* 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.
Step 1 : A stirred solution of 6-bromoquinolin-2(1 /-/)-one (1.0 g, 4.4 mmol, 1.0 equiv) in phosphorous oxychloride (15 mL) was heated to 100°C for 15 h. The solvent was completely evaporated and water was added to the residue. The precipitated solid was filtered and dried under vacuum to obtain 6-bromo-2-chloroquinoline (1.0 g, 92 percent) as pink solid. LCMS (ES) m/z = 241.0, 243.0 [M+H]+. H NMR (400 MHz, DMSO-d6) δ ppm 7.41 (d, J = 8.4 Hz, 1 H), 7.79 - 7.82 (m, 1 H), 7.89 (d, J = 9.2 Hz, 1 H), 7.98 - 7.99 (m, 1 H), 8.02 (d, J = 8.8 Hz, 1 H).
85%
Stage #1: for 1 h; Heating / reflux
6-Bromo-2-chloroquinoline. The solution of the compound from Example 6 b)(3.Og, 13 mmol) in POCI3 (25 ml_) was refluxed for an hour. The mixture was cooled to the ambient temperature and quenched with ice water. The precipitate was filtered, washed with water and dried in vacuo to afford the title compound as a yellow solid. (2.7 g, 85percent). 1 H NMR (400 MHz, CHLOROFORM-of) δ ppm 8.06 (d, J=8.34 Hz, 1 H) 8.02 (d, J=2.02 Hz, 1 H) 7.93 (d, J=9.09 Hz, 1 H) 7.84(dd, J=9.09, 2.27 Hz, 1 H) 7.44 (d, J=8.59 Hz, 1 H).
80%
for 1 h; Heating / reflux
Part C. Preparation of 6-bromo-2-chloroquinoline.; [00795] To phosphorus oxychloride (2.5ml, 26.8mmol) was added, in portions, the product from Part B(200mg, 0.893mmol). Refluxed for Ih, cooled to room temperature and poured onto crushed ice.Extracted with CHCl3, extracts combined, dried overmgSO4, filtered and concentrated under vacuum to give the title compound (173mg, 80percent).
80%
for 1 h; Heating / reflux
[00537] Part C. Preparation of -bromo-^-chloroquinoline.; [00538] To phosphorus oxychloride (2.5ml, 26.8mmol) was added, in portions, the product from Part B(200mg, 0.893mmol). Refluxed for Ih, cooled to room temperature and poured onto crushed ice.Extracted with CHCI3, extracts combined, dried overmgSO,), filtered and concentrated under vacuum to give the title compound (173mg, 80percent).
67%
at 60 - 100℃;
Example A4; a. Preparation of intermediate 5; A mixture of 6-bromo-2 (lH)-quinolinone (0.089 mol) in POC13 (55 ml) was stirred at 60°C overnight, then at 100°C for 3 hours and the solvent was evaporated. The residue was taken up in CH2Cl2, poured out into ice water, basified with NHaOH concentrated, filtered over celite and extracted with CH2C12. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. Yield: 14. 5g of intermediate 5 (67percent).
67%
Stage #1: at 60 - 100℃; Stage #2: With ammonia In dichloromethane; water at 0℃;
A mixture of 6-bromo-2(7H)-quinolinone (0.089 mol) in POCl3 (55 ml) was stirred at 60°C overnight, then at 100°C for 3 hours and the solvent was evaporated. The residue EPO <DP n="39"/>was taken up in CH2CI2, poured out into ice water, basified with NH4OH concentrated, filtered over celite and extracted with CH2CI2. The organic layer was separated, dried(MgSO4), filtered and the solvent was evaporated. Yield: 14.5g of intermediate 5(67percent).
Reference：
[1] Patent: WO2017/46739, 2017, A1, . Location in patent: Page/Page column 78
[2] Journal of the American Chemical Society, 2016, vol. 138, # 25, p. 7808 - 7811
[3] Patent: WO2006/132739, 2006, A2, . Location in patent: Page/Page column 36
[4] European Journal of Medicinal Chemistry, 2000, vol. 35, # 10, p. 931 - 940
[5] Patent: WO2009/39127, 2009, A1, . Location in patent: Page/Page column 181
[6] Patent: WO2009/39134, 2009, A1, . Location in patent: Page/Page column 110
[7] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 22, p. 5907 - 5912
[8] Patent: WO2005/75428, 2005, A1, . Location in patent: Page/Page column 31-32
[9] Patent: WO2007/14941, 2007, A2, . Location in patent: Page/Page column 36-37
[10] Journal of Medicinal Chemistry, 1988, vol. 31, # 10, p. 2048 - 2056
[11] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 18, p. 2753 - 2758
[12] Patent: WO2004/24731, 2004, A1, . Location in patent: Page 50
[13] Chemical and Pharmaceutical Bulletin, 2014, vol. 62, # 6, p. 508 - 518
[14] Patent: WO2015/96035, 2015, A1, . Location in patent: Page/Page column 53; 54
[15] Patent: WO2015/100147, 2015, A1, . Location in patent: Page/Page column 54
2
[ 6563-11-7 ]
[ 1810-71-5 ]
Yield
Reaction Conditions
Operation in experiment
76%
With trichlorophosphate In dichloromethane; N,N-dimethyl-formamide at 0 - 25℃; Inert atmosphere
General procedure: To a stirred solution of the appropriate azine N-oxides in anhydrous CH2Cl2 (0.1M) at 0 °C is added POCl3 (1.2 equiv) followed by dropwise addition of DMF (0.5 equiv) under argon. The resulting reaction mixture was warmed to 25 °C and stirred for several hours until the reaction is complete as indicated by TLC. Saturated aqueous sodium carbonate solution is added to the reaction mixture slowly to adjust the pH to 7~8. The resulting mixture is separated and the aqueous phase is extracted with CH2Cl2 thoroughly. The organic phase is combined and washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product, which is purified by flash column chromatography using PE/EA (80:1) as eluent.
30.1%
for 6 h; Reflux
A solution of 6-bromoquinoline N-oxide (15.4 g, 68.75 mmol) in SOCIi (100 ml) was heated to refluxed for 6h and was cooled to R.T. SOCI2 was removed in vacuo, to the residue was added water (100 ml) and DCM (200 ml). The organic layer was separated, washed with brine, dried over Νa2SO4> and filtered. The filtrate was evaporated to give 2-chloro-6-bromoquinoline (7.8 g, 30.1percent).
Reference：
[1] European Journal of Organic Chemistry, 2016, vol. 2016, # 8, p. 1606 - 1611
[2] Tetrahedron Letters, 2014, vol. 55, # 51, p. 7130 - 7132
[3] Patent: WO2009/155527, 2009, A2, . Location in patent: Page/Page column 132
3
[ 106-40-1 ]
[ 1810-71-5 ]
Reference：
[1] European Journal of Medicinal Chemistry, 2000, vol. 35, # 10, p. 931 - 940
[2] Patent: US6034093, 2000, A,
[3] Patent: US5731315, 1998, A,
[4] Patent: WO2006/132739, 2006, A2,
4
[ 3279-90-1 ]
[ 1810-71-5 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 14, p. 1559 - 1562
5
[ 5332-25-2 ]
[ 1810-71-5 ]
Reference：
[1] European Journal of Organic Chemistry, 2016, vol. 2016, # 8, p. 1606 - 1611
[2] Patent: WO2009/155527, 2009, A2,
6
[ 327058-51-5 ]
[ 1810-71-5 ]
Reference：
[1] European Journal of Medicinal Chemistry, 2000, vol. 35, # 10, p. 931 - 940
[2] Chemical and Pharmaceutical Bulletin, 2014, vol. 62, # 6, p. 508 - 518
[3] Patent: WO2006/132739, 2006, A2,
7
[ 66416-72-6 ]
[ 1810-71-5 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 22, p. 5907 - 5912
8
[ 71205-21-5 ]
[ 1810-71-5 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 22, p. 5907 - 5912
9
[ 553-03-7 ]
[ 1810-71-5 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 14, p. 1559 - 1562
10
[ 54934-81-5 ]
[ 1810-71-5 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 18, p. 2753 - 2758
11
[ 1810-66-8 ]
[ 1810-71-5 ]
Reference：
[1] Journal of Medicinal Chemistry, 2011, vol. 54, # 16, p. 5836 - 5857
2-Chloro-6-bromo-quinoline (142.5 g, 0.6 mol; European Journal of Medicinal Chemistry, 35(10), 931-940; 2000; colourless crystals m.p.: 99.8-101.40C) was dissolved in methanol (700 mL), then sodium methoxide (43.9 g; 0.8 mmol) was added and the resulting reaction mixture was refluxed for 16 hours. The reaction mixture was cooled at r.t. and poured in ice-water (1.8 L), the titled product precipitated as a cream solid (133 g, 95%), melting at 157.9-161.1°C. C10H8BrNO2, MW: 238.09. MS (ESI) m/z: 239 (M+l). 1H-NMR (200 MHz, CDCl3) ppm: 4.06 (s, 3H), 6.91 (d, IH), 7.64-7.75 (m, 2H), 7.88 (d, 2H).
92%
In methanol at 90℃; Inert atmosphere;
General Procedure for Preparing 2-Substituted-6-bromoquinolines (10a-e)
General procedure: A mixture of 6-bromo-2-chloroquinoline 9 (2.50 mmol) and amines (for 10a-e) or sodium methoxide in MeOH (for 10g) was stirred at 90 °C on an oil bath for 6-40 h. The reaction was quenched by excessive water andthe resulting solution was extracted with EtOAc. The organic layer was separated, dried over MgSO4, and filtered. The solvent was removed under reduced pressure to give the crude product, which was purified by column chromatography over silica gel (CH2Cl2-MeOH) to afford 2-aminoquinoline 10a-g.
76%
In methanol for 16h; Heating;
In methanol at 50℃; for 16h;
170
6-Bromo-2-chioroquinoline (200 mg, 0.8 mmol) and 25% methanolic NaOMe (2 mE) were heated at 50°C. for 16 hours. Extraction from water into EtOAc and drying on Na2SO4 gave the crude ether. This was converted, via Methods 3 and 5, to compound 202(110mg, 6 6%). [M-H]=202. 1 mlz. Activity: B
Step 1 : A stirred solution of 6-bromoquinolin-2(1 /-/)-one (1.0 g, 4.4 mmol, 1.0 equiv) in phosphorous oxychloride (15 mL) was heated to 100C for 15 h. The solvent was completely evaporated and water was added to the residue. The precipitated solid was filtered and dried under vacuum to obtain 6-bromo-2-chloroquinoline (1.0 g, 92 %) as pink solid. LCMS (ES) m/z = 241.0, 243.0 [M+H]+. H NMR (400 MHz, DMSO-d6) delta ppm 7.41 (d, J = 8.4 Hz, 1 H), 7.79 - 7.82 (m, 1 H), 7.89 (d, J = 9.2 Hz, 1 H), 7.98 - 7.99 (m, 1 H), 8.02 (d, J = 8.8 Hz, 1 H).
85%
6-Bromo-2-chloroquinoline. The solution of the compound from Example 6 b)(3.Og, 13 mmol) in POCI3 (25 ml_) was refluxed for an hour. The mixture was cooled to the ambient temperature and quenched with ice water. The precipitate was filtered, washed with water and dried in vacuo to afford the title compound as a yellow solid. (2.7 g, 85%). 1 H NMR (400 MHz, CHLOROFORM-of) delta ppm 8.06 (d, J=8.34 Hz, 1 H) 8.02 (d, J=2.02 Hz, 1 H) 7.93 (d, J=9.09 Hz, 1 H) 7.84(dd, J=9.09, 2.27 Hz, 1 H) 7.44 (d, J=8.59 Hz, 1 H).
80%
With trichlorophosphate; for 1h;Heating / reflux;
Part C. Preparation of 6-bromo-2-chloroquinoline.; [00795] To phosphorus oxychloride (2.5ml, 26.8mmol) was added, in portions, the product from Part B(200mg, 0.893mmol). Refluxed for Ih, cooled to room temperature and poured onto crushed ice.Extracted with CHCl3, extracts combined, dried overmgSO4, filtered and concentrated under vacuum to give the title compound (173mg, 80%).
80%
With trichlorophosphate; for 1h;Heating / reflux;
[00537] Part C. Preparation of -bromo-^-chloroquinoline.; [00538] To phosphorus oxychloride (2.5ml, 26.8mmol) was added, in portions, the product from Part B(200mg, 0.893mmol). Refluxed for Ih, cooled to room temperature and poured onto crushed ice.Extracted with CHCI3, extracts combined, dried overmgSO,), filtered and concentrated under vacuum to give the title compound (173mg, 80%).
67%
With trichlorophosphate; at 60 - 100℃;
Example A4; a. Preparation of intermediate 5; A mixture of 6-bromo-2 (lH)-quinolinone (0.089 mol) in POC13 (55 ml) was stirred at 60C overnight, then at 100C for 3 hours and the solvent was evaporated. The residue was taken up in CH2Cl2, poured out into ice water, basified with NHaOH concentrated, filtered over celite and extracted with CH2C12. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. Yield: 14. 5g of intermediate 5 (67%).
67%
A mixture of 6-bromo-2(7H)-quinolinone (0.089 mol) in POCl3 (55 ml) was stirred at 60C overnight, then at 100C for 3 hours and the solvent was evaporated. The residue EPO <DP n="39"/>was taken up in CH2CI2, poured out into ice water, basified with NH4OH concentrated, filtered over celite and extracted with CH2CI2. The organic layer was separated, dried(MgSO4), filtered and the solvent was evaporated. Yield: 14.5g of intermediate 5(67%).
With 2,3-dicyano-5,6-dichloro-p-benzoquinone; trichlorophosphate; In toluene; at 92℃; for 2h;
A suspension of 6-bromo-3, [4-DIHYDRO-2-1 H-QUINOLIN-2-ONE] (4.068 g, 18 [MMOL)] and 2, [3-DICHLORO-5,] 6-dicyano-1,4-benzoquinone (4.92 g, 21.6 [MMOL)] in toluene (60 mL) is treated dropwise with phosphorous [OXYCHLORIDE] (8.5 mL, 90 [MMOL).] After heating for 2 hours at [92C] the mixture is cooled, quenched with ice water, basified with 50% aqueous sodium hydroxide and extracted with ethyl acetate. The extracts are dried over anhydrous magnesium sulfate and evaporated. The residue is flash chromatographed on silica [GEL MERCK-60] using a gradient of ethyl acetate (10-25%) in hexane to provide the title compound (4.27 g). [MS [] (+) [APCI,] m/z]: 242.1 [[M+H] +] Anal. [CALCD.] For [C9H5BRCIN] : C 44.58, H 2.08, N 5.78. Found: C 44.46, H 2.04, N 5.78
With trichlorophosphate; at 120℃; for 6h;Inert atmosphere;
A mixture of <strong>[1810-66-8]6-bromoquinolin-2(1H)-one</strong> 8 (804 mg, 3.59 mmol) and phosphorous oxychloride (3.00 mL, 3.22 mmol) was stirred at 120 C for 6 h. The reaction was quenched by transferring the reaction mixture to ice fragments. Then, 4 N NaOH solution was slowly added. The resulting solution was separated and extracted with EtOAc. The organic layer was separated, dried over MgSO4, and filtered. The solvent was removed under reduced pressure to afford chloroquinoline 9 (863 mg, 99 %) as a brownish solid, which was used in the next step without further purification:
With trichlorophosphate; for 1h;Reflux;
Step A: 6-bromo-2-chloroquinoline: 6-bromoquinolin-2(lH)-one (3.40 g, 0.15 mol) in POCl3 (12 mL) was heated under reflux for 1 h. The mixture was cooled, concentrated, dissolved in chloroform (20 mL) and poured onto crushed ice (50 g). The mixture was neutralized with ammonia. The phases were separated and the aqueous phase was extracted with chloroform (2 x 15 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (petroleum ether: EtOAc from 50:1 to 5: 1) to afford the title compound.
With trichlorophosphate; for 1h;Reflux;
Step A: 6-bromo-2-chloroquinoling: 6-bromoquinolin-2(lH)-one (3.40 g, 0.15 mol) in POCI3 (12 mL) was heated under reflux for 1 h. The mixture was cooled, concentrated, dissolved in chloroform (20 mL) and poured onto crushed ice (50 g). The mixture was neutralized with ammonia. The phases were separated and the aqueous phase was extracted with chloroform (2 x 15 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (petroleum ether: EtOAc from 50: 1 to 5: 1) to afford the title compound.
1.I-1.I
To a solution of Na (0.14g, 6.0 mmol) in methanol (15 ml) was added 2-chloro-6- bromoquinoline (1.2 g, 5.0 mmol). The mixture was heated to reflux for 17h. The mixture was cooled to R.T. and evaporated to dryness. To the residue was added water (15ml) and DCM (20 ml). The organic layer was separated, washed with brine, dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo to give crude product, which was purified via column chromatography (PE:EA=40:l) to yield 2-methoxy-6-bromoquinoline as off white powder (0.36g, 30.2%). MS (m/z) (M~+H): 238, 240.
With potassium <i>tert</i>-butylate In methanol at 0 - 60℃; for 4h;
1
To a stirred solution of 6-bromo-2-chloroquinoline 1 (0.05 g, 0.2 mmol) in CH3OH (3.0 mL), t-BuOK (0.046 g, 0.4 mmol) was charged portionwise at 0 °C. The reaction mixture was heated at 60 °C for 4 h. The reaction mixture was allowed to room temperature and diluted with water (5.0 mL) and and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over anhydrous NaiSCL and concentrated under reduced pressure (Hexane: EtOAc = 95: 5) to afford 2 [0.05 g (crude)] as a gummy solid. NMR (400 MHz, CDCb): d ppm 7.85 - 7.89 (m, 2 H), 7.66 - 7.73 (m, 2 H), 6.91 (d, J= 8.8 Hz, 1H), 4.06 (s, 3 H).
With acetamide; potassium carbonate; at 200℃; for 2h;
Part D. Preparation of 6-bromo-2-aminoquinoline.; [00797] The product from Part C (173mg, 0.713mmol), acetamide (843mg, 14.27mmol) and potassium carbonate (493mg, 3.57mmol) were combined and heated at 200 0C for 2h. Cooled to room temperature, whereupon it solidified. Dissolved in a mixture of CHCl3 and water. Aqueous layer was extracted twice more with CHCI3, extracts were combined, washed with brine, dried over Na2SOφ filtered and concentrated under vacuum. Purification by silica gel column chromatography eluting with MeOH/CHCl3 gave title compound (92mg, 58 %).
58%
[00539] Part D. Preparation of 6-bromo-2-aminoquinoline.; [00540] The product from Part C (173mg, 0.713mmol), acetamide (843mg, 14.27mmol) and potassium carbonate (493mg, 3.57mmol) were combined and heated at 200 0C for 2h. Cooled to room temperature, whereupon it solidified. Dissolved in a mixture of CHCI3 and water. Aqueous layer was extracted twice more with CHCI3, extracts were combined, washed with brine, dried over Na2SOφ filtered and concentrated under vacuum. Purification by silica gel column chromatography eluting with MeOH/CHCl3 gave title compound (92mg, 58 %).
34%
With acetamide; potassium carbonate; at 200℃; for 2h;
A mixture of 6-bromo-2-chloro-quinoline (2.0 g, 8.3 mmol), acetamide (9.74 g, 165 mmol) and potassium carbonate (3.4 g, 25 mmol) was heated at 200 C for 2 h. The reaction mixture was allowed to cool to rt whereupon the mixture solidified. The residue was taken up in DCM (15 ml_) and water (10 ml_), and the layers separated. The aqueous layer was extracted with DCM (2 x 15 ml_), the combined organic extracts were washed with brine, dried (MgSCU) and concentrated under vacuum to yield the title compound as a beige solid (780 mg, 34 %).1H NMR dH(400 MHz, Chloroform-d) 8.01 (d, J = 8.6 Hz, 1 H), 7.83 - 7.78 (m, 1 H), 7.78 - 7.73 (m, 1 H), 7.61 (dd, J = 8.9, 2.2 Hz, 1 H), 7.51 (d, J = 8.9 Hz, 1 H), 4.94 (s, 2H); LCMS (Method B): 1.10 min, (222.9/224.9, MH+).
Multi-step reaction with 2 steps
1: dimethylformamide / 80 °C
2: 4 M aq. H2SO4 / 80 °C
With piperazine In DMF (N,N-dimethyl-formamide) at 110℃; for 3h;
27.b Example 27; Preparation of (2S)-2-[4-(6-bromoquinolin-2-yl)-piperazin-1-yl]methyl}-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline; Step B; Preparation of 6-bromo-2-piperazin-1-yl-quinoline
To a solution of 6-bromo-2-chloroquinoline of Step A (1.25 g, 5.15 [MMOL)] in N, N-dimethylformamide (35 mL) is added piperazine (4.43 g, 51.4 [MMOL)] and the mixture is heated at [110C] under nitrogen for 3 hours. After cooling, it is diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The extracts are dried over anhydrous magnesium sulfate and evaporated to dryness. [0096] The residue is flash chromatographed on silica gel Merck-60 using a gradient of methanol (0-15%) in dichloromethane containing 0.2% ammonium hydroxide to provide the title compound as an off-white solid (1.3 g), m. p. [129-130 C] MS [[ (+)] ES, [M/Z]] : 292.1 [[M+H]+ Anal. Calcd for [C13H14BRN3] : C 53.44, H 4.83, N 14.38. Found: C 53.17, H 4.81, N 14.41
Multi-step reaction with 2 steps
1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 0.75 h / 150 °C / Microwave irradiation
2: hydrogenchloride / 1,4-dioxane / 16 h / 0 - 20 °C
2 2-Methoxy-6-bromoquinoline (alternative to Preparation 1) STR137
PREPARATION 2 2-Methoxy-6-bromoquinoline (alternative to Preparation 1) STR137 A solution of 2-chloro-6-bromoquinoline (4.0 g) in methanol (20 cm3) was heated under reflux with sodium methoxide [made from sodium (0.5 g) and methanol (20 cm3)] for 16 hours. The solvent was removed in vacuo and the residue was partitioned between water (20 cm3) and chloroform (100 cm3). The aqueous phase was extracted with chloroform (2*30 cm3) and the dried (MgSO4) extracts were evaporated to give a solid which was recrystallized from petroleum ether (b.p. 60°-80°) to yield 2-methoxy-6-bromoquinoline, m.p. 93°-96°, (3.0 g). Analysis %: Found: C, 50.4; H, 3.4; N 6.0; Calculated for C10 H8 NOBr: C, 50.4; H, 3.4; N, 5.9.
With sodium methylate; sodium In methanol; chloroform
17 6-Bromo-2-methoxyquinoline (alternative to Preparation 16) STR44
PREPARATION 17 6-Bromo-2-methoxyquinoline (alternative to Preparation 16) STR44 A solution of 2-chloro-6-bromoquinoline (4.0 g) in methanol (20 cm3) was heated under reflux with sodium methoxide [made from sodium (0.5 g) and methanol (20 cm3)] for 16 hours. The solvent was removed in vacuo and the residue was partitioned, between water (20 cm3) and chloroform (100 cm3). The aqueous phase was extracted wth chloroform (2*30 cm3) and the dried (MgSO4) organic extracts were evaporated to give a solid which was recrystallized from petroleum ether (b.p. 60°-80°) to yield the title compound, m.p. 93°-96°, (3.0 g). Analysis %: Found: C, 50.4; H, 3.4; N, 6.0; Calculated for C10 H8 NOBr: C, 50.4; H, 3.4; N, 5.9.
ethyl 2-[4-(6-bromoquinolin-2-yloxy)phenoxy]-propionate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 6 Ethyl 2-[4-(6-bromoquinolin-2-yloxy)phenoxy]-propionate (31) was prepared from 6-bromo-2-chloroquinoline and <strong>[65343-67-1]ethyl 2-(4-hydroxyphenoxy)propionate</strong> following essentially the same procedure as that described in Example 1. The compound had a melting point of 85 C.
A.A1.a
A. Preparation of the intermediate compounds; Example Al; a. Preparation of intermediate 1; A solution of 6-bromo-2-chloroquinoline (11.56 g, 0.048 mol) and sodium methoxide 30 % in CH3OH (45.4 ml, 0.238 mol) in CH3OH (159 ml) was stirred at 80 0C for 16 hours. The mixture was cooled down and poured out into ice water. The organic layer was extracted with EtOAc, washed with brine, dried over MgSO4, filtered and the solvent was evaporated. Yield: 11.38 g of intermediate 1 (99 %).
31%
at 100℃; for 0.5h; Microwave irradiation;
15.a
6-Bromo-2-(methyloxy)quinoline. To a solution of Example 6 c) (100 mg, 0.82 mmol) in dry MeOH (2 ml_) was added sodium methoxide ( 25% in methanol, 187 μl_, 0.82 mmol). The mixture was heated to 100 0C for 30 minutes in a BiotageInitiator microwave synthesizer, then cooled to the ambient temperature and quenched with ice water. The precipitate was filtered, washed with water and EPO dried in vacuo to afford the title compound as a white solid (30 mg, 31%). MS(ES+) m/e 239 [M+H]+.
Heating / reflux;
A.A4.a
Example A4; a) Preparation of intermediate 9; A mixture of 6-bromo-2-chloroquinoline (0.06 mol) in CH3ONa 30% CH3OH (70 ml) and CH3OH (140 ml) was stirred and refluxed overnight, poured out into H2O and extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue (12.6 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/cyclohexane 40/60; 15-35 μm). The desired fraction was collected and the solvent was evaporated. Yield: 7.5 g of intermediate 9.
2.A Step A: 2-chloroquinoline-6-carbonitrile
Step A: 2-chloroquinoline-6-carbonitrile: To a flask containing a stir bar was added 6-bromo-2- chloroquinoline (0.90 g, 3.7 mmol), CuCN (0.50 g, 5.6 mmol) followed by addition of DMF (10 mL). The resulting mixture was then refluxed at 150 °C overnight. When the reaction appeared complete by LC analysis, the reaction flask was taken out of the oil bath and cooled to room temperature. To the reaction mixture was then poured DCM (20 mL) and a precipitate formed immediately, which was filtered, redissolved in DCM, absorbed onto silica gel, and purified by flash chromatography to provide the title product.
(R)-6-bromo-2-((1-methylpyrrolidin-3-yl)oxy)quinoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
With sodium hydride; In tetrahydrofuran; mineral oil; for 5h;Reflux;
Preparation of Compound 3, (R)-6-bromo-2-((1-methylpyrrolidin-3-yl)oxy)quinoline[0005] NaH (60% in mineral oil, 0.049 g, 1.24 mmol) was added to a solution of (R)-(-)-1- methyl-3-hydroxypyrrolidine (0.125 g, 1.24 mmol) in dry THF (3.5 mL) at 0 C. The reaction mixture was stirred at 0 C for 5 min, then allowed to warm to rt, and stirred for 35 min before 6-bromo-2-chloroquinoline (0.250 g, 1.03 mmol) was added. The reaction mixture was then heated at reflux for 5 h, cooled to rt, concentrated to remove most of the THF, diluted with water and saturated NaHC03(aq), extracted with DCM (3x). The combined organic phases were washed with water (1x), dried (MgS04), andconcentrated. The crude material was purified by silica gel column chromatography using a gradient of 2 to 5% MeOH in DCM to afford the title compound (206 mg, 65%) as a pale yellow oil. 1H NMR (500 MHz, CDCI3) delta 7.86 (d, J= 8.9 Hz, 1 H), 7.85-7.83 (m, 1 H), 7.68-7.64 (m? 2H), 6.92 (d, J = 8.8 Hz, 1 H), 5.68-5.63 (m, 1 H), 2.94 - 2.88 (m, 2H), 2.83 (dd, J= 10.8, 5.9 Hz, 1 H), 2.49 - 2.36 (m, 5H), 2.08-2.01 (m, 1 H). HRMS (ESI+): calcd for C14H1579BrN20 (M+H)+, 307.0440; found 307.0447.
3-((6-bromoquinolin-2-yl)(methyl)amino)propanenitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
32%
at 140℃; for 5h;Microwave irradiation;
Preparation of Compound 207, 3-((6-bromoquinolin-2-yl)(methyl)amino)propanenitrile[00287] 6-Bromo-2-chloroquinoline (250 mg, 1 .031 mmol) and N-methyl-beta- alanine nitrile (0.482 ml_, 5.15 mmol) in NMP (10 mL) were heated to 140 C in the microwave for 5 h. The reaction mixture was poured into sat. NaHC03aq. (50 ml) and extracted with EtOAc (3 x 50 ml) - further water and brine had to be added in order to clear the aqueous layer. The combined organic layer was washed with water (2 x 50 ml), brine (50 ml) and concentrated in vacuo to give a pale brown semi-solid. Purification by biotage chromatography using a gradient of 5 to 40% MeOH/DCM gave the title compound as a yellow solid (193 mg, 32%).1H NMR (500 MHz, Chloroform-d) delta 7.86 (d, J = 9.1 Hz, 1 H), 7.78 (d, J = 2.2 Hz, 1 H), 7.62 (dd, J = 8.9, 2.2 Hz, 1 H), 7.57 (d, J = 8.9 Hz, 1 H), 6.93 (d, J = 9.1 Hz, 1 H), 4.05 (t, J = 6.5 Hz, 2H), 3.31 (s, 3H), 2.86 (t, J = 6.5 Hz, 2H). HRMS (ESI+): calcd for C13H1379BrN3(M + H)+, 290.0287; found 290.0283.
2-(2-(4-(6-bromoquinol-2-yl)-1-piperazinyl)-1-ethyl)-5-chloroisoindole-1,3-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
With sodium carbonate; In acetonitrile; at 120℃; for 24h;
2-chloro-6-bromoquinoline (240 mg, 1 mmol), triethylene diamine (224 mg, 2 mmol)<strong>[7147-90-2]5-chlorophthalimide</strong> (360 mg, 2 mmol), sodium carbonate (210 mg, 2 mmol),Acetonitrile (2 ml) was added to the dry reaction tube and suspended in an oil bath at 120 C for 24 h.After cooling the reaction system, 15 ml of water was added and the aqueous phase was extracted three times with 30 ml of ethyl acetate,The organic phases were combined and the solvent was evaporated under reduced pressure to give 378 mg of colorless solid2- (2- (4- (6-bromoquinolyl) 2-piperazinyl) 1-ethyl) -<strong>[7147-90-2]5-chloroisoindole-1,3-dione</strong>,The yield was 76%.
1-(3-((6-bromoquinolin-2-yl)oxy)propyl)pyrrolidin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
46 mg
With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 6h; Inert atmosphere;
241 Reference Example 241
Sodium hydride (61% in oil, 14 mg) and 6-bromo-2-chloroquinoline (80 mg) were added to a DMF (0.5 ml) solution containing 1-(3-hydroxypropyl)-2-pyrrolidone (52 mg) in a nitrogen atmosphere, followed by stirring at room temperature for 6 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane : ethyl acetate = 1:0 to 0:1), and 1-(3-((6-bromoquinolin-2-yl)oxy)propyl)pyrrolidin-2-one (46 mg) was thus obtained. MS (ESI m/z): 349, 351 (M+H) RT (min): 1.48
6-bromo-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)quinolin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
With caesium carbonate In N,N-dimethyl-formamide at 100℃; for 2h;
1.A Step A:
6-Bromo-2-chloro-quinoline (121 mg, 0.5 mmol) was combined with N,2,2,6,6- pentamethylpiperidin-4-amine (170 mg, 0.95 mmol) and Cs2C03 (325 mg, 1.0 mmol) in DMF (2 mL) and the mixture was stirred at 100 °C for 2 h. The mixture was partitioned between EtOAc and H20. The organic layer was washed with brine, dried over Na2S04, filtered and concentrated. The residue was chromatographed on silica gel, eluting with 0-5% MeOH in CH2C12 to yield 6- bromo-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)quinolin-2-amine (480 mg, 65%). MS m/z 375.9, 377.9 [M+H]+.
Stage #1: 6-bromo-2-chloroquinoline; ethanol With sodium ethanolate In 1,4-dioxane Reflux;
Stage #2: With sodium hydride In 1,4-dioxane for 4h;
19 6-bromo-2-ethoxyquinoline
The procedure reported by Johnson et al. was followed.[19] To a flame-dried flask was added 6-bromo-2-chloroquinoline (0.800 g, 3.20 mmol, 1.0 equiv.) and sodium ethoxide (2.268 g, 32.0 mmol, 10.0 equiv.). Subsequently, 35 mL of a 1/1 mixture of dioxane/ethanol was added and the resulting mixture was refluxed overnight. To achieve full conversion of the starting material, sodium hydride (0.153 g, 6.40 mmol, 2 equiv.) was added (caution: H2 gas formation) and the mixture was stirred for an additional 4 h. Afterwards, the solvent was evaporated under reduced pressure and ethyl acetate was added. The mixture was washed three times with water and once with brine. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated via rotary evaporation. Compound 19 was obtained as a white solid (0.706 g, 2.80 mmol, 88% yield).
4-(6-bromoquinolin-2-yl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 80℃; for 2h;Inert atmosphere;
To a stirred mixture of Intermediate-5 (2.50 g, 5.84 mmol) and 6-bromo-2-chloroquinoline (1.41 g, 5.84 mmol) in 4: 1 mixture of 1,4-dioxane, H2O (125 mL), K2CO3 (1.60 g, 11.68 mmol) was added at room temperature. The solution was purged with argon for 10 min followed by addition of Pd(PPh3)4 (0.660 g, 0.58 mmol) and reaction mixture was heated at 80 C for 2 h. The solvent was evaporated under reduced pressure and crude product was purified by combiflash chromatography (CH2CI2: CH3OH = 97: 3) to afford Intermediate-6 (1.90 g, 63%) as an off-white solid. NMR (400 MHz, DMSO-i) : d ppm 8.39 (d, J= 2.0 Hz, 1H), 8.36 (s, 1H), 8.25 (d, J= 2.0 Hz, 1H), 8.09 (d, J= 3.2 Hz, 1H), 7.95 - 8.06 (m, 4 H), 7.88 (dd, =2.4, 9.2 Hz, 1H), 7.72 (d, J= 3.2 Hz, 1H), 7.43 (d, J=8.0 Hz, 2 H), 3.92 (s, 3 H), 2.38 (s, 3 H). ESI-MS m/z [C24Hi8BrN3C)3S +H]+ 508.0
4-{2-[4-(6-bromoquinolin-2-yl)phenoxy]ethyl}morpholine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
31%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,4-dioxane at 90℃; for 3h; Inert atmosphere;
1
To a stirred solution of Intermediate-10 (0.480 g, 1.44 mmol7), in dioxane (8.0 mL) were charged with 6-bromo-2-chloroquinoline 1 (0.347 g, 1.44 mmol), K2CO3 (0.397 g, 2.88 mmol) at room temperature and degassed it with argon for 5 min. Pd(PPh3)4 (0.162 g, 0.14 mmol) at room temperature and was heated at 90 °C for 3 h. TLC indicated at which time the reaction gone to completion. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 35 mL). Combined organic layers were dried over anhydrous NaiSCri and concentrated under reduced pressure. The crude product was purified by combiflash chromatography (EtOAc: Hexanes = 80: 20) to afford 2 (0.185 g, 31%0) as a light brown solid. NMR (400 MHz, DMSO-i): d ppm 8.07 - 8.10 (m, 2 H), 7.95 - 8.00 (m, 2 H), 7.85 (d, =8.8 Hz, 1H), 7.76 (dd, =2.0,8.8 Hz, 1H), 7.05 (d, =8.8 Hz, 2 H), 6.76 (d, =6.4 Hz, 1H), 4.20 (t, J= 5.6 Hz, 2 H), 3.74 - 3.77 (m, 4 H), 2.85 (t, J= 5.6 Hz, 2 H), 2.60 - 2.62 (m, 4 H).
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In ethanol; water; toluene for 4h; Inert atmosphere; Reflux;
3.1 (1) Preparation of compound 3-1:
Combine 2-chloro-6-bromoquinoline (24.1g, 100mmol), 4-cyano-[1,1'-biphenyl]-boronic acid (22.3g, 100mmol), Potassium carbonate (41.4g, 300mmol), tetrakis(triphenylphosphine) palladium (1.15g, 1mmol) were added containing 500mL of toluene, In a flask of 100 mL ethanol and 100 mL water, the reaction was heated and refluxed in a nitrogen atmosphere for 4 hours. TLC showed that the reaction was complete. Cool to room temperature, separate the liquids, extract the aqueous phase with ethyl acetate, combine the organic phases, and dry with anhydrous sodium sulfate. The crude product was filtered and spin-dried under reduced pressure to obtain the crude product, which was separated and purified by column chromatography to obtain compound 3-1 (28.9 g, 85%).
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