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CAS No. : | 206257-39-8 | MDL No. : | MFCD00173367 |
Formula : | C12H9BrClNO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | YGMLKBFPHVLHGT-UHFFFAOYSA-N |
M.W : | 314.56 | Pubchem ID : | 2764138 |
Synonyms : |
|
Num. heavy atoms : | 17 |
Num. arom. heavy atoms : | 10 |
Fraction Csp3 : | 0.17 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 70.54 |
TPSA : | 39.19 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.57 cm/s |
Log Po/w (iLOGP) : | 2.44 |
Log Po/w (XLOGP3) : | 3.73 |
Log Po/w (WLOGP) : | 3.83 |
Log Po/w (MLOGP) : | 3.11 |
Log Po/w (SILICOS-IT) : | 3.96 |
Consensus Log Po/w : | 3.41 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -4.38 |
Solubility : | 0.0132 mg/ml ; 0.0000419 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -4.24 |
Solubility : | 0.0179 mg/ml ; 0.0000569 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -5.63 |
Solubility : | 0.000734 mg/ml ; 0.00000233 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.91 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H319 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With trichlorophosphate In N,N-dimethyl-formamide at 20℃; for 3 h; Inert atmosphere | Suspend 6-bromo-4-hydroxyquinoline-3-carboxylic acid ethyl ester (11 g, 37 mmol) in anhydrous dimethylformamide (148.6 mL) under nitrogen atmosphere. Add phosphoryl chloride (20.7 mL, 222 mmol, 6 eq.) via syringe over 5 minutes and stir vigorously at room temperature for 3 hours. Quench the reaction by pouring the mixture into ice water (1.5 L) and continue stirring until all the ice has melted. Obtain the solid formed by filtration, rinse with water and allow complete drying to afford the titled compound (11.4 g, 94percent). MS (ESI) m/z (M+H)+314.0, 316.0 |
94.1% | at 120℃; for 3 h; | 6-Bromo-4-hydroxyquinoline-3-carboxylic acid ethyl ester (10 g) in phosphorus oxychloride(100 mL) was stirred at 120 ° C under reflux for 3 hours.The reaction mixture was evaporated in vacuo to remove phosphorous oxychloride.The residue was poured into ice-water and the pH was adjusted to 6 with saturated aqueous sodium bicarbonate.The resulting mixture was extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated.The residue was purified by flash column chromatography (silica gel, petroleum ether / ethyl acetate = 80: 1) to give the product as a white solid (10 g, 94.1percent yield). |
93% | for 4 h; Reflux | To a suspension of 5 (4.00 g, 13.6 mmol) in POCl3 (15.0 mL) was added catalytic amount of N,N-dimethylformamide (DMF) and the mixture was heated to reflux for 4 h. It was then cooled to room temperature and carefully poured onto ice. After vigorous agitation, the precipitate was filtered, washed with water and dissolved in DCM. The solution was subsequently washed with saturated NaHCO3 solution, brine, dried with anhydrous Na2SO4 and concentrated in vacuo to provide the title intermediate as a light yellow solid. Yield: 93percent; 1H NMR (500 MHz, CDCl3): δ 9.21 (s, 1H, Ar-H), 8.47 (d, 1.5 Hz, 1H, Ar-H), 8.02 (d, 9.0 Hz, 1H, Ar-H), 7.95 (dd, 1.5 Hz, 9.0 Hz, 1H, Ar-H), 4.40 (q, 7.0 Hz, 2H, CH2), 1.60 (t, 7.0 Hz, 3H, CH3). ESI-MS: m/z = 314 [M+H]+. |
83% | With trichlorophosphate In N,N-dimethyl-formamide for 6 h; Reflux | To a 100 mL round-bottomed flask was added ethyl 6-bromo-4-hydroxyquinoline-3- carboxylate (6) (10.0 g, 33.90 mmol), POCl3(100 mL) and DMF (2 mL). The mixture was stirred at reflux for 6 h.After cooling to room temperature, the reaction mixture waspoured into ice water (100 mL) and stirred for 1 h. Then the pH ofthe mixture was adjusted to 8 using saturated aqueous NaHCO3. The mixture was extracted with EtOAc and the organic phase wasdried over sodium sulfate and concentrated in vacuo to give thetitle compound (8.82 g, 28.18 mmol, 83percent yield) as a brown solid.ESI-MS: m/z = 314 [M+H]+. |
72% | Stage #1: Heating / reflux |
Ethyl 6-bromo-4-chloro-3-quinolinecarboxylate. The mixture of the compound from Example 17 a) (2.0 g, 6.8 mmol) in POCI3 (20 ml_) was ref luxed overnight. The product was cooled, quenched with ice water, diluted with ethyl acetate, washed with NaHCO3 and brine. The organic layer was separated, dried over magnesium sulfate, filtered, concentrated under vacuo and purified via flash chromatography (0-100percent ethyl acetate in hexane) to afford the title compound as a white solid (1.5 g, 72percent). 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.22 (s, 1 H) 8.59 (d, J=2.02 Hz, 1 H) 8.03 (d, J=8.84 Hz, 1 H) 7.93 (dd, J=8.97, 2.15 Hz, 1 H) 4.53 (q, J=7.24 Hz, 2 H) 1.49 (t, J=7.20 Hz, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.8% | for 1 h; Reflux | Compound 2 (19.4g, 0.O6mol) was suspended in POC13 (45m1) and heated at reflux for 1 hour. The excess solvent was evaporated under reduced pressure and the deep brown residue was taken up in dichloromethane (1 50m1) and washed sequentially by water (1 OOml), saturated sodium bicarbonate (lOOml), and brine (lOOml). The organic phase was dried over sodium sulfate, the solid was filtered off and the filtrate was concentrated to give ethyl 6-bromo-4-chloroquinoline-3-carboxylate (compound 3, 17.67g, 93.8percent) as a yellowish solid. |
93.8% | for 1 h; Reflux | Compound 2 (19.4g, 0.06mol) was suspended in POCI3 (45ml) and heated at reflux for 1 hour. The excess solvent was evaporated under reduced pressure, the deep brown residue was taken up in dichloromethane (150ml) and washed sequentially by water (100ml), saturated sodium bicarbonate (100ml), and brine (100ml). The organic phase was dried over sodium sulfate, the solid was filtered off and the filtrate was concentrated to give ethyl 6-bromo-4-chloroquinoline-3- carboxylate (compound 3, 17.67g, 93.8percent) as a yellowish solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | Stage #1: at 180℃; for 0.583333 h; Microwave Stage #2: With sodium hydroxide In dichloromethane; water |
A 20 niL microwave vial was charged with 2-[(4-bromo-phenylamino)methylene]malonic acid diethyl ester (1.711 g, 5.0 mmol) and POCl3 (phosphoryl chloride, 10.0 mL, 16.8 g, 109 mmol). The vial was capped and the mixture was microwave heated stepwise up to 1800C(watching the pressure) over 5 min and then kept at 1800C for 30 min. Excess POCl3 was evapo- rated and the residue partitioned between CH2Cl2 (40 mL) and 2 N NaOH (aq) (40 mL). The aqueous layer was extracted with CH2Cl2 (2x40 mL). The organic layers were combined, dried with Na2CO3 and evaporated. The residue was purified on column (silica gel, CH2Cl2 as eluent).Pure fractions were pooled, evaporated and the residue dried under vacuum to give 0.821 g(52percent) of 6-bromo-4-chloroquinoline-3-carboxylic acid ethyl ester. MS (ESI+) m/z 314, 316 (MH+). |
52% | Stage #1: at 180℃; for 0.583333 h; Microwave irradiation Stage #2: With sodium hydroxide; water In dichloromethane |
Example 2; Intermediary Compound 2. 6-Bromo-4-chloroquinoline-3-carboxylic acid ethyl ester; A 20 niL microwave vial was charged with 2-[(4-Bromo-phenylamino)-methylene]-malonic acid diethyl ester (1.711 g, 5.0 mmol) and phosphoryl chloride (10.0 mL, 16.8 g, 109 mmol. The vial was capped and the mixture was microwave heated stepwise up to 1800C (watching the pressure) over 5 min and then kept at 1800C for 30 min. Excess POCI3 was evaporated and the residue partitioned between CH2Cl2 (40 mL) and 2 M NaOH (aq) (40 mL). The aqueous layer was ex- tracted with CH2Cl2 (2x40 mL). The organic layers were combined, dried with Na2CO3 and evaporated. The residue was purified by silica flash chromatography using CH2Cl2 as eluent. Pure fractions were combined, evaporated and the residue dried under vacuum to give 0.821 g (52percent) of the title compound. MS (ESI+) m/z 314, 316 (MH+) |
50% | Stage #1: at 150℃; for 6 h; Stage #2: With sodium hydroxide In dichloromethane; water |
2-[(4-Bromophenylamino)methylene]malonic acid diethyl ester (5g) was heated with POCI3 (phosphoryl chloride, 31.5 mL) at 150 0C in a sealed tube for about 6h. The excess POCI3 was removed by rotavapor and the crude mixture was diluted with dichloromethane. The di- chloromethane extract was washed with 10percent NaOH solution, dried over sodium sulphate and purified by column chromatography (Silica gel, hexane/ethyl acetate 80:20) to give 2.3g (50percent) of 6-bromo-4-chloroquinoline-3-carboxylic acid ethyl ester. 1H NMR (300 MHz, CDCI3) δ 9.22 (s, IH, aromatic), 8.60 (d, IH, J = 2.1 Hz, aromatic), 8.04 (d, IH, J = 9 Hz, aromatic),7.95-7.85 (m, IH, aromatic), 4.53 (q, 2H, J = 7 Hz, -CH2-), 1.50 (t, 3η, J = 7 Hz, -CH3); LC-MS(m/z) 315.8 (M+l). |
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