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Product Details of [ 1620515-86-7 ]

CAS No. :1620515-86-7 MDL No. :MFCD29059222
Formula : C10H8BrNO Boiling Point : -
Linear Structure Formula :- InChI Key :UACHUBQTGCSWOR-UHFFFAOYSA-N
M.W : 238.08 Pubchem ID :86727147
Synonyms :

Calculated chemistry of [ 1620515-86-7 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 13
Num. arom. heavy atoms : 10
Fraction Csp3 : 0.1
Num. rotatable bonds : 1
Num. H-bond acceptors : 2.0
Num. H-bond donors : 0.0
Molar Refractivity : 55.94
TPSA : 22.12 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.73 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.39
Log Po/w (XLOGP3) : 2.85
Log Po/w (WLOGP) : 3.01
Log Po/w (MLOGP) : 2.19
Log Po/w (SILICOS-IT) : 3.1
Consensus Log Po/w : 2.71

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -3.61
Solubility : 0.0578 mg/ml ; 0.000243 mol/l
Class : Soluble
Log S (Ali) : -2.97
Solubility : 0.253 mg/ml ; 0.00106 mol/l
Class : Soluble
Log S (SILICOS-IT) : -4.69
Solubility : 0.00489 mg/ml ; 0.0000206 mol/l
Class : Moderately soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.48

Safety of [ 1620515-86-7 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P301+P312-P302+P352-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H320-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 1620515-86-7 ]

* 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.

  • Downstream synthetic route of [ 1620515-86-7 ]

[ 1620515-86-7 ] Synthesis Path-Downstream   1~50

  • 1
  • [ 19056-40-7 ]
  • [ 98-47-5 ]
  • [ 1620515-86-7 ]
YieldReaction ConditionsOperation in experiment
50% With sulfuric acid; glycerol In water at 110 - 140℃; for 3h;
46.2% With sulfuric acid In water; glycerol at 110 - 140℃; for 3h; 31.1 Step 1:
6-Bromo-7-methoxyquinoline Step 1: 6-Bromo-7-methoxyquinoline In a 100 mL round-bottom flask, a solution of concentrated sulfuric acid (2.1 mL, 39.6 mmol) in water (2.4 mL) was treated with 3-nitrobenzenesulfonic acid (2.06 g, 10.1 mmol) and glycerol (2.5 mL, 34.8 mmol) to give a thick grey suspension. The mixture was heated to 110° C. (oil bath) and 4-bromo-3-methoxyaniline (1.952 g, 9.66 mmol) was added portion-wise, resulting in an immobile slurry. Additional portions of water (3 mL), glycerol (3 mL), and concentrated sulfuric acid (3 mL) were added and the temperature increased to 140° C. After three hours the mixture had become a homogeneous dark brown solution, and LCMS analysis indicated reaction completion. The solution was cooled to RT, poured onto ice, and the pH was adjusted to 8 by addition of concentrated (30%) aqueous ammonium hydroxide. The mixture was partitioned between ethyl acetate and water, washed with water, brine, dried over magnesium sulfate and concentrated to a brown liquid. Purification by flash column chromatography (24 g silica gel, gradient of 0-20% ethyl acetate in dichloromethane over 25 column volumes) provided 6-bromo-7-methoxyquinoline (1.18 g, 46.2%) as a light brown fluffy solid. 1H NMR (400 MHz, CHLOROFORM-d) ppm 8.86 (dd, J=4.0, 1.5 Hz, 1H), 8.01-8.12 (m, 2H), 7.53 (s, 1H), 7.34 (dd, J=8.1, 4.5 Hz, 1H), 4.07 (s, 3H). NMR indicates the presence of about 10% 7-methyoxyquinoline.
  • 2
  • [ 1620515-86-7 ]
  • [ 1620515-87-8 ]
YieldReaction ConditionsOperation in experiment
1.185 g Stage #1: 6-bromo-7-methoxy-quinoline With n-butyllithium In n-heptane at -78℃; for 0.5h; Stage #2: With Trimethyl borate In n-heptane at 20℃; 31.2 Step 2: (7-Methoxyquinolin-6-yl)boronic acid Step 2: (7-Methoxyquinolin-6-yl)boronic acid10333] To a solution of 6-bromo-7-methoxyquinoline (90% purity, 0.65 g, 2.73 mmol) cooled to -78° C. was added drop-wise nl3uEi (1.6 M in heptanes, 1.877 mE, 3.00 mmol). The solution was stirred for 0.5 h after which time trimethyl borate (0.763 mE, 6.83 mmol) was added in a single portion. The solution was allowed to warm slowly to RT overnight. The crude reaction mixture was rotovapped to dryness, concentrated from heptane (2x), triturated with diethyl ether (3x) and concentrated to provide a crude mixture of (7-methox- yquinolin-6-yl)boronic acid as a tan colored solid (1.185 g, 2 14%). ECMS is clean, and based on the recovered mass the mixture was used without further purification assuming 50% purity by weight. MS=204.1 (M+1). ‘H NMR (400 MHz, METHANOE-d4) ppm 8.48 (br s, 1H), 8.07 (d, J=8.1 Hz, 1H), 7.85 (s, 1H), 7.16 (dd, J=8.1, 4.5 Hz, 1H), 7.11 (s, 1H), 3.82 (s, 3H).
778 mg Stage #1: 6-bromo-7-methoxy-quinoline With n-butyllithium In n-heptane at -78℃; for 0.5h; Stage #2: With Trimethyl borate In n-heptane at -78 - 20℃; 6.2 Step 2: (7-Methoxyquinolin-6-yl)boronic acid Butyllithium (1.6 M in heptane, 4.90 mL, 7.90 mmol) was added dropwise to a solution of 6- bromo-7-methoxyquinoline (1 .71 g, 7.18 mmol) cooled to -78 °C. The solution was stirred for 0.5 h after which time trimethyl borate (2.0 mL, 18 mmol) was added in a single portion. The reaction was allowed to warm to room temperature and stir overnight. The crude reaction was concentrated to dryness, then concentrated from heptane (2x). The resulting solids were passed through a plug of silica gel (80 mL, dry measure) eluting with 9:1 DCM/MeOH to provide (7-methoxyquinolin-6- yl)boronic acid, Intermediate 6, as an orange solid (778 mg). MS (M+1 ) = 204.1
  • 3
  • [ 1620515-86-7 ]
  • [ 1620514-94-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: n-butyllithium / n-heptane / 0.5 h / -78 °C 1.2: 20 °C 2.1: tetrakis(triphenylphosphine) palladium(0); sodium carbonate / water; 1,2-dimethoxyethane / 0.5 h / 140 °C / Microwave irradiation; Inert atmosphere
  • 4
  • [ 1620515-86-7 ]
  • [ 1620514-96-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: n-butyllithium / n-heptane / 0.5 h / -78 °C 1.2: 20 °C 2.1: tetrakis(triphenylphosphine) palladium(0); sodium carbonate / water; 1,2-dimethoxyethane / 0.5 h / 140 °C / Microwave irradiation; Inert atmosphere 3.1: pyridine hydrochloride; sodium hydrogencarbonate / methanol / 0.5 h / 160 °C / Microwave irradiation
  • 5
  • [ 19056-40-7 ]
  • [ 56-81-5 ]
  • [ 1620515-86-7 ]
YieldReaction ConditionsOperation in experiment
83% With sulfuric acid; 3-Nitrobenzenesulfonic acid In water at 110 - 140℃; for 3h; B1.1 Step 1: Synthesis of 6-bromo-7-methoxyquinoline. H2SO4 (10.5 mL) in 12 mL of H2O was added 4- bromo-3-methoxyaniline (10.5 g, 51.7 mmol) and propane-1,2,3-triol (12.5 g, 135.7 mmol). The mixture was heated to 110 °C, 3-nitrobenzenesulfonic acid (10 g, 49.5 mmol) was added portion-wise. Then 15 mL of H2O, 15 mL of propane-1,2,3-triol and 15 mL of H2SO4 were added successively. The mixture was stirred at 140 oC for 3 h. After cooling to room temperature, the mixture was poured onto ice, and the pH was adjusted to 8 by addition NH3H2O. The mixture was extracted with EtOAc (100 mL X 3). The combined organic solvents were dried over anhydrous Na2SO4, concentrated and purified by silica gel chromatography (25- 100% EtOAc/petroleum ether) to give 9.9 g of 6-bromo-7-methoxyquinoline as a gray solid (83% yield). LCMS: m/z 240.1 [M+H]+; tR = 1.54 min.
50% With sulfuric acid; 3-Nitrobenzenesulfonic acid In water at 110 - 140℃; for 5h;
36.8% With sulfuric acid; 3-Nitrobenzenesulfonic acid In water at 110 - 140℃; for 3h; B17 6-Bromo-7-methoxyquinoline. Into a 500-mL round-bottom flask, was placed 3- nitrobenzenesulfonic acid (28.3 g, 139.3 mmol, 1.05 equiv.), glycerol (34.8 mL), H2SO4 (28.4 mL), and H2O (26 mL). This was followed by the addition of 4-bromo-3-methoxyaniline (26.8 g, 132.4 mmol, 1.0 equiv.) in portions at 110 degrees C. Additional glycerol (24 mL), H2SO4 (24 mL), H2O (24 mL) was added and the resulting solution was stirred for 3 h at 140 degrees C. The reaction was then quenched by the addition of water/ice. The pH value of the solution was adjusted to 12 with NaOH (aq, 20 %). The resulting solution was extracted with 3x500 mL of dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with dichloromethane/ethyl acetate (30%) to give 13 g (36.8%) of 6-bromo-7-methoxyquinoline as off-white solid. LCMS: (ES, m/z)=238 (M+H).
3.94 g With sulfuric acid; 3-Nitrobenzenesulfonic acid In water at 110 - 140℃; for 3h; 6.1 Step 1: 6-Bromo-7-methoxyquinoline In a 100 mL round bottom flask, a solution of sulfuric acid (7.1 mL, 130 mmol) in water (6.5 mL) was treated with 3-nitrobenzenesulfonic acid (7.07 g, 34.8 mmol) and glycerol (8.7 mL, 120 mmol) to give a thick grey suspension. The suspension was heated to 1 10 °C and 4-bromo-3- methoxyaniline (6.7 g, 33 mmol) was added resulting in a slurry. Additional quantities of water (6 mL), glycerol (6 mL), sulfuric acid (6 mL) were added and the temperature increased to 140 °C. After about 3 h the mixture became a homogeneous dark brown solution. The solution was cooled to room temperature, poured onto ice, and the pH adjusted to 8 by addition of concentrated ammonium hydroxide. The mixture was extracted with 1 :1 EtOAc/diethyl ether (5x), dried over Mg2S04 and concentrated to a brown liquid. Silica gel chromatography (0-20% EtOAc in DCM) provided the title compound which was further purified by silica gel chromatography (0-20% MeOH in DCM) to provide 6-bromo-7-methoxyquinoline (3.94 g) as an off-white solid. MS (M+1 ) = 240.1 . 1H NMR (400 MHz, CHLOROFORM-d) δ 8.86 (dd, J=4.0, 1 .5 Hz, 1 H), 8.01 -8.12 (m, 2H), 7.53 (s, 1 H), 7.34 (dd, J=8.1 , 4.5 Hz, 1 H), 4.07 (s, 3H).
With sulfuric acid; 3-Nitrobenzenesulfonic acid In water at 20 - 140℃; for 3h; Inert atmosphere; 11.1 Step 1: Synthesis of intermediate WX011-2 At room temperature and under nitrogen atmosphere, concentrated sulfuric acid (37.15 g, 371.20 mmol, purity: 98%) was dissolved in water (20 mL), and 3-nitrobenzenesulfonic acid hydrate (15.99 g, 78.69 mmol) and glycerine (25.30 g, 274.69 mmol, 20.57 mL) were added. The reaction mixture was warmed to 110°C, and then compound WX011-1 (15 g, 74.24 mmol), water (20 mL), concentrated sulfuric acid (20 mL, purity: 98%) and glycerine (20 mL) were added; and the reaction mixture was warmed to 140 °C and stirred and reacted for 3 hours. After completion of the reaction, the reaction mixture was poured into ice water (500 mL), adjusted to pH 8 with 2 N sodium hydroxide aqueous solution, and then extracted with ethyl acetate (500 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate and filtered, and concentrated under reduced pressure to obtain a residue. The resulting residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate =1/0-6/1, volume ratio) to obtain intermediate WX011-2. 1H NMR (400 MHz, CDCl3) δ: 8.85 (dd, J=1.6, 4.4 Hz, 1H), 8.04 (s, 1H), 8.01 (dd, J=1.0, 8.2 Hz, 1H), 7.46 (s, 1H), 7.30 (dd, J=4.4, 8.0 Hz, 1H), 4.04 (s, 3H).
With sulfuric acid In water at 20 - 140℃; for 3h; Inert atmosphere; 7.1 Step 1: synthesis of intermediate WX007-2 Propane-1,2,3-triol (25.30 g, 274.69 mmol, 20.57 mL) was added to a solution of concentrated sulfuric acid (29.72 g, 296.96 mmol, 16.15 mL, purity: 98%) in water (15 mL) at room temperature under nitrogen atmosphere. The reaction mixture was heated to 110 °C, and then WX007-1 (15 g, 74.24 mmol), concentrated sulfuric acid (15 mL, purity: 98%), water (15 mL) and propane-1,2,3-triol (15 mL) were added sequentially. The resulting reaction mixture was heated to 140 °C and stirred at 140 °C for 3 h. After the reaction was completed, the reaction mixture was cooled to room temperature and poured into ice water (300 mL). 2 N aqueous sodium hydroxide solution was added to adjust the pH to 8, and ethyl acetate (400 mL × 3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The resulting residue was separated by column chromatography (eluent: petroleum ether/ethyl acetate = 1/0-1/1, volume ratio) to give intermediate WX007-2. 1H NMR (400 MHz, DMSO_d6) δ: 8.85 (dd, J=1.8, 4.2 Hz, 1H), 8.31 (s, 1H), 8.25 (dd, J=1.6, 8.0 Hz, 1H), 7.50 (s, 1H), 7.41 (dd, J=4.4, 8.4 Hz, 1H), 4.00 (s, 3H).

  • 6
  • [ 1620515-86-7 ]
  • 6-(3-chloro-7-methoxyquinolin-6-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: n-butyllithium / n-heptane / 0.5 h / -78 °C 1.2: -78 - 20 °C 2.1: sodium carbonate; tetrakis(triphenylphosphine) palladium(0) / water; 1,2-dimethoxyethane / 0.5 h / 140 °C / Inert atmosphere; Microwave irradiation 3.1: (1,5-cyclooctadiene)(methoxy)iridium(I) dimer; bis(pinacol)diborane / 1,4-dioxane / 85 °C 3.2: 1 h / 65 °C
  • 7
  • [ 1620515-86-7 ]
  • 6-(3-bromo-7-methoxyquinolin-6-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: n-butyllithium / n-heptane / 0.5 h / -78 °C 1.2: -78 - 20 °C 2.1: sodium carbonate; tetrakis(triphenylphosphine) palladium(0) / water; 1,2-dimethoxyethane / 0.5 h / 140 °C / Inert atmosphere; Microwave irradiation 3.1: (1,5-cyclooctadiene)(methoxy)iridium(I) dimer; bis(pinacol)diborane / 1,4-dioxane / 85 °C 3.2: 20 °C
  • 8
  • [ 1620515-86-7 ]
  • (7-methoxy-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin-3-yl)boronic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: n-butyllithium / n-heptane / 0.5 h / -78 °C 1.2: -78 - 20 °C 2.1: sodium carbonate; tetrakis(triphenylphosphine) palladium(0) / water; 1,2-dimethoxyethane / 0.5 h / 140 °C / Inert atmosphere; Microwave irradiation 3.1: (1,5-cyclooctadiene)(methoxy)iridium(I) dimer; bis(pinacol)diborane / 1,4-dioxane / 85 °C
  • 9
  • [ 1620515-86-7 ]
  • 6-(7-methoxy-3-(1-methyl-1H-imidazol-4-yl)quinolin-6-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: n-butyllithium / n-heptane / 0.5 h / -78 °C 1.2: -78 - 20 °C 2.1: sodium carbonate; tetrakis(triphenylphosphine) palladium(0) / water; 1,2-dimethoxyethane / 0.5 h / 140 °C / Inert atmosphere; Microwave irradiation 3.1: (1,5-cyclooctadiene)(methoxy)iridium(I) dimer; bis(pinacol)diborane / 1,4-dioxane / 85 °C 4.1: sodium carbonate; tetrakis(triphenylphosphine) palladium(0) / water; 1,4-dioxane / 1 h / 130 °C / Microwave irradiation
  • 10
  • [ 1620515-86-7 ]
  • 6-(3-(1H-imidazol-1-yl)-7-methoxyquinolin-6-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: n-butyllithium / n-heptane / 0.5 h / -78 °C 1.2: -78 - 20 °C 2.1: sodium carbonate; tetrakis(triphenylphosphine) palladium(0) / water; 1,2-dimethoxyethane / 0.5 h / 140 °C / Inert atmosphere; Microwave irradiation 3.1: (1,5-cyclooctadiene)(methoxy)iridium(I) dimer; bis(pinacol)diborane / 1,4-dioxane / 85 °C 4.1: copper nitrate hemi(pentahydrate); N,N,N,N,-tetramethylethylenediamine / methanol / 40 °C
  • 11
  • [ 1620515-86-7 ]
  • 6-bromo-7-methoxyquinoline 1-oxide [ No CAS ]
YieldReaction ConditionsOperation in experiment
1.76 g With dihydrogen peroxide; methyltrioxorhenium(VII) In dichloromethane; water 9-1.1 Step 1: 6-Bromo-7-methoxyquinoline 1 -oxide To a solution of 6-bromo-7-methoxyquinoline (PREPARATION 6 Step 1 , 2 g, 8.40 mmol) in DCM (42 mL) was added methyltrioxorhenium(VII) (0.209 g, 0.840 mmol). The solution was stirred for 5 min after which time hydrogen peroxide (30 wt % in water, 1 .03 mL, 10.1 mmol) was added. The solution was allowed to stir overnight during which time a thick precipitate formed. The mixture was diluted with heptane and the solids were isolated by filtration, washing with heptane. Drying of the solids in vacuo provided 6-bromo-7-methoxyquinoline 1-oxide (1.76 g). MS (M+1 ) = 255.9. 1H NMR (400 MHz, METHANOL-^) δ 8.57 (dd, J=6.1 , 1 .0 Hz, 1 H), 8.28 (s, 1 H), 7.95 (d, J=8.6 Hz, 1 H), 7.93 (s, 1 H), 7.34 (dd, J=8.3, 6.3 Hz, 1 H), 4.01 (s, 3H).
  • 12
  • [ 1620515-86-7 ]
  • 7-methoxy-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin-2(1H)-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: methyltrioxorhenium(VII); dihydrogen peroxide / water; dichloromethane 2.1: trifluoroacetic anhydride / N,N-dimethyl-formamide / 20 °C 3.1: potassium acetate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / dimethyl sulfoxide / 80 °C 3.2: 1 h / 130 °C / Microwave irradiation
  • 13
  • [ 1620515-86-7 ]
  • 6-(7-methoxyquinolin-6-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: n-butyllithium / n-heptane / 0.5 h / -78 °C 1.2: -78 - 20 °C 2.1: sodium carbonate; tetrakis(triphenylphosphine) palladium(0) / water; 1,2-dimethoxyethane / 0.5 h / 140 °C / Inert atmosphere; Microwave irradiation
Multi-step reaction with 2 steps 1.1: tert.-butyl lithium / n-heptane / 0.5 h / -78 °C 1.2: -78 - 20 °C 2.1: sodium carbonate / water; 1,2-dimethoxyethane / Heating; Sealed tube
  • 14
  • [ 1620515-86-7 ]
  • 6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin-7-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: n-butyllithium / n-heptane / 0.5 h / -78 °C 1.2: -78 - 20 °C 2.1: sodium carbonate; tetrakis(triphenylphosphine) palladium(0) / water; 1,2-dimethoxyethane / 0.5 h / 140 °C / Inert atmosphere; Sealed tube; Microwave irradiation 2.2: 160 - 190 °C / Microwave irradiation
Multi-step reaction with 3 steps 1.1: tert.-butyl lithium / n-heptane / 0.5 h / -78 °C 1.2: -78 - 20 °C 2.1: sodium carbonate / water; 1,2-dimethoxyethane / Heating; Sealed tube 3.1: pyridine hydrochloride / 160 - 190 °C / Microwave irradiation
  • 16
  • [ 1620515-86-7 ]
  • [ 1759-53-1 ]
  • 6-bromo-2-cyclopropyl-7-methoxyquinoline [ No CAS ]
YieldReaction ConditionsOperation in experiment
8.6% Stage #1: 6-bromo-7-methoxy-quinoline; cyclopropanecarboxylic acid With sulfuric acid; silver nitrate In water at 70℃; for 6h; Stage #2: With ammonium persulfate In water at 70℃; for 12h;
With sulfuric acid; silver nitrate In water at 70℃; for 6h; 31.1 Step 1: Preparation of 6-bromo-2-cyclopropyl-7-methoxyquinoline (C9 B): AgNOi (43 mg, 0.253 mmol), cyclopropanecarboxylic acid (37 mg, 0.430 mmol) and 6-bromo-7- methoxy quinoline (C9_A, 100 mg, 0.420 mmol) was added to a stirred mixture of H2SO4 (0.05 mL, 0.938 mmol) in water (3 mL) at 20°C and the mixture was warmed to 70°C, and stirred at 70°C for 6 h. Then (NH4)2S2O8 (288 mg, 1.260 mmol) in water (2 mL) was added drop-wise. After adding, the mixture was cooled to room temperature. Then the mixture was stirred at 70°C for 12 h. The mixture was cooled, diluted with EtOAc (10 mL), washed with water (3 x 10 mL), dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column flash chromatography, eluting with EtOAc / petroleum ether = 0 - 60% to give 6-bromo-2-cyclopropyl-7-methoxy quinoline (C9_B). LCMS (ESI) calc’d for C13H12BrNO [M+H]+: 278.0, found: 278.0.1H NMR (400 MHz, CDCl3) d 7.95 (s, 1H), 7.85 (d, J= 8.4 Hz, 1H), 7.34 (s, 1H), 7.07 (d, J = 8.4 Hz, 1H), 4.03 (s, 3H), 2.16-2.26 (m, 1H), 1.09-1.15 (m, 3H), 0.85 (dd, J= 5.7, 19.85 Hz, 1H).
  • 17
  • [ 1620515-86-7 ]
  • 6-bromoquinolin-7-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
1.02 g Stage #1: 6-bromo-7-methoxy-quinoline With boron tribromide In dichloromethane at 25℃; for 16h; Stage #2: With ammonia; water In methanol B1.2 Step 2: Synthesis of 6-bromoquinolin-7-ol. To a solution of 6-bromo-7-methoxyquinoline (2 g, 8.4 mmol) in CH2Cl2 (4 mL) at 25 oC was added BBr3 (40 mL, 1N in CH2Cl2) and stirred at 25 oC for 16 h, monitored by LCMS. Then water (15 mL) and ammonia methanol solution was added to pH to 8~9. The precipitate was collected by filtration to give 1.02 g of 6-bromoquinolin-7-ol. LCMS: m/z 226.0 [M+H]+; tR = 1.15 min.
With hydrogen bromide In water at 100℃; for 16h; B17 6-Bromoquinolin-7-ol. Into a 250-mL round-bottom flask, was placed 6-bromo-7-methoxyquinoline (10 g, 42.0 mmol, 1.0 equiv.), and HBr (aq, 100 mL). The resulting solution was stirred for 16 h at 100 degrees C. The resulting solution was concentrated under vacuum to give 10 g 6-bromoquinolin-7-ol as a brown solid which was used without further purification I the next step. LCMS: (ES, m/z)=224 (M+H).
With boron tribromide In dichloromethane at -20 - 20℃; for 37h; Inert atmosphere; 11.2 Step 2: Synthesis of intermediate WX011-3 At room temperature and under nitrogen atmosphere, intermediate WX011-2 (12.6 g, 52.92 mmol) was dissolved in dichloromethane (1500 mL) and cooled to - 20 °C; boron tribromide (66.29 g, 264.62 mmol) was added; and the reaction mixture was stirred and reacted at -20 °C for 1 hour. Then, the reaction mixture was stirred and reacted at 20 °C for 12 hours. At 20 °C, boron tribromide (13.5 g) was added; and the reaction mixture was stirred and reacted at 20 °C for 12 hours. At 0 °C, boron tribromide (13.5 g) was added; and the reaction mixture was stirred and reacted at room temperature for 12 hours. After completion of the reaction, the reaction mixture was poured into ice water (2000 mL) and filtered; the filter cake was dissolved in water (4000 mL), adjusted to pH 8-9 with saturated sodium bicarbonate solution, and then extracted with 2-methyl tetrahydrofuran (1500 mL×3). The organic phase was combined, successively washed with saturated brine (200 mL×2), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The resulting residue was purified by preparative HPLC (mobile phase: acetonitrile/water; acid system: 0.05% HCl) to obtain intermediate WX011-3. 1H NMR (400 MHz, DMSO_d6) δ: 12.53 (s, 1H), 9.07 (dd, J=1.2, 5.6 Hz, 1H), 8.86 (d, J=8.4 Hz, 1H), 8.65 (s, 1H), 7.81-7.74 (m, 2H).
  • 18
  • [ 1620515-86-7 ]
  • 6-bromo-7-(methoxymethoxy)quinoline [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: boron tribromide / dichloromethane / 16 h / 25 °C 1.2: pH 8 - Ca. 9 2.1: sodium hydride / tetrahydrofuran; mineral oil / 0.5 h / 25 °C 2.2: 1 h / 20 °C
Multi-step reaction with 2 steps 1.1: hydrogen bromide / water / 16 h / 100 °C 2.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 °C 2.2: 3 h / 0 - 25 °C
  • 19
  • [ 1620515-86-7 ]
  • 7-(methoxymethoxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: boron tribromide / dichloromethane / 16 h / 25 °C 1.2: pH 8 - Ca. 9 2.1: sodium hydride / tetrahydrofuran; mineral oil / 0.5 h / 25 °C 2.2: 1 h / 20 °C 3.1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate / 1,4-dioxane / 2 h / 100 °C / Inert atmosphere
  • 20
  • [ 1620515-86-7 ]
  • 6-bromo-7-(methoxymethoxy)quinoline 1-oxide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: hydrogen bromide / water / 16 h / 100 °C 2.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 °C 2.2: 3 h / 0 - 25 °C 3.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 12 h / 0 - 20 °C
  • 21
  • [ 1620515-86-7 ]
  • 6-bromo-7-(methoxymethoxy)quinolin-2(1H)-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: hydrogen bromide / water / 16 h / 100 °C 2.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 °C 2.2: 3 h / 0 - 25 °C 3.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 12 h / 0 - 20 °C 4.1: p-toluenesulfonyl chloride; potassium carbonate / 1,2-dichloro-ethane / 0.5 h / 90 °C
  • 22
  • [ 1620515-86-7 ]
  • 6-bromo-2-(fluoromethoxy)-7-(methoxymethoxy)quinoline [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: hydrogen bromide / water / 16 h / 100 °C 2.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 °C 2.2: 3 h / 0 - 25 °C 3.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 12 h / 0 - 20 °C 4.1: p-toluenesulfonyl chloride; potassium carbonate / 1,2-dichloro-ethane / 0.5 h / 90 °C 5.1: sodium hydride / N,N-dimethyl-formamide / 0.33 h / 0 - 20 °C / Sealed tube 5.2: 2 h / 50 °C
  • 23
  • [ 1620515-86-7 ]
  • 2-(fluoromethoxy)-7-(methoxymethoxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1.1: hydrogen bromide / water / 16 h / 100 °C 2.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 °C 2.2: 3 h / 0 - 25 °C 3.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 12 h / 0 - 20 °C 4.1: p-toluenesulfonyl chloride; potassium carbonate / 1,2-dichloro-ethane / 0.5 h / 90 °C 5.1: sodium hydride / N,N-dimethyl-formamide / 0.33 h / 0 - 20 °C / Sealed tube 5.2: 2 h / 50 °C 6.1: potassium acetate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 1,4-dioxane / 3 h / 100 °C / Inert atmosphere; Sealed tube
  • 24
  • [ 1620515-86-7 ]
  • racemic tert-butyl (1S,2R,3R,5R)-2-fluoro-3-((5-(2-(fluoromethoxy)-7-(methoxymethoxy)quinolin-6-yl)pyrazin-2-yl)(methyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: hydrogen bromide / water / 16 h / 100 °C 2.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 °C 2.2: 3 h / 0 - 25 °C 3.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 12 h / 0 - 20 °C 4.1: p-toluenesulfonyl chloride; potassium carbonate / 1,2-dichloro-ethane / 0.5 h / 90 °C 5.1: sodium hydride / N,N-dimethyl-formamide / 0.33 h / 0 - 20 °C / Sealed tube 5.2: 2 h / 50 °C 6.1: potassium acetate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 1,4-dioxane / 3 h / 100 °C / Inert atmosphere; Sealed tube 7.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate / dimethyl sulfoxide / 16 h / 80 °C / Inert atmosphere
  • 25
  • [ 1620515-86-7 ]
  • tert-butyl (1S,2R,3R,5R)-2-fluoro-3-([5-[2-(fluoromethoxy)-7-(methoxymethoxy)quinolin-6-yl]pyrazin-2-yl](methyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 8 steps 1.1: hydrogen bromide / water / 16 h / 100 °C 2.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 °C 2.2: 3 h / 0 - 25 °C 3.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 12 h / 0 - 20 °C 4.1: p-toluenesulfonyl chloride; potassium carbonate / 1,2-dichloro-ethane / 0.5 h / 90 °C 5.1: sodium hydride / N,N-dimethyl-formamide / 0.33 h / 0 - 20 °C / Sealed tube 5.2: 2 h / 50 °C 6.1: potassium acetate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 1,4-dioxane / 3 h / 100 °C / Inert atmosphere; Sealed tube 7.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate / dimethyl sulfoxide / 16 h / 80 °C / Inert atmosphere 8.1: CHIRAL ART Cellulose-SB / methanol; carbon dioxide / Resolution of racemate; Supercritical conditions; liquid CO2
  • 26
  • [ 1620515-86-7 ]
  • 6-(5-(((1S,2S,3R,5R)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino) pyrazin-2-yl)-2-(fluoromethoxy)quinolin-7-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 9 steps 1.1: hydrogen bromide / water / 16 h / 100 °C 2.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 °C 2.2: 3 h / 0 - 25 °C 3.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 12 h / 0 - 20 °C 4.1: p-toluenesulfonyl chloride; potassium carbonate / 1,2-dichloro-ethane / 0.5 h / 90 °C 5.1: sodium hydride / N,N-dimethyl-formamide / 0.33 h / 0 - 20 °C / Sealed tube 5.2: 2 h / 50 °C 6.1: potassium acetate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 1,4-dioxane / 3 h / 100 °C / Inert atmosphere; Sealed tube 7.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate / dimethyl sulfoxide / 16 h / 80 °C / Inert atmosphere 8.1: CHIRAL ART Cellulose-SB / methanol; carbon dioxide / Resolution of racemate; Supercritical conditions; liquid CO2 9.1: hydrogenchloride / dichloromethane; 1,4-dioxane / 2 h / 20 °C / Inert atmosphere
  • 27
  • [ 1620515-86-7 ]
  • 6-(5-(((1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino) pyrazin-2-yl)-2-(fluoromethoxy)quinolin-7-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 9 steps 1.1: hydrogen bromide / water / 16 h / 100 °C 2.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 °C 2.2: 3 h / 0 - 25 °C 3.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 12 h / 0 - 20 °C 4.1: p-toluenesulfonyl chloride; potassium carbonate / 1,2-dichloro-ethane / 0.5 h / 90 °C 5.1: sodium hydride / N,N-dimethyl-formamide / 0.33 h / 0 - 20 °C / Sealed tube 5.2: 2 h / 50 °C 6.1: potassium acetate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 1,4-dioxane / 3 h / 100 °C / Inert atmosphere; Sealed tube 7.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate / dimethyl sulfoxide / 16 h / 80 °C / Inert atmosphere 8.1: CHIRAL ART Cellulose-SB / methanol; carbon dioxide / Resolution of racemate; Supercritical conditions; liquid CO2 9.1: hydrogenchloride / dichloromethane; 1,4-dioxane / 2 h / 20 °C / Inert atmosphere
  • 28
  • [ 1620515-86-7 ]
  • tert-butyl (1R,2S,3S,5S)-2-fluoro-3-([5-[2-(fluoromethoxy)-7-(methoxymethoxy)quinolin-6-yl]pyrazin-2-yl](methyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 8 steps 1.1: hydrogen bromide / water / 16 h / 100 °C 2.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 °C 2.2: 3 h / 0 - 25 °C 3.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 12 h / 0 - 20 °C 4.1: p-toluenesulfonyl chloride; potassium carbonate / 1,2-dichloro-ethane / 0.5 h / 90 °C 5.1: sodium hydride / N,N-dimethyl-formamide / 0.33 h / 0 - 20 °C / Sealed tube 5.2: 2 h / 50 °C 6.1: potassium acetate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 1,4-dioxane / 3 h / 100 °C / Inert atmosphere; Sealed tube 7.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate / dimethyl sulfoxide / 16 h / 80 °C / Inert atmosphere 8.1: CHIRAL ART Cellulose-SB / methanol; carbon dioxide / Resolution of racemate; Supercritical conditions; liquid CO2
  • 29
  • [ 1620515-86-7 ]
  • [ 847818-74-0 ]
  • 7-methoxy-6-(2-methylpyrazol-3-yl)quinoline [ No CAS ]
YieldReaction ConditionsOperation in experiment
80% With dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); sodium carbonate In 1,4-dioxane; water at 80℃; for 2h; Inert atmosphere; 1 Step 1: A mixture of 6-bromo-7-methoxy-quinoline (100 mg, 0.420 mmol, 1.00 eq.), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (105 mg, 0.504 mmol, 1.20 eq.), Pd(dtbpf)Cl2 (27 mg, 0.042 mmol, 0.10 eq.) and sodium carbonate (89 mg, 0.840 mmol, 2.00 eq.) in dioxane (1.0 mL) and water (0.2 mL) was degassed with nitrogen. The mixture was then stirred at 80° C. for 2 hours, concentrated under reduced pressure and the residue purified by prep-TLC (SiO2, ethyl acetate) to give 7-methoxy-6-(2-methylpyrazol-3-yl)quinoline (80 mg, 0.334 mmol, 80% yield) as a yellow solid. LCMS [M+1]+=240.2; 1H NMR (400 MHz, CDCl3) δ=8.82 (dd, J=1.6, 4.4 Hz, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.65 (s, 1H), 7.51 (d, J=1.6 Hz, 1H), 7.48 (s, 1H), 7.27 (dd, J=4.4, 8.0 Hz, 1H), 6.28 (d, J=1.6 Hz, 1H), 3.91 (s, 3H), 3.70 (s, 3H).
  • 30
  • [ 1620515-86-7 ]
  • 6-(2-methylpyrazol-3-yl)quinolin-7-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: sodium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; 1,4-dioxane / 2 h / 80 °C / Inert atmosphere 2: pyridine hydrochloride / 0.5 h / 160 °C
  • 31
  • [ 1620515-86-7 ]
  • [6-(2-methylpyrazol-3-yl)-7-quinolyl]trifluoromethanesulfonate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: sodium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; 1,4-dioxane / 2 h / 80 °C / Inert atmosphere 2: pyridine hydrochloride / 0.5 h / 160 °C 3: triethylamine / dichloromethane / 1 h / 0 - 20 °C
  • 32
  • [ 1620515-86-7 ]
  • 6-(2-methylpyrazol-3-yl)quinoline-7-carbonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: sodium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; 1,4-dioxane / 2 h / 80 °C / Inert atmosphere 2: pyridine hydrochloride / 0.5 h / 160 °C 3: triethylamine / dichloromethane / 1 h / 0 - 20 °C 4: tris-(dibenzylideneacetone)dipalladium(0); zinc; 1,1'-bis-(diphenylphosphino)ferrocene / N,N-dimethyl-formamide / 2 h / 100 °C / Inert atmosphere
  • 33
  • [ 1620515-86-7 ]
  • 6-(4-bromo-2-methyl-pyrazol-3-yl)quinoline-7-carbonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: sodium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; 1,4-dioxane / 2 h / 80 °C / Inert atmosphere 2: pyridine hydrochloride / 0.5 h / 160 °C 3: triethylamine / dichloromethane / 1 h / 0 - 20 °C 4: tris-(dibenzylideneacetone)dipalladium(0); zinc; 1,1'-bis-(diphenylphosphino)ferrocene / N,N-dimethyl-formamide / 2 h / 100 °C / Inert atmosphere 5: N-Bromosuccinimide / acetonitrile / 0.5 h / 20 °C
  • 34
  • [ 1620515-86-7 ]
  • 7-hydroxyquinoline-6-carbonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: tris-(dibenzylideneacetone)dipalladium(0); zinc; 1,1'-bis-(diphenylphosphino)ferrocene / N,N-dimethyl-formamide / 2 h / 100 °C / Inert atmosphere 2: aluminum (III) chloride / toluene / 1 h / 100 °C
  • 35
  • [ 1620515-86-7 ]
  • (6-cyano-7-quinolyl)trifluoromethanesulfonate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: tris-(dibenzylideneacetone)dipalladium(0); zinc; 1,1'-bis-(diphenylphosphino)ferrocene / N,N-dimethyl-formamide / 2 h / 100 °C / Inert atmosphere 2: aluminum (III) chloride / toluene / 1 h / 100 °C 3: triethylamine / dichloromethane / 1 h / 0 - 20 °C
  • 36
  • [ 1620515-86-7 ]
  • 7-(2-methylpyrazol-3-yl)quinoline-6-carbonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: tris-(dibenzylideneacetone)dipalladium(0); zinc; 1,1'-bis-(diphenylphosphino)ferrocene / N,N-dimethyl-formamide / 2 h / 100 °C / Inert atmosphere 2: aluminum (III) chloride / toluene / 1 h / 100 °C 3: triethylamine / dichloromethane / 1 h / 0 - 20 °C 4: sodium hydrogencarbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; 1,4-dioxane / 1 h / 80 °C / Inert atmosphere
  • 37
  • [ 1620515-86-7 ]
  • 7-(4-bromo-2-methyl-pyrazol-3-yl)quinoline-6-carbonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: tris-(dibenzylideneacetone)dipalladium(0); zinc; 1,1'-bis-(diphenylphosphino)ferrocene / N,N-dimethyl-formamide / 2 h / 100 °C / Inert atmosphere 2: aluminum (III) chloride / toluene / 1 h / 100 °C 3: triethylamine / dichloromethane / 1 h / 0 - 20 °C 4: sodium hydrogencarbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; 1,4-dioxane / 1 h / 80 °C / Inert atmosphere 5: N-Bromosuccinimide / acetonitrile / 2 h / 20 °C / Inert atmosphere
  • 38
  • [ 557-21-1 ]
  • [ 1620515-86-7 ]
  • 7-methoxyquinoline-6-carbonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
72% With 1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium(0); zinc In N,N-dimethyl-formamide at 100℃; for 2h; Inert atmosphere; 1 Step 1: A mixture of 6-bromo-7-methoxy-quinoline (100 mg, 0.420 mmol, 1.00 eq.), zinc cyanide (98 mg, 0.840 mmol, 2.00 eq.), Pd2(dba)3 (38 mg, 0.042 mmol, 0.10 eq.), DPPF (47 mg, 0.084 mmol, 0.20 eq.) and zinc powder (2.8 mg, 0.042 mmol, 0.10 eq.) in DMF (2 mL) was degassed and purged with nitrogen. The mixture was then stirred at 100° C. for 2 hours then diluted with water (2 mL) and extracted with ethyl acetate (2 mL×3). The combined organic extracts were washed with brine (2 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by HPLC (0.1% formic acid) to give 7-methoxyquinoline-6-carbonitrile (56 mg, 0.304 mmol, 72% yield) as a white solid. LCMS [M+1]+=185.2; 1H NMR (400 MHz, CDCl3) δ=8.97 (dd, J=1.6, 4.0 Hz, 1H), 8.17 (s, 1H), 8.15 (dd, J=1.2, 8.4 Hz, 1H), 7.53 (s, 1H), 7.40 (dd, J=4.0, 8.4 Hz, 1H), 4.09 (s, 3H).
  • 39
  • [ 1620515-86-7 ]
  • (S)-N-((S)-1-(5-(7-methoxyquinolin-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-7-oxononyl)-6-methyl-6-azaspiro[2.5]octane-1-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate / 1,4-dioxane / 4 h / 75 °C / Inert atmosphere 2: potassium phosphate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / tetrahydrofuran; water / 4 h / 70 °C / Inert atmosphere
  • 40
  • [ 1620515-86-7 ]
  • (S)-N-((S)-1-(5-(7-methoxyquinolin-6-yl)-1H-imidazol-2-yl)-7-oxononyl)-6-methyl-6-azaspiro[2.5]octane-1-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate / 1,4-dioxane / 4 h / 75 °C / Inert atmosphere 2: potassium phosphate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / tetrahydrofuran; water / 4 h / 70 °C / Inert atmosphere 3: trifluoroacetic acid / 2 h / 20 °C
  • 41
  • [ 1620515-86-7 ]
  • (2-cyclopropyl-7-methoxyquinolin-6-yl)boronic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: sulfuric acid; silver nitrate / water / 6 h / 70 °C 1.2: 12 h / 70 °C 2.1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane / 4 h / 80 °C / Inert atmosphere
  • 42
  • [ 1620515-86-7 ]
  • (S)-N-((S)-1-(5-(7-methoxyquinolin-6-yl)-1H-imidazol-2-yl)-7-oxononyl)-6-methyl-6-azaspiro[2.5]octane-1-carboxamide 2,3-dihydroxysuccinate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate / 1,4-dioxane / 4 h / 75 °C / Inert atmosphere 2: potassium phosphate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / tetrahydrofuran; water / 4 h / 70 °C / Inert atmosphere 3: trifluoroacetic acid / 2 h / 20 °C 4: acetonitrile
  • 43
  • [ 1620515-86-7 ]
  • [ 73183-34-3 ]
  • [ 1620515-87-8 ]
YieldReaction ConditionsOperation in experiment
67% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 75℃; for 4h; Inert atmosphere;
  • 44
  • [ 1620515-86-7 ]
  • 1-(7-hydroxyquinolin-6-yl)ethan-1-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: bis-triphenylphosphine-palladium(II) chloride / 1,4-dioxane / 4 h / 20 - 90 °C / Inert atmosphere 1.2: 1 h / 25 °C 2.1: hydrogenchloride / water / 12 h / 20 - 120 °C / Inert atmosphere
  • 45
  • [ 1620515-86-7 ]
  • C12H7NO3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: bis-triphenylphosphine-palladium(II) chloride / 1,4-dioxane / 4 h / 20 - 90 °C / Inert atmosphere 1.2: 1 h / 25 °C 2.1: hydrogenchloride / water / 12 h / 20 - 120 °C / Inert atmosphere 3.1: sodium hydride / toluene / 12 h / 0 - 120 °C / Inert atmosphere
  • 46
  • [ 1620515-86-7 ]
  • C12H8N2O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: bis-triphenylphosphine-palladium(II) chloride / 1,4-dioxane / 4 h / 20 - 90 °C / Inert atmosphere 1.2: 1 h / 25 °C 2.1: hydrogenchloride / water / 12 h / 20 - 120 °C / Inert atmosphere 3.1: sodium hydride / toluene / 12 h / 0 - 120 °C / Inert atmosphere 4.1: hydroxylamine hydrochloride; sodium acetate / methanol / 13.5 h / 20 - 80 °C / Inert atmosphere
  • 47
  • [ 1620515-86-7 ]
  • C14H12N2O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: bis-triphenylphosphine-palladium(II) chloride / 1,4-dioxane / 4 h / 20 - 90 °C / Inert atmosphere 1.2: 1 h / 25 °C 2.1: hydrogenchloride / water / 12 h / 20 - 120 °C / Inert atmosphere 3.1: sodium hydride / toluene / 12 h / 0 - 120 °C / Inert atmosphere 4.1: hydroxylamine hydrochloride; sodium acetate / methanol / 13.5 h / 20 - 80 °C / Inert atmosphere 5.1: sulfuric acid / 12 h / 20 - 90 °C / Inert atmosphere
  • 48
  • [ 1620515-86-7 ]
  • C15H11N3O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1.1: bis-triphenylphosphine-palladium(II) chloride / 1,4-dioxane / 4 h / 20 - 90 °C / Inert atmosphere 1.2: 1 h / 25 °C 2.1: hydrogenchloride / water / 12 h / 20 - 120 °C / Inert atmosphere 3.1: sodium hydride / toluene / 12 h / 0 - 120 °C / Inert atmosphere 4.1: hydroxylamine hydrochloride; sodium acetate / methanol / 13.5 h / 20 - 80 °C / Inert atmosphere 5.1: sulfuric acid / 12 h / 20 - 90 °C / Inert atmosphere 6.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 13 h / 15 - 30 °C / Inert atmosphere
  • 49
  • [ 1620515-86-7 ]
  • [ 97674-02-7 ]
  • C12H11NO2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: 6-bromo-7-methoxy-quinoline; tributyl(1-ethoxyvinyl)stannane With bis-triphenylphosphine-palladium(II) chloride In 1,4-dioxane at 20 - 90℃; for 4h; Inert atmosphere; Stage #2: With hydrogenchloride In 1,4-dioxane; water at 25℃; for 1h; 7.2 Step 2: synthesis of intermediate WX007-3 Intermediate WX007-2 (8 g, 33.60 mmol) was dissolved in 1,4-dioxane (100 mL) at room temperature under nitrogen atmosphere, and then tributyl(1-ethoxyvinyl)stannane (18.20 g, 50.40 mmol, 17.01 mL) and bis(triphenylphosphine)palladium(II) dichloride (1.18 g, 1.68 mmol) were added sequentially. The reaction mixture was heated to 90 °C and stirred at 90 °C for 4 h. After the reaction mixture was cooled to room temperature (25 °C), diluted hydrochloric acid (2 M, 16.80 mL) was added, and the reaction mixture was stirred for 1 h. After the reaction was completed, an aqueous potassium fluoride solution (100 mL) and ethyl acetate (100 mL) were added, followed by filtration. The organic phase was collected after liquid separation, and the aqueous phase was extracted with ethyl acetate (100 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The resulting residue was separated by column chromatography (eluent: petroleum ether/ethyl acetate = 1/0-1/1, volume ratio) to give intermediate WX007-3. MS-ESI m/z: 202.2 [M+H]+ 1H NMR (400 MHz, DMSO_d6) δ: 8.89 (dd, J=1.6, 4.0 Hz, 1H), 8.39 (dd, J=1.2, 8.0 Hz, 1H), 8.17 (s, 1H), 7.51 (s, 1H), 7.42 (dd, J=4.2, 8.2 Hz, 1H), 4.01 (s, 3H), 2.61 (s, 3H).
  • 50
  • [ 1620515-86-7 ]
  • C15H14BrNO3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: boron tribromide / dichloromethane / 37 h / -20 - 20 °C / Inert atmosphere 2: potassium carbonate / acetonitrile / 12 h / 20 °C / Inert atmosphere
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