=5.02 Hz, 1 H) 7.73 (dd, J=8.78, 2.26 Hz, 1 H) 7.93 (d, J=9.03 Hz, 1 H) 8.16 (d, J=2.01 Hz, 1 H) 8.75 (d, J=4.52 Hz, 1 H).
To a solution of <strong>[65340-70-7]6-bromo-4-chloro-quinoline</strong> (1.5 g, 6.18 mmol) in DMF (60 mL) was added sodium thioethoxide (624 mg, 7.42 mmol) at 0 C. After addition, it was turned to a dark green solution which then turned to a yellow cloudy solution after 15 h at room temperature. Then, the mixture was diluted with water and extracted with ethyl acetate (3*50 mL). The combined extracts were washed with brine solution and dried over anhydrous magnesium sulfate. After filtration of the drying agent, the filtrate was removed under the vacuum and the residue was purified by using a Biotage silica gel column chromatography to afford 1.48 g (89.6% yield) of 6-bromo-4-ethylsulfanyl-quinoline as an yellow solid: EI-HRMS m/e calcd for C11H10BrNS (M+) 266.9717, found 266.9715.
To a solution of <strong>[65340-70-7]<strong>[65340-70-7]6-bromo-4-chloroquinolin</strong>e</strong> (17 g, 70.10 mmol) in ethanol (400 mL) was added sodium ethoxide (23.85 g, 350.5 mmol) at room temperature. Then, the reaction mixture was heated to 120 C. for 15 h in a sealed reaction flask. After cooling to room temperature, the ethanol was removed under the vacuum and the residue was diluted with water. The aqueous suspension was neutralized with 3.0N hydrochloric acid until the precipitate formed and later it was diluted with saturated sodium bicarbonate solution. Then, the solids were collected by filtration and washed with water. After drying in air, 15.94 g (90.2% yield) of 6-bromo-4-ethoxy-quinoline was isolated as a white solid which can be crystallized from acetonitrile: EI-HRMS m/e calcd for C11H10BrNO (M+) 250.9946, found 250.9946.
To a solution of 6-bromo-4-chloro-quinoline (12.12 g, 50 mmol) in methanol (200 mL) was added sodium methoxide (13.50 g, 250 mmol) at room temperature. Then, the reaction mixture was heated to 120 C. for 15 h in a sealed reaction flask. After cooling to room temperature, the methanol was removed under the vacuum and the residue was diluted with water. Then, the solids were collected by filtration and washed with water. After drying in air, 10.8 g (90.8% yield) of 6-bromo-4-methoxy-quinoline was isolated as a white solid which can be crystallized from acetonitrile: EI-HRMS m/e calcd for C10H8BrNO (M+) 236.9789, found 236.9784.
36%
In methanol; at 120℃; for 1h;Microwave irradiation;
300 mg (1.24 mmol) of 6-bromo-4-chloroquinoline [Lin et al., J. Med. Chem. 1978, 21, 268] was taken up in 4 ml methanol and 1.15 ml (6.19 mmol) methanolic sodium methylate solution (30 wt.%) was added. Then it was reacted in a single mode microwave for 1 h at 1200C. The solvent was removed in a rotary evaporator and the residue was partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate and the combined organic phases were dried over magnesium sulfate. The solvent was removed by distillation at reduced pressure. In this way we obtained 150 mg (36% of theor.) of the target compound.LC-MS (method 2): R, = 1.24 min; MS (EIpos): m/z = 238 [M]+.
With dmap; caesium carbonate; In dimethyl sulfoxide; at 130℃; for 5h;
Dimethylsulfoxide (25 ml) was added to 5,6-dimethyl-[2,2']bipyridinyl-3-ol (500 mg), <strong>[65340-70-7]<strong>[65340-70-7]6-bromo-4-chloroquinolin</strong>e</strong> (723 mg), cesium carbonate (2.4 g), and 4-dimethylaminopyridine (916 mg), and the mixture was stirred at 130C for 5 hr. The reaction mixture was cooled to room temperature, water was added to the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography with a chloroform-acetone system to give the title compound (886 mg, yield 87%). 1H-NMR (CDCl3, 400 MHz): delta 2.40 (s, 3H), 2.66 (s, 3H), 6.44 (d, J = 5.1 Hz, 1H), 7.11 (ddd, J = 7.6, 4.6, 1.0 Hz, 1H), 7.36 (s, 1H), 7.61 (ddd, J = 7.6, 7.6, 1.7 Hz, 1H), 7.79 (dd, J = 8.8, 2.2 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 9.0 Hz, 1H), 8.42 - 8.47 (m, 1H), 8.52 (d, J = 2.2 Hz, 1H), 8.55 (d, J = 5.4 Hz, 1H) Mass spectrometric value (ESI-MS, m/z): 406 (M+1)+
With phosphorus trichloride; In toluene; for 2h;Reflux;
willL0g (44.63 mol) of 6-bromoquinolin-4 (1H) -one, 100 ml of toluene and 12.25 g (89.26 mol) of phosphorus trichloride were added to a 250 ml three-necked flask and heated to reflux for 2 hours. , Dried and dried. The solid was beaten with ether (100 ml), filtered and dried to give a yellow powder (yield 92.6%).
85%
With thionyl chloride;N,N-dimethyl-formamide; for 3h;Heating / reflux;
Diphenyl ether (80 ml) was added to 4-bromoaniline (4.5 g) and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxan-4,6-dione (5.4 g), and the mixture was stirred at 80C for one hr. Biphenyl (24.2 g) was added thereto, and the mixture was stirred at 220C for 3 hr. The reaction mixture was cooled to room temperature, and diethyl ether was added to the cooled mixture. The precipitated crystal was collected by filtration and was washed with diethyl ether. The residue was purified by column chromatography with a hexane-acetone system to give 6-bromoquinolone (1.57 g, yield 27%). Thionyl chloride (5 ml) and a minor amount of dimethylformamide were added to 6-bromoquinolone (1.6 g), and the mixture was stirred under reflux for 3 hr. The reaction mixture was added to a saturated aqueous sodium bicarbonate solution under ice cooling, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography with a hexane-ethyl acetate system to give 6-bromo-4-chloroquinoline (1.43 g, yield 85%).
70%
With trichlorophosphate; In N,N-dimethyl-formamide; for 2h;Reflux;
A mixture of 4 (17.0 g, 131.5 mmol), POCl3 (180 mL) and anhydrous DMF (18 mL) was stirred and heated at reflux for 2 h. After removal of POCl3, the residue was poured into ice water and extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (4:1 hexanes/EtOAc) to afford 5 (12.8 g, 70%) as a white solid, mp 111-112 C (lit31 111-112 C). 1H NMR (CDCl3) delta 8.79 (d, J = 5.0 Hz, 1H, Ar-H), 8.40 (d, J = 2.5 Hz, 1H, Ar-H), 8.00 (d, J = 9.0 Hz, 1H, Ar-H), 7.84 (dd, J = 9.0, 2.0 Hz, 1H, Ar-H), 7.52 (d, J = 5.0 Hz, 1H, Ar-H).
tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 150℃; for 0.333333h;Microwave irradiation;
[0103] To a solution of <strong>[65340-70-7]<strong>[65340-70-7]6-bromo-4-chloroquinolin</strong>e</strong> (2.0 g, 8.3 mmol) and Pd(PPh3)4 (0.095 g, 0.83 mmol) in 1,4-dioxane (7.5 mL) was added tributyl(vinyl)tin (2.4 mL, 8.3 mmol). The reaction mixture was heated for 20 min at 150 C in a Biotage microwave reactor. The resulting mixture was concentrated and purified by silica gel chromatography (hexanes/EtOAc 100:0 to 70:30 gradient) to afford the title compound as a white solid (1.3 g, 84 %).[0104] 1H NMR (500 MHz, DMSOd6): delta 5.49 (d, J = 11.0 Hz, IH), 6.10 (d, J = 17.7 Hz, IH), 7.05 (dd, J = 17.7, 11.0 Hz, IH), 7.76 (d, J= 4.8 Hz, IH), 8.06 (d, J= 6.5 Hz, IH), 8.12 (d, J = 6.5 Hz, IH), 8.13 (s, IH), 8.80 (d, J = 4.6 Hz, IH)MS (ES+): m/z 190 (M+H)+
80%
tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 150℃; for 0.333333h;Microwave;
A solution of the <strong>[65340-70-7]<strong>[65340-70-7]6-bromo-4-chloroquinolin</strong>e</strong> (4g; 16.5 mmol), tributyl(vinyl)tin (4.8 ml, 16.5 mmol), and tetrakis(triphenylpnosphine)palladium(0) (0.19Og; 0.16 mmol) in dioxane (15.0 ml.) was stirred and heated to 150 0C for 20 min. in a Biotage Initiator microwave synthesizer. Concentration in vacuo and purification via flash column chromatography (0-100% ethyl acetate in hexanes) provided the title compound as a yellow solid (2.5 g, 80%). MS(ES+) m/e 190 [M+H]+. 1 H NMR (400 MHz, CHLOROFORM-d) delta ppm 8.72 (d, J=4.55 Hz, 1 H) 8.02 - 8.13 (m, 2 H) 7.91 (dd, J=8.72, 1.89 Hz, 1 H) 7.47 (d, J=4.80 Hz, 1 H) 6.93(dd, J=17.68, 10.86 Hz, 1 H) 5.95 (d, J=17.43 Hz, 1 H) 5.45 (d, J=1 1.12 Hz, 1 H).
80%
tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 150℃; for 0.333333 - 0.666667h;Microwave irradiation;Product distribution / selectivity;
4-Chloro-6-ethenylquinoline. A solution of the <strong>[65340-70-7]<strong>[65340-70-7]6-bromo-4-chloroquinolin</strong>e</strong> (4g; 16.5 mmol), tributyl(vinyl)tin (4.8 ml, 16.5 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.19Og; 0.16 mmol) in dioxane (15.0 mL) was stirred and heated to 1500C for 20 min. in a Biotage Initiator microwave synthesizer. Concentration in vacuo and purification via flash column chromatography (0-100% ethyl acetate in hexanes) provided the title compound as a yellow solid (2.5 g, 80%). MS(ES+) m/e 190 [M+H]+. 1 H NMR (400 MHz, CHLOROFORM-d) delta ppm 8.72 (d, J=4.55 Hz, 1 H) 8.02 - 8.13 (m, 2 H) 7.91 (dd, J=8.72, 1.89 Hz, 1 H) 7.47 (d, J=4.80 Hz, 1 H) 6.93 (dd, J=17.68, 10.86 Hz, 1 H)5.95 (d, J=17.43 Hz, 1 H) 5.45 (d, J=11.12 Hz, 1 H).; 4-Chloro-6-ethenylquinoline. The mixture of the compound from Example 22a)(4.0 g, 16.5 mmol), tetrakis(triphenylphosphine)palladium (190 mg, 0.16 mmol) and tributyl(vinyl)tin (4.8 mL, 16.5 mmol) in dioxane (10 mL) was heated to 15O0C for 40 minutes in a Biotage Initiator microwave synthesizer. The product was concentrated under vacuo and purified via flash chromatography (0-10% methanol in methylene chloride) to afford the title compound as a yellow solid(2.5 g, 80%).
tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; for 2h;Heating / reflux;
A mixture of <strong>[65340-70-7]<strong>[65340-70-7]6-bromo-4-chloroquinolin</strong>e</strong> (6.52 g, 26.88 mmol; see J. Med. Chem., 21_, 268 (1978) ), tributyl(vinyl)tin (8.95 g, 28.22 mmol), and tetrakistriphenylphosphine palladium (0) (0.62 g, 0.54 mmol) in 1 ,4-dioxane (150 ml.) was refluxed for 2.0 h, cooled to room temperature, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-4% MeOH:CH2CI2) to give the title compound (5.1 g) as a pale yellow solid. MS(ES)+ m/e 190 [M+H]+. This material was used directly in the next step.
With N-ethyl-N,N-diisopropylamine; In methanol; at 150℃; for 0.333333h;Microwave;
To a solution of 6-bromo-4- chloroquinoline (200 mg, 0.41 mmol) (prepared by the method of Ai Jeng Lin, J. Med. Chem, 1978, 21, 268) in dry MeOH (2.0 mL) was added dimethylamine hydrochloride (67 mg, 0.82 mmol) and N, N- diisopropylethylamine (0.14 mL, 0.82 mmol). The mixture was heated at 15O0C in a Biotage Initiator microwave synthesizer for 20 minutes, then cooled and quenched with H2O. The resulting mixture was extracted by CH2CI2. The extact was dried over MgSO4, filtered, concentrated in vacuo and purified by flash chromatography ( 0-10% MeOH in CH2CI2 ) to afford colorless oil (130 mg, 62%). MS(ES+) m/e 252[M+H]+. 1 H NMR (400 MHz, CHLOROFORM-d) delta ppm 8.61 (d, J=4.29 Hz, 1 H) 8.17 (d, J=2.02 Hz, 1 H)7.87 (d, J=8.84 Hz, 1 H) 7.66 (dd, J=8.97, 2.15 Hz, 1 H) 6.71 (d, J=5.31 Hz, 1 H) 2.93 - 3.02 (m, 6 H)
62%
With N-ethyl-N,N-diisopropylamine; In methanol; at 150℃; for 0.333333h;Microwave irradiation;
6-Bromo-Lambda/,Lambda/-dimethyl-4-quinolinamine. To a solution of <strong>[65340-70-7]<strong>[65340-70-7]6-bromo-4-chloroquinolin</strong>e</strong> (200 mg, 0.41 mmol) (prepared by the method of AiJeng Lin, J. Med. Chem, 1978, 21, 268) in dry MeOH (2.0 mL) was added dimethylamine hydrochloride (67 mg, 0.82 mmol) and N1N- diisopropylethylamine (0.14 mL, 0.82 mmol). The mixture was heated at 15O0C in a Biotage Initiator microwave synthesizer for 20 minutes, then cooled and quenched with H2O. The resulting mixture was extracted by CH2CI2. The extact was dried over MgSO4, filtered, concentrated in vacuo and purified by flash chromatography ( 0-10% MeOH in CH2CI2 ) to afford colorless oil (130 mg, 62%). EPO <DP n="35"/>MS(ES+) m/e 252[M+H]+. 1 H NMR (400 MHz, CHLOROFORM-of) delta ppm 8.61 (d, J=4.29 Hz, 1 H) 8.17 (d, J=2.02 Hz, 1 H) 7.87 (d, J=8.84 Hz, 1 H) 7.66 (dd, J=8.97, 2.15 Hz, 1 H) 6.71 (d, J=5.31 Hz, 1 H) 2.93 - 3.02 (m, 6 H).
Intermediate 13: 2-(6-Bromo-quinoIin-4-yloxy)-ethanol; [0320] To a suspension of sodium hydride (60% suspension, 40 mg, 0.99 mmol) in DMF (3 mL) under nitrogen atmosphere was added ethylene glycol dropwise. The reaction mixture was stirred for 20 min before adding <strong>[65340-70-7]4-chloro-6-bromoquinoline</strong> (200 mg, 0.825 mmol) in one portion. The reaction mixture was stirred at 9O0C for 22h. Another 20 mg of sodium hydride was added after 16h. The mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in methanol and the solution was adsorbed on silica gel. Purification by flash chromatography on silica gel using a gradient of 0-10% methanol/dichloromethane afforded 127 mg of 2-(6-bromo-quinolin-4-yloxy)- ethanol as a white solid (57% yield): 1H NMR (DMSO-cf°) delta 3.93 (q, 2H), 4.32 (t, 2H), 5.21 (t, IH), 7.14 (d, IH), 7.94 (m, 2H), 8.50 (d, IH), 8.82 (d, IH); MS (m/z) 268, 270 [M+H]+.
With N-ethyl-N,N-diisopropylamine;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In N,N-dimethyl-formamide; at 100℃; for 18h;
Example 18 : 6-(6-Methyl- [1 ,2,4] triazolo [4,3-b] pyridazin-3-ylsulf anyl)-4-(4-methyl-4No.- [l,2,4]triazol-3-ylsulfanyl)-quinoline (compound 57); [0388] A solution of <strong>[65340-70-7]4-chloro-6-bromoquinoline</strong> (1.6 g, 6.63 mmol), diisopropylethylamine (1.93 mL, 11.05 mmol) in DMF (20 mL) under nitrogen was degassed by bubbling in nitrogen for 30 min. Tris(dibenzylideneacetone)dipalladium (506 mg, 0.552 mmol), Xantphos (640 mg, 1.105 mmol), and 6-methyl-[l,2,4]triazolo[4,3- b]pyridazine-3 -thiol (1.0 g, 5.525 mmol) were added. The reaction mixture was stirred at 1000C for 18 h. The reaction mixture was cooled to room temperature, and partitioned between 1 N aqueous NaOH and 10% methanol/di-chloromethane. The aqueous layer was extracted with 10% methanol/dichloromethane (3x) and the combined organic layers were adsorbed on silica gel. Purification by flash chromatography on silica gel using a gradient of 0-6% methanol/dichloromethane afforded 468 mg of a (1 :1) mixture of 4-chloro-6-(6- methyl-[ 1 ,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-quinoline and 6-bromo-4-(6-methyl- [l,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-quinoline as a beige solid. The (1 :1) mixture (70 mg) was dissolved in DMF (0.5 mL), and 4-methyl-4//-[l,2,4]triazole-3-thiol (12 mg, 0.1 mmol) was added. The reaction mixture was stirred at 6O0C for 21 h then at 8O0C for 25 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was partitioned between 1 N aqueous NaOH and 10% methanol/dichloromethane. The aqueous layer was extracted with 10% methanol/dichloromethane (2x) and the combined organic layers were adsorbed on silica gel. Purification by flash chromatography on silica gel using a gradient of 0-10% methanol/dichloromethane afforded 16 mg of 6-(6- methyl-[l,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-4-(4-methyl-4H-[l,2,4]triazol-3- ylsulfanyl)-quinoline as a cream color solid (78% yield).
With potassium carbonate; In N,N-dimethyl-formamide; at 60 - 90℃; for 42h;
Intermediate 14: 6-Bromo-4-(4-methyl-4T-[l ,2,4]triazol-3-ylsulfanyl)-quinoline; [0321] A capped vial was charged with <strong>[65340-70-7]4-chloro-6-bromoquinoline</strong> (500 mg, 2.06 mmol), 4-methyl-4//-[l,2,4]triazole-3-thiol (238 mg, 2.06 mmol), potassium carbonate (427 mg, 3.09 mmol), and DMF (5 mL). The reaction mixture was stirred at 6O0C for 18h then at 9O0C for another 24h, and cooled to room temperature. The reaction mixture was poured onto water (50 mL), and the resulting precipitate was filtered, washed with water and dried EPO <DP n="88"/>in a vacuum oven at 7O0C overnight to provide 600 mg of 6-bromo-4-(4-methyl-4H- [l,2,4]triazol-3-ylsulfanyl)-quinoline as a white solid (91% yield): 1H NMR (DMSO-d<5) delta 3.63 (s, 3H), 6.90 (d, IH), 8.02 (m, 2H), 8.40 (d, IH), 8.74 (d, IH), 8.92 (s, IH); MS (m/z) 321, 323 [M+H]+.
With 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 110℃;
Intermediate 11 : Preparation of 4-chloro-6-[dimethyl(oxido)-lambda4- sulphanylidene]amino}quinoline768 mg (8.25 mmol) of S,S-dimethylsulphoximine, 189 mg (0.21 mmol) of <n="42"/>tris(dibenzylideneacetone)dipalladium, 286 mg (0.5 mmol) of 9,9-dimethyl- 4,5-bis(diphenylphosphino)xanthene and 724 mg (9.9 mmol) of sodium tert- butoxide are added to 2 g (8.25 mmol) of <strong>[65340-70-7]<strong>[65340-70-7]6-bromo-4-chloroquinolin</strong>e</strong> in 85 ml of 1 ,4-dioxane under argon. After stirring at 110C overnight, the mixture is cooled and filtered through Celite. The filtrate is washed with water and sat. NaCl solution, and the org. phase is dried and concentrated under reduced pressure. The residue is purified by chromatography on a silica gel column (mobile phase: dichloromethane: methanol 100:2). 1.41 g (67%) of the title compound are obtained. 1H-NMR (400 MHz, D6-DMSO): delta = 3.35 (s, 6H), 7.47 (dd, 1 H), 7.60 (d, 1 H), 7.65 (d, 1H), 7.92 (d, 1 H), 8.60 (d, 1H). MS (ESpos): 255.0 [M+H]+.
With 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 110℃;
Intermediate 10: Preparation of 4-chloro-6-[methyl(oxido)phenyl-lambda4- sulphanylidene]amino}quinoline960 mg (6.19 mmol) of R-(-)-S-methyl-S-phenylsulphoximine, 142 mg (0.16 mmol) of tris(dibenzylideneacetone)dipalladium, 215 mg (0.37 mmol) of 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene and 543 mg (7.42 mmol) of sodium tert-butoxide are added to 1.5 g (6.19 mmol) of 6-bromo-4- chloroquinoline in 64 ml of 1,4-dioxane under argon. After stirring at 1100C overnight, the mixture is cooled and filtered through Celite. The solvent is removed from the filtrate under reduced pressure, and the residue is purified by chromatography on a silica gel column (mobile phase: dichloromethane: methanol 100:1 ). 1.43 g (73%) of the title compound are obtained.1H-NMR (500 MHz, D6-DMSO): delta = 3.52 (s, 3H), 7.4-7.46 (m, 2H), 7.53-7.7 (m, 4H), 7.86 (d, 1H), 8.0 (d, 2H), 8.56 (d, 1 H). MS (ESpos): 317.1 [M+H]
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 90℃; for 3h;Inert atmosphere;
Material (II) (0.50 g, 2.06 mmol) was added into 50 ml eggplant-shaped flask, and dissolved in 13 mL dioxane, bis (pinacolato) diboron (0.79 g, 3.10 mmol), potassium acetate (0.81 g, 8.25 mmol) and palladium catalyst PdCl2 (dppf) CH2Cl2 (0.128 g, 0.157 mmol) were added to the system, heated and refluxed with stirring for 3 hours at 90 C under nitrogen protected condition. After cooled to room temperature, the solvent was evaporated to dry, and the mixture was extracted with ethyl acetate (20 mL) and water (20 mL). The aqueous layer was extracted with a small amount of ethyl acetate (15 mL × 2), the organic layers were combined, dried with anhydrous sodium sulfate, and concentrated to obtain the crude product 1.15g (PH = 6), purified by silica gel column chromatography (gradient elution with dichloromethane in petroleum ether with the content of 30% -50%) to obtain 0.40g yellowish white solid, yield 68.7%.
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 100℃; for 4h;Inert atmosphere;
A mixture of 4a (1.00 g, 4.12 mmol), bis(pinacolato)diboron (1.05 g, 4.12 mmol), PdCl2(dppf)-CH2Cl2 (0.17 g, 0.20 mmol) and potassium acetate (1.21 g, 12.36 mmol) in anhydrous 1,4-dioxane (15 mL) was heated at 100 C for 4 h. The solvent was purged with argon. The resulting mixture was then treated with compound 3 (1.57 g, 4.12 mmol), 2.0 M aqueous Na2CO3 (5 mL) and another portion of PdCl2(dppf)-CH2Cl2 (0.17 g, 0.20 mmol), then heated at 110 C for 12 h under argon. The reaction mixture was cooled to room temperature, filtered, and concentrated. The final compound was purified by MPLC (ISCO CombiFlash purification system) (MeOH/DCM, eluted from 0% to 10%). The fractions were collected, concentrated to afford 5a (0.23 g, 12.1% yield) as an off-white solid.
2.1 g
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 90 - 100℃; for 16h;Inert atmosphere;
To a solution of <strong>[65340-70-7]<strong>[65340-70-7]6-bromo-4-chloroquinolin</strong>e</strong> (CAS registry number 65340-70-7; 2 g,8.4 mmol) in anhydrous dioxane (80 mL) was added 4,4,4?,4?,5,5,5?,5?-octamethyl-2,2?-bi(1,3,2-dioxaborolane) (2.36 g, 9.28 mmol), KOAc (1.6 g, 16.8 mmol) and Pd(dppf)C12 (307 mg, 0.42 mmol) under N2. The mixture was stirred at 90-100C for 16 h. The mixture was concentrated and the residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 5:1) to give 4-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (2.1 g). LCMS method C: R = 0.67 mm; (M+H) = 436.0.
With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 90℃; for 3h;Inert atmosphere;Product distribution / selectivity;
EXAMPLE 24; N-(2-chloro-5-(4-(l-piperidinyl)-6-quinolinyl)-3-pyridinyl)-4- fluorobenzenesulfonamid; (l) 4-chloro-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline.; (Some starting materials may be obtained from Aldrich, St. Louis, MO) To a suspension of 6-bromo-4- chloroquinoline (1.5 g, 6.2 mmol) in dioxane (40 mL) was added bis(pinacolato)diboron (2.4 g, 9.3 mmol), potassium acetate (2.4 g, 25 mmol), and 1,1'- bis(diphenylphosphino)ferrocene]dichloride palladium(II) (0.34 g, 0.47 mmol) in order. The reaction mixture was then heated at 90 0C under N2 for 3 h. The reaction was cooled to rt and the solvent was removed. The residue was partitioned between EtO Ac/water. The aqueous layer was extracted more with EtOAc (2 x 15 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified using Sitheta2 chromatography with DCM:EtOAc:MeOH=85%: 10%:5% solvent system to afford the product as brown solid (1.45 g). MS (ESI pos. ion) m/z: calc'd for Ci5H17BClNO2: 289.1; found: 290.3 (M+l). 1H NMR (300 MHz, CHLOROFORM-d) delta ppm 1.41 (s, 12 H) 7.51 (d, J=4.82 Hz, 1 H) 8.05 - 8.12 (m, 1 H) 8.14 (s, 1 H) 8.73 (s, 1 H) 8.81 (d, J=4.68 Hz, 1 H).
With potassium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 100℃;Inert atmosphere; microwave irradiation;
EXAMPLE 52; 2-chloro-5-(4-chloro-6-quinolinyl)-N,N-dimethyl-3-pyridinamine; (Some starting materials may be obtained from ECA International, Palatine, IL)To a microwave vial (5 mL), 2-chloro-N,N-dimethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)pyridin-3 -amine (0.110 g, 0.390 mmol), <strong>[65340-70-7]<strong>[65340-70-7]6-bromo-4-chloroquinolin</strong>e</strong> (0.102 g, 0.419 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.0183 g, 0.0224 mmol) and potassium carbonate (0.500 mL, 1.00 mmol) were added into 1,4-dioxane (3 mL). The mixture was degassed by bubbling nitrogen through for 10 min. The tube was irradiated with microwave at 100 0C for 10 min. The reaction was cooled to RT then partitioned between water (20 mL) and EtOAc (20 mL). The aqueous phase was extracted with EtOAc (2 X 20 mL). The combined organic phases were washed with saturated aqueous NaCl (40 mL). The organic phase was dried over sodium sulfate, filtered and <n="118"/>concentrated in vacuo. The crude product was purified by column chromatography (eluent: acetone in hexanes 0 % - 30 %) to afford the title compound as a white solid (0.0884 g). m/z: calc'd for Ci6H13Cl2N3; 317.0, found: 318.1 (M+ 1). 1H NMR (300 MHz, CHLOROFORM-tf) delta ppm 2.97 (s, 6 H), 7.55 - 7.63 (m, 2 H), 7.98 (dd, J=8.8, 2.0 Hz, 1 H), 8.25 (d, J=8.8 Hz, 1 H), 8.38 (dd, J=5.3, 2.0 Hz, 2 H), 8.84 (d, J=4.7 Hz, 1 H).
To a solution of 6-bromo-4-chloro-quinoline (0.550 g, 2.27 mmol) in cyclohexylmethanol (5 mL) was added a solution of sodium cyclohexylmethoxide (11.34 mmol, prepared from cyclohexylmethanol and sodium) at room temperature. Then, the reaction mixture was heated to 120 C. for 15 h in a sealed reaction flask. After cooling to room temperature, the reaction mixture was diluted with water and the solvent was removed under the vacuum. Then, the remaining aqueous solution was neutralized with 3.0N hydrochloric acid and the organic compound was extracted into ethyl acetate (3*50 mL). The combined extracts were washed with brine solution and dried over anhydrous magnesium sulfate. After filtration of the drying agent, the filtrate was removed under the vacuum and the residue was purified by using a Biotage silica gel column chromatography to afford 0.518 g (71% yield) of 6-bromo-4-cyclohexylmethoxy-quinoline as a light yellow oil: EI-HRMS m/e calcd for C16H18BrNO (M+) 320.2304, found 320.2314.
5 mL of 4M hydrogen chloride in 1,4-dioxane were added to 6-bromo-4-chloroquinoline 49a (1 g, 4.12 mmol). The reaction solution was stirred for 10 minutes, and concentrated under reduced pressure for following use. The above concentrated residue was added with 60 mL of acetonitrile, followed by addition of sodium iodide (6.18 g, 41.24 mmol). The reaction solution was stirred under reflux for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, added with saturated sodium bicarbonate solution, and extracted with ethyl acetate (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by CombiFlash rapid preparation instrument with elution system B to obtain the title product 49b (850 mg), yield: 61.72%. MS m/z (ESI): 333.9[M+1].
To a solution of 60% NaH in mineral oil (1.75 equiv.) in DMF (0.5 M) was added benzyl alcohol (2.5 equiv.) dropwise. After stirring for 30 minutes, <strong>[65340-70-7]<strong>[65340-70-7]6-bromo-4-chloroquinolin</strong>e</strong> (1.0 equiv.) was added and the solution was heated in a microwave at 100 C. for 30 minutes. Upon cooling, the solution was partitioned between EtOAc and H2O. Upon separation, the organic layer was washed further with H2O (3*) and NaCl(sat.), dried over MgSO4, concentrated and triturated with hexanes to yield 4-(benzyloxy)-6-bromoquinoline (73%). LC/MS=314.0/315.9 (M+H), LC=2.89 min.
With sodium hydride; In 1-methyl-pyrrolidin-2-one; at 20℃; for 12h;
Method of synthesising quinoline D.68NaH (43 mg, 1.07 mmol, 60 %) is placed in NMP (2.0 mL), combined with aminoalcohol ED.15 (0.17 mL, 0.91 mmol) and quinoline D*.9 (200 mg, 0.83 mmol) and stirred for 12 h at 20C. Then the reaction mixture is diluted with H20 (5 mL), extracted with DCM (3 x 5 mL), dried on MgS04, filtered, the solvent is eliminated and quinoline D.68 (255 mg, 90 %; HPLC-MS: MS(M+H)+ = 309/31 1 ; tRel = 1.86 min; method LCMSBAS1 ) is obtained.
With copper(l) iodide; N-ethyl-N,N-diisopropylamine;tetrakis(triphenylphosphine) palladium(0); In dimethyl sulfoxide; at 50℃; for 2h;
Method of synthesising quinoline E.3Quinoline D*.9 (1 .00 g, 4.12 mmol), propargylamide C.1 (1 .50 g, 4.95 mmol), Pd(PPh)3 (238 mg, 10 mol %) and Cul (32 mg, 5 mol %) are placed in DMSO (10.0 mL), combined with DIPEA (7.7 mL) and stirred for 2 h at 50C. The solvent is removed, the residue is purified by chromatography (95:5 to 40:60 in 6 min H20/MeOH) and quinoline E.3 (1.51 g, 79 % HPLC-MS: MS(M+H)+ = 465; tRel = 2.14 min; method FECB6) is obtained.
6-Bromo-4-chloroquinoline (5 g, 20.6 mmol), acetonitrile (54 mL) and tetrakis(triphenylphosphonium) palladium(0) (1.2 g, 1.0 mmol) were added to a RB flask and purged with nitrogen for 10 min. Tetrahydro-2H-pyran-4-thiol (2.9 g, 24.9 mmol) and triethylamine (4.3 mL, 31 mmol) were added and the reaction was heated under nitrogen at 60 C. for 16 h. The reaction was partitioned between EtOAc and satd. aqueous NaHCO3. The aqueous layer was extracted with EtOAc (1*) and the combined organics were dry-loaded onto silica gel and purified via column chromatography (ISCO-Rf, 120 g, 0-80% EtOAc/hexane) to yield 4-chloro-6-((tetrahydro-2H-pyran-4-yl)thio)quinoline (1.75 g, 6.25 mmol, 30.3% yield). 1H NMR (400 MHz, DMSO-d6) delta ppm 8.80 (d, J=4.8 Hz, 1H), 8.06 (d, J=9.6 Hz, 2H), 7.88 (d, J=8.8 Hz, 1H), 7.70-7.82 (m, 1H), 3.86 (dt, J=11.6, 3.5 Hz, 2H), 3.71-3.82 (m, 1H), 3.41-3.50 (m, 2H), 1.94 (d, J=11.9 Hz, 2H), 1.50-1.65 (m, 2H). MS (m/z) 280(M+H+).
With hydrogenchloride; In tetrahydrofuran; diethyl ether; at 20℃; for 0.5h;
To a solution of 5 (11.0 g, 45.6 mmol) in anhydrous THF (150 mL) was added 2 M HCl in Et2O (29 mL, 58.0 mmol) dropwise. After stirring at rt for 30 min, the solvent was removed in vacuo and the solid was dried to afford <strong>[65340-70-7]<strong>[65340-70-7]6-bromo-4-chloroquinolin</strong>e</strong> hydrochloride as an off-white solid. The hydrochloride salt and anhydrous NaI (34.2 g, 228.3 mmol) were suspended in propionitrile (300 mL). After the reaction mixture was stirred and heated at reflux for 96 h, it was cooled to rt. 10% aqueous K2CO3 (200 mL) was added, followed by 5% aqueous Na2SO3 (80 mL), and the mixture was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (100:10:1-100:20:1 hexanes/EtOAc/Et3N) to afford 6 (13.7 g, 90%) as a white solid
3.46 g
With hydrogenchloride; In tetrahydrofuran; diethyl ether; at 20℃; for 0.5h;
To a solution of <strong>[65340-70-7]<strong>[65340-70-7]6-bromo-4-chloroquinolin</strong>e</strong> (3 g, 12.4 mmol) in anhydrous THF (50mL) was added 2M HCl in diethylether (7.4 mL, 14.8 mmol). The reaction was stirred at rt for30 min and concentrated in vacuo to provide <strong>[65340-70-7]6-bromo-4-chloro-quinoline</strong> hydrochloride as anoff-white solid (3.46 g). [0 157] To a suspension of <strong>[65340-70-7]6-bromo-4-chloro-quinoline</strong> hydrochloride (3 .46 g) inpropionitrile (100 mL) was added anhydrous sodium iodide (9.3 g, 62 mmol). The reaction was refluxed for 96 h, then cooled down tort. The mixture was treated with 10% aq. K2C03 (50 mL),followed by 5% aq. Na2S03 (20 mL), and then extracted with DCM (50 mL x 3). The combinedorganic phases were washed with brine (50 mL), dried over anhydrous Na2S04 and concentratedin vacuo to give the title compound as an off-white solid (3.4 g, 82.3%).
3.91 g
With hydrogenchloride; In ethyl acetate; at 20℃; for 0.5h;
4.1.9 6-Bromo-4-iodoquinoline (12) To a solution of <strong>[65340-70-7]<strong>[65340-70-7]6-bromo-4-chloroquinolin</strong>e</strong> (11) (3.50 g, 14.46 mmol) in anhydrous EtOAc (20 mL) was added HCl-saturated EtOAc (40 mL) and a white precipitate formed immediately. After stirring for 30 min, the suspension was concentrated under vacuum to afford <strong>[65340-70-7]<strong>[65340-70-7]6-bromo-4-chloroquinolin</strong>e</strong> hydrochloride as an off white solid (3.91 g, 14.14 mmol). A two-neck flask was charged with <strong>[65340-70-7]<strong>[65340-70-7]6-bromo-4-chloroquinolin</strong>e</strong>hydrochloride (3.91 g, 14.14 mmol), anhydrous potassium iodide(9.76 g, 70.70 mmol) and anhydrous acetonitrile (100 mL). Theresulting slurry was stirred at reflux for 48 h and allowed to cool toroom temperature. Saturated aqueous NaHCO3 solution (40 mL)was added to the mixture, followed by 20 mL of a 5% sodium sulfitesolution. The reaction mixture was extracted with CH2Cl2(200 mL 2). The combined organic extracts were dried overmagnesium sulfate and concentrated in vacuo to give the crudeproduct, which was further purified by silica gel column chromatography(25% ethyl acetate/petroleum ether) to give the titlecompound (4.42 g, 13.27 mmol, 94% yield) as an off-white solid.
With hydrogenchloride; In tetrahydrofuran; diethyl ether; for 0.5h;
Following the general procedure [43], a dry 500mL, single-neck round bottomed flask equipped with a magnetic stirring bar was charged with <strong>[65340-70-7]<strong>[65340-70-7]6-bromo-4-chloroquinolin</strong>e</strong> 4a (10.0g, 41.2mmol), and 170mL of dry THF. The solution was treated with 2N HCl in Et2O (24.7mL, 49.48mmol). A white precipitate formed immediately. After stirring for 30min, the suspension was concentrated in vacuo and dried under vacuum to provide <strong>[65340-70-7]<strong>[65340-70-7]6-bromo-4-chloroquinolin</strong>e</strong> hydrochloride as an off-white solid. A three-neck round bottom flask equipped with a reflux condenser and mechanical stirrer was charged with <strong>[65340-70-7]<strong>[65340-70-7]6-bromo-4-chloroquinolin</strong>e</strong> hydrochloride, anhydrous sodium iodide (31.0g, 206mmol) and anhydrous acetonitrile (250mL). The resulting slurry was stirred vigorously at reflux for 48h. Then the mixture was cooled to room temperature, an aqueous solution of 10% K2CO3 (500mL) was added, followed by a 200mL of a 5% sodium sulfite solution. After the mixture was extracted with CH2Cl2 (500mL×3), the combined organic layers were washed with brine, dried over anhydrous MgSO4 and the solvents were evaporated under reduced pressure to provide the title compound 6 (12.05g, 87.5% yield) as an off-white solid, which was used without further purification.
3.46 g
With hydrogenchloride; In tetrahydrofuran; diethyl ether; at 20℃; for 0.5h;
To <strong>[65340-70-7]<strong>[65340-70-7]6-bromo-4-chloroquinolin</strong>e</strong> (3g, 12.4mmol) anhydrous THF (50 ml) is added to solution 2M HCl ether solution of (7.4 ml, 14 . 8mmol). Reaction solution stirring the mixture at room temperature for 30 minutes, concentrated under reduced pressure, to obtain <strong>[65340-70-7]<strong>[65340-70-7]6-bromo-4-chloroquinolin</strong>e</strong> hydrochloride is a kind of white solid (3.46g). The <strong>[65340-70-7]<strong>[65340-70-7]6-bromo-4-chloroquinolin</strong>e</strong> hydrochloride (3.46g) suspended in propionitrile (100 ml) in, and adding anhydrous sodium iodide (9.3g, 62mmol). Reaction liquid reflux 96 hours, cooling to room temperature, and for sequentially 10% K 2 CO 3 aqueous solution (50 ml) and 5% Na 2 SO 3 aqueous solution (20 ml) treatment. The obtained mixed solution with DCM (50mLx3) extraction, the organic phase of the first combined and salt water (50 ml) to wash, anhydrous Na 2 SO 4 drying, and concentrating under reduced pressure, the title compound is a kind of white solid
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; for 2h;Reflux;
Derivatization with pyridine boronate in Suzuki coupling conditions yields 3-6
61%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; for 2h;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.
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 100℃; for 1h;
Method A-1Synthesis of intermediate 1-01To a sealed tube charged with 6-Bromo-4-chloro-quinoline I-00 (2.3 g, 9.48 mmol) in 1 ,4-dioxane (75 ml), 2-Methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-pyridin-3-yl amine (2.85 g, 1 1.38 mmol), K2C03 (aq. sol. 1 M) (40 ml) and tetrakis(triphenylphosphine)palladium(0) (1.096 g, 0.948 mmol) were added. The reaction mixture was heated at 100C for 1h. The mixture was concentrated and purified by flash chromatography in a Biotage using cyclohexane-EtOAc gradient to give intermediate 1-01 (2.2 g, Y: 81% ).
A 5 mL microwave vial was charged with 4-chloro-6-bromoquinoline (0.15 g, 0.62 mmol) and a 25 wt % solution of sodium methoxide in methanol (2.0 mL, 8.8 mmol). The vial was sealed and heated to 100C for 60 minutes under microwave irradiation (Biotage, Initiator). After cooling, the solvent was removed in vacuo, the residue washed with water, filtered and dried via .yophilization to obtain 6-bromo-4-methoxyquinoline.LRMS (ESI) calc'd for C10H9BrNO [M+H]+: 238, Found: 238.
In N,N-dimethyl-formamide; at 90℃; for 3h;Inert atmosphere;
To a suspension of <strong>[65340-70-7]<strong>[65340-70-7]6-bromo-4-chloroquinolin</strong>e</strong> (0.29 g, 1.2 mmol) in DMF (2 mL)was added 5-azaspiro[2.4]heptan-7-ol (0.34 g, 3 mmol) under N2 atmosphere. The reaction wasstirred at 90C for 3 h, then cooled tort. The mixture was diluted with CHCh (5 mL) and washedwith H20 (5 mL). The resulted solution was dried over anhydrous Na2S04 and concentrated invacuo to give the title compound as a pale yellow solid (0.33 g, 86.8%). The title compound wascharacterized by LC-MS as shown below:LC-MS (ESI, pos. ion) m/z: 319 [M+H]+.
86.8%
In N,N-dimethyl-formamide; at 90℃; for 3h;Inert atmosphere;
Under the protection of nitrogen, to the <strong>[65340-70-7]<strong>[65340-70-7]6-bromo-4-chloroquinolin</strong>e</strong> (0.29g, 1 . 2mmol) of DMF (2 ml) is added in the suspension 5-azaspiro[2.4]heptane-7-ol (0.34g, 3mmol). Reaction solution in 90 C stirring 3 hours, cooling to room temperature. Mixture plus the CHCl 3 (5 ml) dilution, and water (5 ml) for washing. The obtained solution of the anhydrous Na 2 SO 4 drying, concentrating under reduced pressure, to obtain the title compound as a yellow solid (0.33g, 86.8%).
With sodium sulfide; In N,N-dimethyl-formamide; for 2h;Inert atmosphere; Heating;
General procedure: Toa round-bottom flask with magnetic stirrer was added <strong>[65340-70-7]<strong>[65340-70-7]6-bromo-4-chloroquinolin</strong>e</strong> 16 (R1 = Br) (260 mg, 1.1 mmol) and DMF (4 mL). Sodium sulfide (100 mg, 1.3 mmol) was then added and the resulting mixture was heated to 80 C and stirred for 2 hours under an atmosphere of argon. The solution was allowed to cool to room temperature and diluted with water (50 mL). Aqueous HCl(1 M) was added to acidify the mixture and pH value was adjusted to 5~6. The obtained mixture was extracted with EtOAc (50 mL×3), and the organic layer was separated and washed with water and brine, then dried over Na2SO4, filtered, and concentrated in vacuo to give 17 (R1= Br) as an orange oil (257 mg, 97%), which was used in next step without further purification.
92.0%
With thiourea; In tetrahydrofuran; at 40℃;Large scale;
In a 200L reaction kettle, add 40 kg of tetrahydrofuran, add thiourea (1550 g) with stirring, and heat to 40 C.The compound of formula A (4.5 kg) is dissolved in 40 kg of tetrahydrofuran, mixed with a thiourea solution, and reacted.The reaction was detected to be complete by TLC. The solution was filtered and washed with tetrahydrofuran. The obtained solid was added to a tetrahydrofuran-aqueous solution of sodium hydroxide.Stir, adjust the pH value to weak acid with 2N hydrochloric acid, stir, shake and filter,It was washed with water and dried to obtain 4.10 kg of a yellow solid with a yield of 92.0% and an impurity Z content of 0.34%.
89%
With sodiumsulfide nonahydrate; In N,N-dimethyl-formamide; at 100℃;Inert atmosphere;
A mixture of <strong>[65340-70-7]<strong>[65340-70-7]6-bromo-4-chloroquinolin</strong>e</strong> (20, 7.28 g, 30 mmol)and Na2S·9H2O (14.41 g, 60 mmol) in DMF (100 mL) wasstirred at 100 C in N2 atmosphere until the completion ofreaction as indicated by TLC (typically within 5 h). On coolingto room temperature, the reaction mixture was poured intoice-water (300 mL) and the resulting mixture was acidifed(pH = 5-6) with 1M hydrochloric acid to give a yellow slurry The precipitates were collected by vacuum fltration, washedwith water (50 mL), dried in vacuo at 50C and triturated withEtOAc/n-hexane to aord 12j as a yellow solid. M.p. 198 C(dec). 6.41 g (89%). 1H NMR, delta 13.05 (brs, 1H), 8.79 (d, J =2.0 Hz, 1H), 7.86-7.89 (m, 2H), 7.63 (d, J = 8.8 Hz, 1H), 7.32(d, J = 6.8 Hz, 1H). 13C NMR, delta 191.11, 134.77, 134.70, 133.96,133.52, 130.42, 124.59, 122.01, 118.63. ESI-HR-MS, calcd. forC9H7BrNS ([M(79Br)+H]+) 239.9483, found 239.9474; calcd.for C9H7BrNS ([M(81Br)+H]+) 241.9462, found 241.9454.
257 mg
With sodium sulfide; In N,N-dimethyl-formamide; at 80℃; for 2h;
Prepared by the well-known method disclosed in <strong>[65340-70-7]<strong>[65340-70-7]6-bromo-4-chloroquinolin</strong>e</strong> 3a (260 mg, 1.1 mmol, Bioorganic & Medicinal Chemistry Letters, 2012, 22 (4), 1569-1574) Sodium sulfide (100 mg, 1.3 mmol) was added to 4 mL of N, N-dimethylformamide. Upon completion of the addition, the reaction solution was heated to 80 DEG C and stirred for 2 hours. 50 ml of water was added to the reaction solution, the pH was adjusted to 5 to 6 by adding dropwise 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate (50 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 6-bromoquinoline-4-thiol 3b (257 mg, yellow oil) which was used directly in the next step.
257 mg
With sodium sulfide; In N,N-dimethyl-formamide; at 80℃; for 2h;
<strong>[65340-70-7]<strong>[65340-70-7]6-bromo-4-chloroquinolin</strong>e</strong> 3a (260 mg, 1.1 mmol, prepared by a well known method disclosed in "Bioorganic & Medicinal Chemistry Letters, 2012, 22(4), 1569-1574") and sodium sulphide (100 mg, 1.3 mmol) were added to 4 mL of N,N-dimethylformamide. Upon completion of the addition, the reaction solution was heated to 80 C. and stirred for 2 hours. The reaction solution was mixed with 50 mL of water, added dropwise with 1 M hydrochloric acid to adjust the pH to 5?6, and extracted with ethyl acetate (50 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound 6-bromoquinoline-4-thiol 3b (257 mg, a yellow oil), which was used directly in the next step.
N-(5-(4-chloroquinolin-6-yl)-2-methoxypyridin-3-yl)-4-fluorobenzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
35%
General procedure: A mixture of <strong>[65340-70-7]<strong>[65340-70-7]6-bromo-4-chloroquinolin</strong>e</strong> (2.00 g, 8.25 mmol),bis(pinacolato)diboron (2.11 g, 8.25 mmol), Pd(dppf)Cl2-CH2Cl2(0.34 g, 0.40 mmol) and potassium acetate (1.62 g, 16.50 mmol)in anhydrous 1,4-dioxane (30 mL) was heated at 100 C underargon for 3 h. The resulting mixture was added corresponding 5(8.25 mmol), 2.0 M aqueous Na2CO3 (10 mL) and another portionof Pd(dppf)Cl2-CH2Cl2 (0.34 g, 0.40 mmol), then the mixture washeated at 110 C for 20 h under argon. The reaction mixture wascooled to room temperature, filtered, and concentrated. The mixturewas purified by MPLC (ISCO CombiFlash purification system)(MeOH/DCM, eluted from 0% to 8%). The fractions were collected,concentrated to afford 6a
ethyl 1-((6-bromoquinolin-4-yl)thio)cyclopentanecarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
37%
<strong>[65340-70-7]<strong>[65340-70-7]6-bromo-4-chloroquinolin</strong>e</strong> 3a (203 mg, 0.84 mmol, prepared by a well known method disclosed in ?Bioorganic&Medicinal Chemistry Letters,2012, 22 (4), 1569-1574?) was added to 10 mL of N,N-dimethylformamide. Sodium sulfide (88 mg. 1.00 mmol) was grinded and added to the reaction solution. Upon completion of the addition, the reaction solution was heated to 80 C. and stirred for 2 hours. After stopping heating, the reaction solution was cooled down to 50 C., ethyl 1-bromocyclopentanecarboxylate (241 mg, 1.09 mmol) and cesium carbonate (821 mg, 2.52 mmol) were added. Upon completion of the addition, the reaction solution was stirred for a further 16 hours at 40 C. After stopping heating, the reaction solution was mixed with 30 mL of dichloromethane, stirred uniformly, filtered through celite after, and washed with dichloromethane. The filtrate was combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system A to obtain the title compound ethyl 1-((6-bromoquinolin-4-yl)thio)cyclopentanecarboxylate 32a (118 mg, a purple oil), yield: 37.0%.
ethyl 2-((6-bromoquinolin-4-yl)thio)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
<strong>[65340-70-7]<strong>[65340-70-7]6-bromo-4-chloroquinolin</strong>e</strong> 3a (628 mg, 2.59 mmol, prepared by a well known method disclosed in ?Bioorganic&Medicinal Chemistry Letters, 2012, 22 (4), 1569-1574?) was added to 20 mL of N,N-dimethylformamide. Sodium sulfide (242 mg, 3.11 mmol) was grinded and added to the reaction solution. Upon completion of the addition, the reaction solution was heated to 80 C. and stirred for 1 hour. After stopping heating, the reaction solution was cooled down to 50 C., and ethyl bromoacetate (563 mg, 3.37 mmol) and cesium carbonate (2.53 g, 7.77 mmol) were added. Upon completion of the addition, the reaction solution was stirred for a further 6 hours at 40 C. After stopping heating, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent systems A to obtain the title compound ethyl 2-((6-bromoquinolin-4-yl)thio)acetate 33a (658 mg, a yellow solid), yield: 78%.
With acetamide; potassium carbonate; at 180℃; for 5.0h;
A reaction flask with a stir bar was charged with 6-bromo-4-chloroquinoline 17 (500mg, 2.1mmol), acetamide (2.438g, 41.3mmol), and K2CO3 (1.449g, 10.5mmol). The mixture was heated to 180 C for 5 h and was allowed to cool to ambient temperature followed by adding water (50ml). The solution was extracted with ethyl acetate (20ml × 3), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (DCM:MeOH=20:1) to provide 6-bromoquinolin-4-amine 18 (198mg, yield = 43%).1H NMR (400 MHz, DMSO-d6) delta 8.46 (d, J = 2.2 Hz, 1H), 8.25 (d, J = 7.2 Hz, 1H), 7.95 (dd, J = 8.9, 2.3 Hz, 1H), 7.69 (d, J = 8.9 Hz, 1H), 7.12 (d, J = 7.2 Hz, 1H), 5.64 (s, 2H). LC-MS (ESI) m/z = 223.1, 225.1 (M+H, M+2+H).
6-bromo-N-(3-chlorobenzyl)quinolin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68.5%
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 150℃; for 1h;Microwave irradiation; Sealed tube;
In a microwave tube was placed <strong>[65340-70-7]<strong>[65340-70-7]6-bromo-4-chloroquinolin</strong>e</strong> (242 mg, 1 mmol), (3- chlorophenyl)methanamine (283 mg, 2.0 mmol), DMSO (1 ml), and Hunig?s Base (0.349 ml, 2.0 mmol). The tube was sealed and heated at 150 00 for 1 h under microwave irradiation. The mixture was poured into EtOAc/H20 (30 mL/30 mL). The organic layer was washed with H20 (30 mL), dried (Na2504), and filtered. After removal of solvent, the product was triturated with 2% CH2CI2/hexane and then dried to give 6-bromo-N-(3-chlorobenzyl)quinolin-4-amine (238 mg,0.685 mmol, 68.5 % yield). MS (M+H)= 349.
6-bromo-N-(1-methylpiperidin-4-yl)quinoline-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 120 - 150℃; for 64h;Microwave irradiation;
General procedure: A solution of 4-chloro-6-[1-(4-methylbenzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]quinoline (Intermediate 4) (0.15 g, 0.35 mmol, 1.0 eq.), (S)-3-(Boc-amino)piperidine (0.14 g, 0.7 mmol, 2.0 eq.), DIPEA (0.09 g, 0.7 mmol, 2.0 eq.) in i-PrOH (3 mL) was heated at 140 C. under microwave irradiation for 1.5 h. After cooling to rt, solvent was evaporated and the crude reaction mixture was used in consecutive step without further purification (UPLC purity: 71%).
4-chloro-6-[1-(4-methylbenzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]quinoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.3 g
Stage #1: 3-bromo-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; bis(pinacol)diborane In 1,4-dioxane at 85℃; Inert atmosphere; Sealed tube;
Stage #2: With water In ethyl acetate
Stage #3: 6-bromo-4-chloroquinoline With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,4-dioxane; water at 120℃; for 0.416667h; Inert atmosphere; Microwave irradiation;
4-Chloro-6-[1-(4-methylbenzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]quinoline
4-Chloro-6-[1-(4-methylbenzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]quinoline A sealed tube was charged with 1-(4-methylbenzenesulfonyl)-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (Intermediate 1) (0.45 g, 1.1 mmol, 1.0 eq.), 6-bromo-4-chloroquinoline (0.3 g, 1.1 mmol, 1.0 eq.), potassium carbonate (0.42 g, 3.0 mmol, 2.7 eq.) in a mixture of 1,4-dioxane/water 2/1 (1.5 mL) under argon. The mixture was sonicated under a stream of argon before Pd(PPh3)4 (0.04 g, 0.03 mmol, 0.03 eq.) was added. The reaction mixture was heated at 120° C. under microwave irradiation for 25 min. Then it was cooled and filtered through Celite, washed with EtOAc and the filtrate was concentrated. The crude product mixture was purified by flash column chromatography (EtOAc gradient in hexane followed by MeOH gradient in EtOAc) to provide 4-chloro-6-[1-(4-methylbenzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]quinoline (0.3 g; yield: 61%, UPLC purity: 100%).
4-(N-(4-morpholinoethyl))amino-6-bromoquinoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83.6%
at 130℃; for 5h;Inert atmosphere;
The compound <strong>[65340-70-7]4-chloro-6-bromoquinoline</strong> (600 mg, 2.47 mmol) was weighed.N-(2-Aminoethyl)morpholine (0.97 mL, 7.41 mmol), NMP 10 mL.Argon protection, reaction at 130 C for 5 h.Cool to room temperature, add water, extract EA 3 times,Column chromatography gave a yellow solid 15-b (690.1 mg, yield: 83.6%).
83%
In 1-methyl-pyrrolidin-2-one; at 130℃; for 5h;
The mixture of <strong>[65340-70-7]4-chloro-6-bromoquinoline</strong> (600 mg, 2.47 mmol), 2-morpholinoethan-1-amine (0.97 mL, 7.41 mmol) and NMP (5 mL) washeated at 130 C for 5 h and then cooled to room temperature. Addedsaturated NaHCO3 solution to the mixture, extracted with ethyl acetatethree times, and separated by column chromatography to obtain690.5 mg of light brown solid. Yield 83%. mp: 109.3-112.4 C; 1H NMR(CDCl3) delta 8.57 (d, J=5.3 Hz, 1H, Ar-H), 7.91 (dd, J=10.1, 5.4 Hz,2H, Ar-H), 7.73 (dd, J=9.0, 2.0 Hz, 1H, Ar-H), 6.44 (d, J=5.4 Hz, 1H,Ar-H), 5.91 (s, 1H, NH), 3.90-3.75 (m, 4H, CH2×2), 3.36 (dd,J=10.8, 5.2 Hz, 2H, CH2), 2.82 (t, J=5.9 Hz, 2H, CH2), 2.58 (s, 4H,CH2×2); ESI-MS m/z: 335.8/337.8 [M+H]+.
ethyl 2-((6-bromoquinolin-4-yl)thio)-2-methylpropanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
To a 100 mL reaction bottle, were added <strong>[65340-70-7]<strong>[65340-70-7]6-bromo-4-chloroquinolin</strong>e</strong> (2.42 g, 10 mmol), sodium sulfide (1.17 g, 15 mmol), and N-methylpyrrolidone (30 mL), and the mixture was heated to 120 C and allowed to react for 2 hours, to which were then added Cs2CO3 (6.52 g, 20 mmol) and ethyl 2-bromo-2-methylpropanoate (2.15 g, 11 mmol). The mixture continued reacting at 100 C for 2 hours. After completion of reaction, water (150 mL) was added, and the reaction mixture was extracted with ethyl acetate thrice (3*100 mL). The organic layers were combined, washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated by rotatory evaperator. The residue was purified by column chromatography to afford Int 2 (2.1g, yield 60%), MS: 354, 356 (M+H+).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 110℃; for 2h;Inert atmosphere;
To a 50 mL reaction bottle, were added Int. 3 (241 mg, 1 mmol), 2-methoxyphenylboronic acid (152 mg, 1mmol), Na2CO3 (212 mg, 2 mmol), Pd(dppf)Cl2 (37 mg, 0.05 mmol), dioxane (6mL), and water (3mL), and then nitrogenwas purged. The mixture was heated to 110 C under protection of N2 and allowed to react for 2 hours. After completionof reaction, water (50 mL) was added, and the mixture was extracted with ethyl acetate (3 3 50 ml) thrice. The organiclayers were combined, washed with saturated brine, dried over anhydrous Na2SO4, filtered, and rotatory evaporated.The residue was purified by column chromatography to afford Int. 4 (190 mg, yield 50%). MS: 270.0, 272.0 (M+H+).
With potassium carbonate; In N,N-dimethyl-formamide; at 105℃; for 16h;
A mixture of <strong>[65340-70-7]6-bromo-4-chloro-quinoline</strong> (25 g, 1.0 equiv), DMF (6.0 vol), 4-(tert-butoxy carbonylamino)piperidine (2.0 equiv), K2CO3 (2.5 equiv), was stirred and heated to 105 C. for 16 h. Reaction was monitored by IPC-HPLC and showed 93.5% of Compound 4 and 0.12% of Compound 3. Then reaction mixture was cooled to 25-30 C., added with purified water (30 vol), and stirred for 2 h. Solid was filtered and washed with purified water. The crude solid was slurred with n-heptane (5 vol), filtered, and washed with n-heptane (2 vol). The solid was dried at 55 C. provided desired product Compound 4 (35.3 g, 84% yield). 1H NMR (400 MHz, DMSO-d6): delta 8.69 (d, 1H), 8.02 (d, 1H), 7.88 (m, 1H), 7.80 (m, 1H), 7.02 (d, 1H), 6.97 (d, 1H), 3.44 (m, 3H), 2.87 (m, 2H), 1.94 (d, 2H), 1.68 (m, 2H), 1.38 (s, 9H).
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 20℃;
General procedure: A mixture of heteroaryl N-oxide (0.4mmol), AgSCF3 (166.3mg, 0.8mmol), Ts2O (195.8mg, 0.6mmol), and n-Bu4NI (295.5mg, 0.8mmol) was added in a 25mL Schlenk tube, and then THF (4.0mL) was added. The mixture was stirred at room temperature for 4h. After the reaction was complete, saturated NH4Cl solution was added. The resulting mixture was extracted with EtOAc for three times. The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA=100:1) to give the desired product (2a-2w).f
6-[(6-bromoquinolin-4-yl)amino]-2,3-dihydro-1H-isoindol-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
In ethanol; for 18.0h;Reflux; Inert atmosphere;
General procedure: 6-Bromo-4-chloroquinoline (1.0 equiv.) and 3,4,5-trimethoxyaniline (1.1 equiv.) were suspended in ethanol (10 mL) and refluxed for 18 h. The crude mixture was purified by flash chromatography using EtOAc:hexane followed by 1-5% methanol in EtOAc, solvent was removed under reduced pressure to afford the desired product (1, 8-11, 13-31, and 33-43).
5-[(6-bromoquinolin-4-yl)amino]-2,3-dihydro-1H-1,3-benzodiazol-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
In ethanol; for 18h;Reflux; Inert atmosphere;
General procedure: 6-Bromo-4-chloroquinoline (1.0 equiv.) and 3,4,5-trimethoxyaniline (1.1 equiv.) were suspended in ethanol (10 mL) and refluxed for 18 h. The crude mixture was purified by flash chromatography using EtOAc:hexane followed by 1-5% methanol in EtOAc, solvent was removed under reduced pressure to afford the desired product (1, 8-11, 13-31, and 33-43).
6-[(6-bromoquinolin-4-yl)amino]-2,3-dihydro-1,3-benzoxazol-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
In ethanol for 18h; Reflux; Inert atmosphere;
4.3.2. General Procedure for the Synthesis of 4-anilinoquinolines (Scheme 1)
General procedure: 6-Bromo-4-chloroquinoline (1.0 equiv.) and 3,4,5-trimethoxyaniline (1.1 equiv.) were suspended in ethanol (10 mL) and refluxed for 18 h. The crude mixture was purified by flash chromatography using EtOAc:hexane followed by 1-5% methanol in EtOAc, solvent was removed under reduced pressure to afford the desired product (1, 8-11, 13-31, and 33-43).
5-[(6-bromoquinolin-4-yl)amino]-2,3-dihydro-1,3-benzoxazol-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
In ethanol; for 18h;Reflux; Inert atmosphere;
General procedure: 6-Bromo-4-chloroquinoline (1.0 equiv.) and 3,4,5-trimethoxyaniline (1.1 equiv.) were suspended in ethanol (10 mL) and refluxed for 18 h. The crude mixture was purified by flash chromatography using EtOAc:hexane followed by 1-5% methanol in EtOAc, solvent was removed under reduced pressure to afford the desired product (1, 8-11, 13-31, and 33-43).
5-((6-bromoquinolin-4-yl)amino)-1,3-dihydrobenzo[c]thiophene 2,2-dioxide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
In ethanol; for 18.0h;Reflux; Inert atmosphere;
General procedure: 6-Bromo-4-chloroquinoline (1.0 equiv.) and 3,4,5-trimethoxyaniline (1.1 equiv.) were suspended in ethanol (10 mL) and refluxed for 18 h. The crude mixture was purified by flash chromatography using EtOAc:hexane followed by 1-5% methanol in EtOAc, solvent was removed under reduced pressure to afford the desired product (1, 8-11, 13-31, and 33-43).
N-(benzo[d][1,3]dioxol-4-yl)-6-bromoquinolin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
In ethanol; for 18h;Reflux; Inert atmosphere;
General procedure: 6-Bromo-4-chloroquinoline (1.0 equiv.) and 3,4,5-trimethoxyaniline (1.1 equiv.) were suspended in ethanol (10 mL) and refluxed for 18 h. The crude mixture was purified by flash chromatography using EtOAc:hexane followed by 1-5% methanol in EtOAc, solvent was removed under reduced pressure to afford the desired product (1, 8-11, 13-31, and 33-43).
6-bromo-N-(2,5-difluorophenyl)quinolin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
In ethanol; for 18h;Reflux; Inert atmosphere;
General procedure: 6-Bromo-4-chloroquinoline (1.0 equiv.) and 3,4,5-trimethoxyaniline (1.1 equiv.) were suspended in ethanol (10 mL) and refluxed for 18 h. The crude mixture was purified by flash chromatography using EtOAc:hexane followed by 1-5% methanol in EtOAc, solvent was removed under reduced pressure to afford the desired product (1, 8-11, 13-31, and 33-43).
6-bromo-N-(5-fluorobenzo[d][1,3]dioxol-4-yl)quinolin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
In ethanol; for 18.0h;Reflux; Inert atmosphere;
General procedure: 6-Bromo-4-chloroquinoline (1.0 equiv.) and 3,4,5-trimethoxyaniline (1.1 equiv.) were suspended in ethanol (10 mL) and refluxed for 18 h. The crude mixture was purified by flash chromatography using EtOAc:hexane followed by 1-5% methanol in EtOAc, solvent was removed under reduced pressure to afford the desired product (1, 8-11, 13-31, and 33-43).
In ethanol; at 85.0℃; for 18.0h;
General procedure: 4-chloroquin(az)oline derivative (1.0eq.), aniline derivative (1.1 eq.), were suspended in ethanol (10 mL) and refluxed for 18 h. The crudemixture was purified by flash chromatography using EtOAc:hexane followed by 1-5 % methanol in EtOAc; After solvent removal under reduced pressure, the product was obtained as a free following solid or recrystallized from ethanol/water. Compounds 4-31 were synthesized as previous described[38, 48], 32-51 were synthesized as previous described [42]. Representative supporting information provided.
6-bromo-N-(2,3-dimethoxyphenyl)quinolin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
In ethanol; for 18h;Reflux; Inert atmosphere;
General procedure: 6-Bromo-4-chloroquinoline (1.0 equiv.) and 3,4,5-trimethoxyaniline (1.1 equiv.) were suspended in ethanol (10 mL) and refluxed for 18 h. The crude mixture was purified by flash chromatography using EtOAc:hexane followed by 1-5% methanol in EtOAc, solvent was removed under reduced pressure to afford the desired product (1, 8-11, 13-31, and 33-43).
In ethanol; at 85℃; for 18h;
General procedure: 4-chloroquin(az)oline derivative (1.0eq.), aniline derivative (1.1 eq.), were suspended in ethanol (10 mL) and refluxed for 18 h. The crudemixture was purified by flash chromatography using EtOAc:hexane followed by 1-5 % methanol in EtOAc; After solvent removal under reduced pressure, the product was obtained as a free following solid or recrystallized from ethanol/water. Compounds 4-31 were synthesized as previous described[38, 48], 32-51 were synthesized as previous described [42]. Representative supporting information provided.
6-bromo-N-(2,2-difluorobenzo[d][1,3]dioxol-4-yl)quinolin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
In ethanol; for 18h;Reflux; Inert atmosphere;
General procedure: 6-Bromo-4-chloroquinoline (1.0 equiv.) and 3,4,5-trimethoxyaniline (1.1 equiv.) were suspended in ethanol (10 mL) and refluxed for 18 h. The crude mixture was purified by flash chromatography using EtOAc:hexane followed by 1-5% methanol in EtOAc, solvent was removed under reduced pressure to afford the desired product (1, 8-11, 13-31, and 33-43).
6-bromo-N-(2,3-dihydrobenzofuran-4-yl)quinolin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
64%
In ethanol; for 18h;Reflux; Inert atmosphere;
General procedure: 6-Bromo-4-chloroquinoline (1.0 equiv.) and 3,4,5-trimethoxyaniline (1.1 equiv.) were suspended in ethanol (10 mL) and refluxed for 18 h. The crude mixture was purified by flash chromatography using EtOAc:hexane followed by 1-5% methanol in EtOAc, solvent was removed under reduced pressure to afford the desired product (1, 8-11, 13-31, and 33-43).
6-bromo-N-(2,3-dihydrobenzofuran-7-yl)quinolin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
In ethanol; for 18.0h;Reflux; Inert atmosphere;
General procedure: 6-Bromo-4-chloroquinoline (1.0 equiv.) and 3,4,5-trimethoxyaniline (1.1 equiv.) were suspended in ethanol (10 mL) and refluxed for 18 h. The crude mixture was purified by flash chromatography using EtOAc:hexane followed by 1-5% methanol in EtOAc, solvent was removed under reduced pressure to afford the desired product (1, 8-11, 13-31, and 33-43).
N-(6-bromoquinolin-4-yl)benzo[d]oxazol-7-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
31%
In ethanol; for 18.0h;Reflux; Inert atmosphere;
General procedure: 6-Bromo-4-chloroquinoline (1.0 equiv.) and 3,4,5-trimethoxyaniline (1.1 equiv.) were suspended in ethanol (10 mL) and refluxed for 18 h. The crude mixture was purified by flash chromatography using EtOAc:hexane followed by 1-5% methanol in EtOAc, solvent was removed under reduced pressure to afford the desired product (1, 8-11, 13-31, and 33-43).
N-(6-bromoquinolin-4-yl)benzo[d]thiazol-7-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
38%
In ethanol; for 18h;Reflux; Inert atmosphere;
General procedure: 6-Bromo-4-chloroquinoline (1.0 equiv.) and 3,4,5-trimethoxyaniline (1.1 equiv.) were suspended in ethanol (10 mL) and refluxed for 18 h. The crude mixture was purified by flash chromatography using EtOAc:hexane followed by 1-5% methanol in EtOAc, solvent was removed under reduced pressure to afford the desired product (1, 8-11, 13-31, and 33-43).
N-(6-bromoquinolin-4-yl)benzo[d]thiazol-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
In ethanol; for 18.0h;Reflux; Inert atmosphere;
General procedure: 6-Bromo-4-chloroquinoline (1.0 equiv.) and 3,4,5-trimethoxyaniline (1.1 equiv.) were suspended in ethanol (10 mL) and refluxed for 18 h. The crude mixture was purified by flash chromatography using EtOAc:hexane followed by 1-5% methanol in EtOAc, solvent was removed under reduced pressure to afford the desired product (1, 8-11, 13-31, and 33-43).
N-(6-bromoquinolin-4-yl)benzo[c][1,2,5]thiadiazol-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
In ethanol for 18h; Reflux; Inert atmosphere;
4.3.2. General Procedure for the Synthesis of 4-anilinoquinolines (Scheme 1)
General procedure: 6-Bromo-4-chloroquinoline (1.0 equiv.) and 3,4,5-trimethoxyaniline (1.1 equiv.) were suspended in ethanol (10 mL) and refluxed for 18 h. The crude mixture was purified by flash chromatography using EtOAc:hexane followed by 1-5% methanol in EtOAc, solvent was removed under reduced pressure to afford the desired product (1, 8-11, 13-31, and 33-43).
In ethanol at 85℃; for 18h;
General procedure for the synthesis of 4-anilinoquin(az)olines:
General procedure: 4-chloroquin(az)oline derivative (1.0eq.), aniline derivative (1.1 eq.), were suspended in ethanol (10 mL) and refluxed for 18 h. The crudemixture was purified by flash chromatography using EtOAc:hexane followed by 1-5 % methanol in EtOAc; After solvent removal under reduced pressure, the product was obtained as a free following solid or recrystallized from ethanol/water. Compounds 4-31 were synthesized as previous described[38, 48], 32-51 were synthesized as previous described [42]. Representative supporting information provided.
6-bromo-N-(1-methyl-1H-indazol-4-yl)quinolin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
In ethanol; for 18h;Reflux; Inert atmosphere;
General procedure: 6-Bromo-4-chloroquinoline (1.0 equiv.) and 3,4,5-trimethoxyaniline (1.1 equiv.) were suspended in ethanol (10 mL) and refluxed for 18 h. The crude mixture was purified by flash chromatography using EtOAc:hexane followed by 1-5% methanol in EtOAc, solvent was removed under reduced pressure to afford the desired product (1, 8-11, 13-31, and 33-43).
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