[ CAS No. 181950-57-2 ]

Name: 181950-57-2|4-Chloro-7-hydroxyquinoline|98%
Brand: Ambeed
SKU: A235363
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Quality Control of [ 181950-57-2 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 181950-57-2 ]

Product Details of [ 181950-57-2 ]

CAS No. :	181950-57-2	MDL No. :	MFCD09261120
Formula :	C₉H₆ClNO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	SQWLNFPPFMFTIC-UHFFFAOYSA-N
M.W :	179.60	Pubchem ID :	135729083
Synonyms :

Calculated chemistry of [ 181950-57-2 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	10
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	48.78
TPSA :	33.12 Å²

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) :	-5.56 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.7
Log Po/w (XLOGP3) :	2.59
Log Po/w (WLOGP) :	2.59
Log Po/w (MLOGP) :	1.76
Log Po/w (SILICOS-IT) :	2.6
Consensus Log Po/w :	2.25

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-3.2
Solubility :	0.113 mg/ml ; 0.000628 mol/l
Class :	Soluble
Log S (Ali) :	-2.93
Solubility :	0.209 mg/ml ; 0.00116 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.74
Solubility :	0.0327 mg/ml ; 0.000182 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.35

Safety of [ 181950-57-2 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 181950-57-2 ]

* 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.

Upstream synthesis route of [ 181950-57-2 ]
Downstream synthetic route of [ 181950-57-2 ]

[ 181950-57-2 ] Synthesis Path-Upstream 1~7

1
[ 68500-37-8 ]
[ 181950-57-2 ]

Yield	Reaction Conditions	Operation in experiment
98.6%	Reflux	4-chloro-7-methoxyquinoline 8b (3.86 g, 20 mmol), 40percent HBr (30 mL) and acetic anhydride (20 mL) were mixedHeating reflux, TLC tracking test, the reaction is completed, cooling the reaction solution to room temperature. Followed by the addition of lOOmL water to the reaction solution,20percent NaOH solution to adjust the pH to 6.0, a large amount of solid precipitation, filtration, washing and drying to give an off-white solid (3.53 g,98.6percent)
98.6%	Reflux	After mixing 4-chloro-7-methoxyquinoline 8b (3.86 g, 20 mmol), 40percent HBr (30 mL) and acetic anhydrideHeated to reflux, TLC tracking test, the reaction was completed, the reaction was cooled to room temperature.Subsequently, 100 mL of water was added to the reaction mixture to dilute it. The 20percent NaOH solution was adjusted to pH 6.0. A large amount of solid was precipitated, filtered, washed with water and dried to give an off-white solid (3.53 g, 98.6percent).
90%	With N-benzyl-N,N,N-triethylammonium chloride; boron tribromide In dichloromethane at -70 - 20℃; for 20 h; Inert atmosphere	The protection of nitrogen, -70 °C under the condition of, to the 4 - chloro -7 - methoxy quinoline (0.95g, 4 . 9mmol) in dichloromethane (45 ml) solution slowly dropping BBr₃(4.9g, 19 . 6mmol) of dichloromethane (15 ml) diluted solution. Then the reaction system raising the temperature to room temperature, adding benzyl triethyl ammonium chloride (TEBA, 0.19g 0 . 83mmol) of dichloromethane (5 ml) diluted solution, stirring at the room temperature 20h. TLC monitoring (petroleum ether: acetone=20:5, Rf=0.4). In the he stirring under ice bath cooling, in the system slowly adding ice water (25 ml) quenching BBr₃. To remove the majority of dichloromethane, for 1N NaOH PH=7 for regulating surplus solution, a large amount of white solid precipitated, filtered, vacuum (45 °C) dry 24 hours to obtain compound. Yield: 90percent.

Reference： [1] Patent: CN105037266, 2017, B, . Location in patent: Paragraph 0323-0326
[2] Patent: CN105017145, 2017, B, . Location in patent: Paragraph 0327; 0328; 0329
[3] Patent: CN106749231, 2017, A, . Location in patent: Paragraph 0116; 0117; 0118; 0119
[4] European Journal of Medicinal Chemistry, 2019, p. 666 - 678

2
[ 178984-56-0 ]
[ 181950-57-2 ]

Yield	Reaction Conditions	Operation in experiment
79%	at 100℃; for 0.166667 h; Microwave irradiation	In a 5-mL microwave tube dissolved 7-(benzyloxy)-4-chloroquinoline (0.54 g, 2.002 mmol) in 33percent HBr in AcOH (2 mL). Heated at 100 degrees in microwave for 10 min. Neutralized mixture with saturated NaHC0₃, extracted into EtOAc, washed organic layer with water then with brine. Dried organic layer with MgSC^, filtered and concentrated to obtain 4- chloroquinolin-7-ol (0.284 g, 1.581 mmol, 79 percent yield) as a white solid

Reference： [1] Patent: WO2014/160203, 2014, A2, . Location in patent: Page/Page column 92
[2] Patent: EP1154774, 2005, B1, . Location in patent: Page/Page column 59
[3] Patent: WO2007/66181, 2007, A2, . Location in patent: Page/Page column 23-24

3
[ 536-90-3 ]
[ 181950-57-2 ]

Reference： [1] European Journal of Medicinal Chemistry, 2019, p. 666 - 678

4
[ 56881-19-7 ]
[ 181950-57-2 ]

Reference： [1] European Journal of Medicinal Chemistry, 2019, p. 666 - 678

5
[ 71083-05-1 ]
[ 181950-57-2 ]

Reference： [1] European Journal of Medicinal Chemistry, 2019, p. 666 - 678

6
[ 190516-85-9 ]
[ 181950-57-2 ]

Reference： [1] European Journal of Medicinal Chemistry, 2019, p. 666 - 678

7
[ 181950-57-2 ]
[ 100-39-0 ]
[ 178984-56-0 ]

Yield	Reaction Conditions	Operation in experiment
46.8%	With potassium carbonate In acetone at 20℃;	To a 100 ml round bottom flask was added 4-chloro-7-hydroxyquinoline (0.89 g, 5 mmol), acetone (40 ml), benzyl bromide(7.5 mmol) and anhydrous K2C03 (2. Og)The reaction was stirred at room temperature,TLC trace detection.After completion of the reaction, acetone was distilled off under reduced pressure, 150 mL of water was added,Extracted with ethyl acetate, the organic phase was combined, acidified with concentrated hydrochloric acid and anhydrous ethanol was added to give a dark oilThe crystals were recrystallized from acetone and the crystals were precipitated and filtered and basified to give a white solid (0.63 g, yield 46.8percent)
46.8%	With potassium carbonate In acetone at 20℃;	A 100 ml round bottomed flask was charged with 4-chloro-7-hydroxyquinoline (0.89 g, 5 mmol), acetone (40 ml), benzyl bromide(7.5 mmol) and anhydrous K2CO3 (2.0 g). The reaction was stirred at room temperature and checked by TLC.After completion of the reaction, the acetone was distilled off under reduced pressure, 150 mL of water was added and the mixture was extracted with ethyl acetate. The combined organic phases were acidified with concentrated hydrochloric acid and brought to absolute ethanol with water to give a dark oil. The crystals were recrystallized from acetone to precipitate crystals. To give a white solid (0.63 g, 46.8percent yield).
0.5 g	With sodium hydride In N,N-dimethyl-formamide at 20℃;	General procedure: A mixture of 4-chloroquinolin-7-ol 8 (0.72g, 4mmol) and anhydrous DMF (10mL) was stirred at room temperature until clear, and then, 60percent NaH (0.4g, 10mmol) and halogenated alkane (20–30mmol) were added. The mixture was stirred at room temperature. After completion of the reaction as indicated by TLC, the solution was poured into H₂O (100mL) and extracted with ethyl acetate. The organic phase was made acidic with concentrated hydrochloric acid. Upon removal of solvent, the residue was crystallized from acetone to afford a yellow solid. The solid was dissolved in water and made basic with sodium bicarbonate, and the aqueous mixture was extracted with ethyl acetate. The organic phase was washed with water and brine and then dried over anhydrous sodium sulfate, filtered and evaporated. The resulting oil was purified by column chromatography using a mixture of dichloromethane and methanol 100:1 as the eluent to successfully afford the target products 9a-k in good yield.

Reference： [1] Patent: CN105037266, 2017, B, . Location in patent: Paragraph 0323-0324; 0339-0340
[2] Patent: CN105017145, 2017, B, . Location in patent: Paragraph 0327; 0342; 0343
[3] European Journal of Medicinal Chemistry, 2019, p. 666 - 678

[ 181950-57-2 ] Synthesis Path-Downstream 1~69

1
[ 181950-57-2 ]
[ 196195-13-8 ]
4-(4-chloroquinolin-7-yloxy)-6-methoxy-7-(3-morpholinopropoxy)quinazoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide;	Example 22 To 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (250mg, 0.74mmol), (prepared as described for the starting material in Example 1), in suspension in DMF (4ml) were successively added <strong>[181950-57-2]4-chloro-7-hydroxyquinoline</strong> (133mg, 0.74mmol) and potassium carbonate (153mg, 1mmol) and the reaction mixture heated to 100C. More <strong>[181950-57-2]4-chloro-7-hydroxyquinoline</strong> (27mg, 0.15mmol) was added after one hour and heating was continued for a further 30 minutes. The product precipitated upon cooling to ambient temperature. The reaction mixture was diluted with water, the product was collected by filtration and washed with more water. The dried solid was triturated with ether and filtered to give 4-(4-chloroquinolin-7-yloxy)-6-methoxy-7-(3-morpholinopropoxy)quinazoline (166mg, 47%). 1H NMR Spectrum: (DMSOd6, CF3CO2D) 2.3(m, 2H); 3.2(m, 2H); 3.4(m, 2H); 3.5(m, 2H); 3.7(m, 2H); 4.0(m, 2H); 4.1(s, 3H); 4.4(m, 2H); 7.55(s, 1H); 7.75(s, 1H); 7.90(dd, 1H); 7.95(d, 1H); 8.15(d, 1H); 8.45 (d, 1H); 8.80(s, 1H); 9.05(d, 1H) MS - ESI: 481 [MH]+

Reference： [1]Patent: EP1154774,2005,B1 .Location in patent: Page/Page column 59

2
[ 264209-11-2 ]
[ 181950-57-2 ]
4-(4-chloroquinolin-7-yloxy)-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		a) Using <strong>[181950-57-2]4-chloro-7-hydroxyquinoline</strong> (96 mg) gave 4-(4-chloroquinolin-7-yloxy)-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline. 1H NMR Spectrum: (DMSOd6) 2.24 (m, 2H); 3.04 (s, 3H); 3.35 (m, 2H); 3.99 (s, 3H); 4.32 (m, 2H); 7.42 (s, 1H); 7.64 (s, 1H); 7.80 (d, 2H); 8.04 (d, 1H); 8.29 (d, 1H); 8.55 (s, 1H); 8.87 (d, 1H)

Reference： [1]Patent: EP1154774,2005,B1 .Location in patent: Page/Page column 115

3
[ 178984-56-0 ]
[ 181950-57-2 ]

Yield	Reaction Conditions	Operation in experiment
79%	With hydrogen bromide; acetic acid; at 100℃; for 0.166667h;Microwave irradiation;	In a 5-mL microwave tube dissolved 7-(benzyloxy)-4-chloroquinoline (0.54 g, 2.002 mmol) in 33% HBr in AcOH (2 mL). Heated at 100 degrees in microwave for 10 min. Neutralized mixture with saturated NaHC03, extracted into EtOAc, washed organic layer with water then with brine. Dried organic layer with MgSC^, filtered and concentrated to obtain 4- chloroquinolin-7-ol (0.284 g, 1.581 mmol, 79 % yield) as a white solid
	With sodium hydrogencarbonate; In trifluoroacetic acid; for 2h;Heating / reflux;	The starting material was prepared as follows: A solution of 7-benzyloxy-4-chloroquinoline (17g, 56mmol), (Konishi et al. WO 96/11187), in TFA (170ml) was heated at reflux for 2 hours. The solvent was removed under vacuum and the residue was triturated with ether, filtered and washed with ether. The solid was suspended in an aqueous solution of sodium hydrogen carbonate (5.5g, 65mmol in 200ml of water) and stirred at ambient temperature for 30 minutes. The solid was collected by filtration, washed with water and dried overnight under vacuum and over phosphorus pentoxide to give 4-chloro-7-hydroxyquinoline (9.85g, 98%). 1H NMR Spectrum: (DMSOd6) 7.37(s, 1H); 7.39(d, 1H); 7.62(d, 1H); 8.15(d, 1H); 8.8(d, 1H) MS - EI: m/z 179 [M.]+
		A 5-L, 3-neck flask was charged with MSA (600 mL), and external cooling was initially set to 21 to 22C. DL-methionine (220 g, 1.4830 mol) was then added in 4 to 5 portions over approximately 45 minutes. After complete addition of methionine, the reaction mixture was stirred for 1 to 2 hours at ~20C. A compound of formula ^a(100.00 g, 0.3707 mol) was then added, and the thick suspension was heated at 60 to650C for 60 to 90 minutes. The mixture was then cooled to 20 to 25C, and a cold (- 50C) solution of NaOH (490 g) in H2O (1500 mL) was added until pH~7. The suspension was then granulated, filtered, rinsed with H2O (1000 mL), and pulled dry by suction. The collected solids were recharged to the reaction flask, H2O (1800 mL) was added, and the contents of the flask were cooled to 20 to 25C. The pH was then adjusted to pH=1 to 2 by addition of 37% HCI. A clear yellow/orange solution was obtained. This solution was neutralized to pH~7 by addition of 10% aqueous NaOH solution (~400 mL). Once pH~7 was obtained, the mixture was granulated for at least 2 hours at 20 to 25C, and then filtered. The contents of the flask were rinsed forward with H2O and the filter cake was rinsed thoroughly with H2O (total amount for rising flask and wetcake: 3x1000 mL). The collected solids were pulled dry and then dried in vacuo at 60 to 7O0C with a nitrogen bleed to afford 3+/-a as an off-white solid.1H NMR of 3-a (300MHz1 d6-DMSO): 10.46 (s, 1 H, OH); 8.68 (d, J = 4.8 Hz, 1 H); 8.06 (d, J = 9.6 Hz, 1 H); 7.49(d, J = 4.8 Hz, 1 H); 7.30-7.34 (m, 2 H).13C NMR of 3-a (75 MHz, d6-DMSO): 159.8, 151.0, 150.9, 141.3, 125.4, 121.1 , 120.0, 118.9, 110.9.

Reference： [1]Patent: WO2014/160203,2014,A2 .Location in patent: Page/Page column 92
[2]Patent: EP1154774,2005,B1 .Location in patent: Page/Page column 59
[3]Patent: WO2007/66181,2007,A2 .Location in patent: Page/Page column 23-24

4
[ 181950-57-2 ]
[ 64-17-5 ]
[ 178984-50-4 ]

Yield	Reaction Conditions	Operation in experiment
	With tributylphosphine; 1,1'-azodicarbonyl-dipiperidine; In dichloromethane; at 17 - 25℃; for 14h;	The 2-[4-(7-ethoxyquinolin-4-yloxy)-2-methoxyphenyl] acetic acid used as starting material was prepared as follows :- Tributylphosphine (4.57 ml) and 1,1 '-(azodicarbonyl)dipiperidine (4.62 g) were added in turn to a stirred mixture of <strong>[181950-57-2]4-chloro-7-hydroxyquinoline</strong> (International Application WO 02/00622, preparation 37 thereof; 2.74 g), ethanol (1.34 ml) and methylene chloride (100 ml) and the resultant mixture was stirred at ambient temperature for 14 hours. The mixture was filtered and the filtrate was concentrated by evaporation. The residue was purified by column chromatography on silica using a 1 :1 mixture of methylene chloride and diethyl ether as eluent. There was thus obtained 4-chloro-7-ethoxyquinoline (2.23 g); <n="159"/>1H NMR: (DMSOd6) 1.42 (t, 3H), 4.23 (q, 2H), 7.39 (m, IH), 7.45 (d, IH), 7.58 (d, IH), 8.1 (d, IH), 8.75 (d, IH); Mass Spectrum: M+H+ 208.

Reference： [1]Patent: WO2007/99326,2007,A1 .Location in patent: Page/Page column 157-158

5
[ 181950-57-2 ]
[ 3647-69-6 ]
4-(2-((4-chloroquinolin-7-yl)oxy)ethyl)morpholine [ No CAS ]