[ CAS No. 13669-57-3 ] {[proInfo.proName]}

Name: 13669-57-3|3-Bromoquinolin-6-ol|97%
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Quality Control of [ 13669-57-3 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 13669-57-3 ]

Product Details of [ 13669-57-3 ]

CAS No. :	13669-57-3	MDL No. :	MFCD18260430
Formula :	C₉H₆BrNO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	IGCRMJVOMNKTGB-UHFFFAOYSA-N
M.W :	224.05	Pubchem ID :	14807871
Synonyms :

Calculated chemistry of [ 13669-57-3 ]

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 :	51.47
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) :	-5.77 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.78
Log Po/w (XLOGP3) :	2.67
Log Po/w (WLOGP) :	2.7
Log Po/w (MLOGP) :	1.9
Log Po/w (SILICOS-IT) :	2.64
Consensus Log Po/w :	2.34

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.53
Solubility :	0.0664 mg/ml ; 0.000297 mol/l
Class :	Soluble
Log S (Ali) :	-3.02
Solubility :	0.215 mg/ml ; 0.000961 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.98
Solubility :	0.0232 mg/ml ; 0.000104 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.39

Safety of [ 13669-57-3 ]

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 [ 13669-57-3 ]

* 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 [ 13669-57-3 ]
Downstream synthetic route of [ 13669-57-3 ]

[ 13669-57-3 ] Synthesis Path-Upstream 1~6

1
[ 1022151-47-8 ]
[ 13669-57-3 ]

Yield	Reaction Conditions	Operation in experiment
86%	With methanol; potassium carbonate In water at 20℃; for 2 h;	A solution of J.ii (1 g, 3.76 mmol) and K₂C0₃ (1.04 g, 7.52 mmol) in MeOH/H₂0 (5 mL/3 mL) was stirred at rt for 2 hours. The reaction mixture was concentrated under reduced pressure to afford a crude solid which was further purified by washing with water, dried under vaccum to give the title compound J.iii as white solid (760 mg, yield 86percent). LCMS (method B): [M+H]⁺ = 224, t_R = 2.29 min
86%	With water; potassium carbonate In methanol at 20℃; for 2 h;	A solution of Intermediate A (1 g, 3.76 mmol) and K₂C0₃ (1.04 g, 7.52 mmol) in MeOH/H₂0 (5 mL/3 ml.) was stirred at rt for 2 hours. The reaction mixture was concentrated under reduced pressure to afford a crude solid which was further purified by washing with water, dried under vaccum to give the title compound as white solid (760 mg, yield 86percent). LCMS (method N): [M+H]⁺ = 224, t_R = 2.29 min.
86%	With water; potassium carbonate In methanol at 20℃; for 1 h;	A solution of Intermediate A (1 g, 3.76 mmol) and K₂CO₃(1.04 g, 7.52 mmol) in MeOH/H₂O (5 mL/3 mL) was stirred at rt for 2 hours. The reaction mixture was concentrated under reduced pressure to afford a crude solid which was further purified by washing with water, dried under vacuum to give the title compound as white solid (760 mg, yield 86percent). LCMS (method N): [M+H]⁺=224, t_R=2.29 min.

86%

With potassium carbonate In methanol; water at 20℃; for 2 h;

A solution of J.ii (1 g, 3.76 mmol) and K₂CO₃(1.04 g, 7.52 mmol) in MeOH/H₂O (5 mL/3 mL) was stirred at rt for 2 hours. The reaction mixture was concentrated under reduced pressure to afford a crude solid which was further purified by washing with water, dried under vacuum to give the title compound J.iii as white solid (760 mg, yield 86percent). LCMS (method B): [M+H]⁺=224, t_R=2.29 min.

Reference： [1] Patent: WO2012/107500, 2012, A1, . Location in patent: Page/Page column 63; 64
[2] Patent: WO2013/38362, 2013, A1, . Location in patent: Page/Page column 75
[3] Patent: US2013/245002, 2013, A1, . Location in patent: Paragraph 0702
[4] Patent: US2013/324526, 2013, A1, . Location in patent: Paragraph 0456; 0459

2
[ 7101-96-4 ]
[ 13669-57-3 ]

Reference： [1] Synlett, 2014, vol. 25, # 6, p. 858 - 862

3
[ 580-16-5 ]
[ 13669-57-3 ]

Reference： [1] Patent: WO2012/107500, 2012, A1,
[2] Patent: WO2013/38362, 2013, A1,
[3] Patent: US2013/245002, 2013, A1,
[4] Patent: US2013/324526, 2013, A1,

4
[ 24306-33-0 ]
[ 13669-57-3 ]

Reference： [1] Patent: WO2012/107500, 2012, A1,
[2] Patent: WO2013/38362, 2013, A1,
[3] Patent: US2013/245002, 2013, A1,
[4] Patent: US2013/324526, 2013, A1,

5
[ 7101-95-3 ]
[ 13669-57-3 ]

Reference： [1] Synlett, 2014, vol. 25, # 6, p. 858 - 862

6
[ 13669-57-3 ]
[ 889660-68-8 ]

Reference： [1] Patent: WO2009/49716, 2009, A2, . Location in patent: Page/Page column 27
[2] Patent: WO2006/58700, 2006, A1, . Location in patent: Page/Page column 96-97
[3] Patent: WO2008/110355, 2008, A1, . Location in patent: Page/Page column 82

[ 13669-57-3 ] Synthesis Path-Downstream 1~88

1
[ 13669-57-3 ]
[ 79-22-1 ]
[ 74-88-4 ]
[ 132438-35-8 ]

Reference： [1]Journal of Organic Chemistry,1991,vol. 56,p. 1692 - 1694

2
[ 13669-57-3 ]
[ 132438-36-9 ]

Reference： [1]Journal of Organic Chemistry,1991,vol. 56,p. 1692 - 1694

3
[ 13669-57-3 ]
[ 132410-41-4 ]

Reference： [1]Journal of Organic Chemistry,1991,vol. 56,p. 1692 - 1694

4
[ 13669-57-3 ]
[ 132438-38-1 ]

Reference： [1]Journal of Organic Chemistry,1991,vol. 56,p. 1692 - 1694

5
[ 872-50-4 ]
[ 13669-57-3 ]
[ 696612-04-1 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium chloride; copper(l) chloride; at 120 - 170℃; for 4h;	To a stirred solution of <strong>[13669-57-3]3-bromo-6-hydroxyquinoline</strong> (l.Og) in N-methylpyrrolidin-2-one (12ml, deoxygenated by bubbling nitrogen through the solution)was added copper (1) chloride (l.lOg) and potassium chloride (1.66g). The mixture washeated to 120C for 2 hours under an atmosphere of nitrogen then for 2 hours at 170C. The reaction was diluted with saturated aqueous ammonium chloride solution, ethylacetate was added and the mixture was stirred to dissolve the required product. Themixture was filtered to remove the insoluble material and the organic phase separated.The aqueous phase was extracted with ethyl acetate (three times) and the insolublematerial washed with warm ethyl acetate. The ethyl acetate fractions were combined,washed with water, dried over magnesium sulphate then evaporated under reducedpressure to give a solid. The solid was fractionated by chromatography (silica; ethylacetate /hexane 9:1 by volume) to give 3-chloro-6-hydroxyquinoline, 0.7g, as a colourlesssolid..H NMR (CDC13) 8 ppm: 7.06 (lH,d); 7.35 (lH,dd); 7.91 (lH,d); 7.96 (lH,d); 8.59(lH,d); 9.55 (lH,s).

Reference： [1]Patent: WO2004/108663,2004,A1 .Location in patent: Page 95-96

6
[ 773837-37-9 ]
[ 13669-57-3 ]
copper(II) cyanide [ No CAS ]
[ 13669-59-5 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium chloride; In 1-methyl-pyrrolidin-2-one; water; at 20 - 150℃; for 25.25h;	3-Bromo-6-hydroxyquinoline (1. 12g) in dry N-methylpyrrolidin-2-one ( Oml) was treated with cuprous cyanide (0.55g) and stirred at 150C for 7 hours under an atmosphere of nitrogen then stored at ambient temperature for 18 hours. The mixture was treated with sodium cyanide (1.5g) in water (5ML) and heated at 75C for 15 minutes. 10% Aqueous ammonium chloride solution (25ML) was added and the mixture cooled to ambient temperature. The reaction mixture was extracted with ethyl acetate and the organic phase separated, washed with water, dried over magnesium sulphate and evaporated under reduced pressure to give a yellow brown solid. The solid was fractionated by chromatography to give the required product as a yellow solid.

Reference： [1]Patent: WO2004/47538,2004,A1 .Location in patent: Page 59-60

7
[ 543690-76-2 ]
[ 13669-57-3 ]
2-(3-bromo-6-quinolinyloxy)-N-(4-methylpent-2-yn-4-yl)butyramide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 80℃; for 15h;	To a stirred mixture of <strong>[13669-57-3]3-bromo-6-hydroxyquinoline</strong> (0.179g) and anhydrous potassium carbonate (0. 121G) in dry N-DIMETHYLFORMAMIDE (2ml) at 80C was added 2- BROMO-N- (4-METHYLPENT-2-YN-4-YL) butyramide (0.197g) and the reaction maintained at this temperature for 15 hours. The brown suspension produced was cooled to ambient temperature, poured into water and extracted with diethyl ether. The extract was washed with water, dried over magnesium sulphate then evaporated under reduced pressure to give a brown gum. The gum was fractionated by chromatography (silica; hexane/ethyl acetate) to give 2- (3-BROMO-6-QUINOLINYLOXY)-N- (4-METHYLPENT-2-YN-4-YL) butyramide (0.125g) as a colourless solid, m. p. 109-112C, LHNMR (CDCL3) O : 1.08 (3H, T) ; 1.58 (3H, s); 1.59 (3H, s); 1.77 (3H, s); 1.99-2. 06 (2H, M) ; 4.54 (1H, t); 6.37 (1H, s); 7.02 (1H, M) ; 7.42 (1H, dd); 8.02 (1H, d); 8.19 (1H, M) ; 8.78 (LH, m).

Reference： [1]Patent: WO2004/47538,2004,A1 .Location in patent: Page 56-57

8
[ 13669-57-3 ]
[ 808755-53-5 ]

Yield	Reaction Conditions	Operation in experiment
		To a stirred solution of <strong>[13669-57-3]3-bromo-6-hydroxyquinoline</strong> (0.67g) in drytetrahydrofuran (15ml) cooled to -78C under an atmosphere of nitrogen was addeddropwise a solution of n.butyl lithium (2.4ml, 2.5M solution in hexanes) such that thereaction was maintained below -72C. The orange suspension that was produced wasstirred at -78C and a solution of ./V-fluorobenzensulphonimide (0.97g) in tetrahydrofuran(10ml) was added dropwise maintaining the reaction below -68C during the addition.The red solution that formed was stirred, allowing the reaction to gradually reach ambienttemperature. The solution was treated with water then taken to pH 4-5 with aqueoushydrochloric acid. The emulsion that formed was extracted with ethyl acetate, separated and the organic phase was washed with brine, dried over magnesium sulphate andevaporated under reduced pressure. The residual gum was fractionated bychromatography (silica; hexane/ethyl acetate) to give an orange solid containing thedesired product.

Reference： [1]Synlett,2014,vol. 25,p. 858 - 862
[2]Patent: WO2004/108663,2004,A1 .Location in patent: Page 96

9
[ 13669-57-3 ]
[ 696612-04-1 ]

Yield	Reaction Conditions	Operation in experiment
		3-Bromo-6-hydroxyquinoline (2.75g) and cuprous chloride (9g) in DRY N methylpyrrolidin-2-one (25ML) were stirred and heated at 150C under an atmosphere of nitrogen for 2 hours. The dark red suspension was cooled to ambient temperature, poured into water then treated with sufficient aqueous ammonia to dissolve the solid material. The blue solution was taken to pH 5-6 with hydrochloric acid (2M) then ethyl acetate was added. The mixture was filtered and the insoluble solids washed with ethyl acetate. The organic component of the filtrate was separated and the aqueous phase was further extracted with ethyl-acetate. The ethyl acetate fractions were combined, washed with brine, dried over magnesium sulphate then evaporated under reduced pressure to give a solid. The solid was fractionated by chromatography (silica; hexane/ethyl acetate, 2: 1 by volume) to give 3-CHLORO-6-HYDROXYQUINOLINE as a pale yellow solid, 0.95g. (M+179, LXCL). LH NMR (CDCL3) 8 : 7.06 (1H, d); 7.35 (1H, dd); 7.91 (1H, d); 7.96 (1H, d); 8.59 (1H, d); 9.55 (1H, s).
	With potassium chloride; copper(l) chloride; In 1-methyl-pyrrolidin-2-one; at 120 - 170℃; for 4h;	EXAMPLE 5; This Example illustrates the preparation of 2-(3-chloroquinolinyl-6-oxy)-2-methylthio-iV- (2-methylprop-2-yl) acetamide (Compound No. 12 of Table 58); Stage 1: Preparation of 3-chloro-6-hydroxyquinoline; To a stirred solution of <strong>[13669-57-3]3-bromo-6-hydroxyquinoline</strong> (1.Og) inJV- methylpyrrolidin-2-one (12ml, deoxygenated by bubbling nitrogen through the solution) was added copper (1) chloride (1.1 Og) and potassium chloride (1.66g). The mixture was heated to 12O0C for 2 hours under an atmosphere of nitrogen then for 2 hours at 17O0C. The reaction was diluted with saturated aqueous ammonium chloride solution, ethyl acetate was added and the mixture was stirred to dissolve the required product. The mixture was filtered to remove the insoluble material and the organic phase separated. The aqueous phase was extracted with ethyl acetate (three times) and the insoluble material washed with warm ethyl acetate. The ethyl acetate fractions were combined, washed with water, dried over magnesium sulphate then evaporated under reduced pressure to give a solid. The solid was fractionated by chromatography (silica; ethyl acetate /hexane 9:1 by volume) to give 3-chloro-6-hydroxyquinoline, 0.7g, as a colourless solid.1H NMR (CDCl3) delta ppm: 7.06 (lH,d); 7.35 (lH,dd); 7.91 (lH,d); 7.96 (lH,d); 8.59 (lH,d); 9.55 (lH,s).

Reference： [1]Patent: WO2004/47538,2004,A1 .Location in patent: Page 57
[2]Patent: WO2006/58700,2006,A1 .Location in patent: Page/Page column 80

10
[ 13669-57-3 ]
[ 889660-68-8 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium iodide; N,N`-dimethylethylenediamine;copper(l) iodide; In 1,4-dioxane; at 120℃; for 14h;	Step 2: Preparation of 3-iodo-6-hydroxyquinolineTo a stirred mixture of <strong>[13669-57-3]3-bromo-6-hydroxyquinoline</strong> (preparation described in Liebigs Ann Chem 1966, 98-106), (3.Og), sodium iodide (4.0g) and copper iodide (0.25g) in dioxane (19.5ml) is added N,N'-tetramethyl-ethane-1 ,2-diamine (0.24g) in a sealed tube under argon. The mixture is stirred at 1200C for 14h and upon cooling is treated with aqueous ammonia followed by aqueous hydrochloric acid to reach pH 5. Extraction with ethyl acetate, drying of the organic phase over magnesium sulphate, filtration and evaporation under reduced pressure gives the required product ((M+1)+ 272) as a light brown coloured powder that is used as such in the next step.
	With copper(l) iodide; N,N,N,N,-tetramethylethylenediamine; sodium iodide; In 1,4-dioxane; at 120℃; for 12h;	EXAMPLE 13A; This Example illustrates the preparation of 2-(3-iodo-quinolinyl-6-oxy)-2-methylthio-N-(2-methylprop-2-yl) acetamide (Compound No. 12 of Table 58A); Step 1 : Preparation of 3-iodo-6-hydroxyquinoline; To a stirred mixture of <strong>[13669-57-3]3-bromo-6-hydroxyquinoline</strong> (preparation described in Liebigs Ann Chbetam (1966), 98-106) (1.Og), sodium iodide (1.34g) and copper iodide(0.09g) in dioxane (6.5ml) was added N,N,N',N'-tetramethyl-ethane-l,2-diamine (0.1ml) in a sealed tube. The mixture was stirred at 12O0C for 12h and upon cooling was treated with aqueous ammonia followed by aqueous hydrochloric acid. Extraction with ethyl EPO <DP n="98"/>acetate, drying of the organic phase over magnesium sulphate, filtration and evaporation under reduced pressure gave the required product (MH+ 272) as a light brown coloured powder that was used as such in the next step.
	With copper(l) iodide; N,N,N,N,-tetramethylethylenediamine; In 1,4-dioxane; at 120℃; for 14h;sealed tube;	To a stirred mixture of <strong>[13669-57-3]3-bromo-6-hydroxyquinoline</strong> (preparation described in Liebigs Ann Chem 1966, 98-106), (3.Og), sodium iodide (4.Og) and copper iodide (0.25g) in dioxane (19.5ml) was added N,N,N',N'-tetramethyl-ethane-1 ,2-diamine (0.24g) in a sealed tube. The mixture was stirred at 1200C for 14h and upon cooling was treated with aqueous ammonia followed by aqueous hydrochloric acid. Extraction with ethyl acetate, drying of the organic phase over magnesium sulphate, filtration and evaporation under reduced pressure gave the required product (M+ 272) as a light brown coloured powder that was used as such in the next step

Reference： [1]Patent: WO2009/49716,2009,A2 .Location in patent: Page/Page column 27
[2]Patent: WO2006/58700,2006,A1 .Location in patent: Page/Page column 96-97
[3]Patent: WO2008/110355,2008,A1 .Location in patent: Page/Page column 82

11
[ 13669-57-3 ]
[ 62383-81-7 ]
[ 1128039-17-7 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h;	Step 1 : (S-Bromo-quinolin-theta-yloxyJ-methylsulfanyl-acetic acid methyl ester 3-Bromo-quinolin-6-ol (17.47 g) (preparation described in Liebigs Ann Chem., 1966, 98-106), was dissolved in dry DMF (150 ml). Chloro-methylsulfanyl-acetic acid methyl ester(18.07 g) and dry potassium carbonate (43.12 g) were added at room temperature (rt).The resulting suspension was stirred for 2 hours after which time the reaction mixture was diluted with ethyl acetate and poured onto sat. sodium hydrogen carbonate (200ml). The two phases were separated and the aqueous layer was extracted three times with ethyl acetate (3x200ml). The combined organic layers were dried over magnesium sulphate, filtered and evaporated. The residue was purified by column chromatography <n="76"/>(heptane/ethyl acetate 7:3) to provide (S-bromo-quinolin-e-yloxyJ-methylsulfanyl-acetic acid methyl ester as yellowish solid (24 g).1H NMR (CDCI3) delta ppm: 8.81 (1 H, d); 8.23 (1 H, d); 8.02 (1H, d); 7.50 (1H, dd); 7.14 (1 H, d); 5.72 (1 H, s); 3.88 (3H, s); 2.24 (3H, s)

Reference： [1]Patent: WO2009/30467,2009,A2 .Location in patent: Page/Page column 74-75

12
[ 13669-57-3 ]
[ 877397-65-4 ]
[ 1236301-32-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 1405 - 1409

13
[ 13669-57-3 ]
[ 100-39-0 ]
[ 1337882-50-4 ]

Yield	Reaction Conditions	Operation in experiment
89%	With potassium carbonate; In acetone; at 20℃;	A solution of J.iii (760 mg, 3.39 mmol), benzyl bromide (0.44 mL, 3.73 mmol) and K2C03 (563 mg, 4.07 mmol) in acetone (20 mL) was stirred at rt overnight. The reaction mixture was concentrated under reduced pressure. The crude product was purified by chromatography (eluting with 20% EtOAc in haxane) to give the title compound as white solid (970 mg, yield 89%). H-NMR (400 MHz, DMSO-d6) delta ppm 8.76 (d, 1 H), 8.23 (d, 1 H), 8.05 (d, 1 H), 7.49-7.34 (m, 6H), 7.08 (d, 1 H), 5.20 (s, 2H). LCMS (method B): [M+H]+ = 314, tR = 2.91 min.
89%	With potassium carbonate; In acetone; at 20℃;	A solution of B.i (760 mg, 3.39 mmol), benzyl bromide (0.44 ml_, 3.73 mmol) and K2C03 (563 mg, 4.07 mmol) in acetone (20 ml.) was stirred at rt overnight. The reaction mixture was concentrated under reduced pressure. The crude product was purified by chromatography (eluting with 20% EtOAc in haxane) to give the title compound as white solid (970 mg, yield 89%). LCMS (method N): [M+H]+ = 314, tR = 2.91 min. 1 H-NMR (400 MHz, DMSO-d6) delta ppm 8.76 (d, 1 H), 8.23 (d, 1 H), 8.05 (d, 1 H), 7.49-7.34 (m, 6H), 7.08 (d, 1 H), 5.20 (s, 2H).
89%	With potassium carbonate; In acetone; at 20℃;	A solution of B.i (760 mg, 3.39 mmol), benzyl bromide (0.44 mL, 3.73 mmol) and K2CO3 (563 mg, 4.07 mmol) in acetone (20 mL) was stirred at rt overnight. The reaction mixture was concentrated under reduced pressure. The crude product was purified by chromatography (eluting with 20% EtOAc in haxane) to give the title compound as white solid (970 mg, yield 89%). LCMS (method N): [M+H]+=314, tR=2.91 min. 1H-NMR (400 MHz, DMSO-d6) delta ppm 8.76 (d, 1H), 8.23 (d, 1H), 8.05 (d, 1H), 7.49-7.34 (m, 6H), 7.08 (d, 1H), 5.20 (s, 2H).

89%	With potassium carbonate; In acetone; at 20℃;	A solution of J.iii (760 mg, 3.39 mmol), benzyl bromide (0.44 mL, 3.73 mmol) and K2CO3 (563 mg, 4.07 mmol) in acetone (20 mL) was stirred at rt overnight. The reaction mixture was concentrated under reduced pressure. The crude product was purified by chromatography (eluting with 20% EtOAc in haxane) to give the title compound as white solid (970 mg, yield 89%). 1H-NMR (400 MHz, DMSO-d6) delta ppm 8.76 (d, 1H), 8.23 (d, 1H), 8.05 (d, 1H), 7.497.34 (m, 6H), 7.08 (d, 1H), 5.20 (s, 2H). LCMS (method B): [M+H]+=314, tR=2.91 min.
68%	With potassium carbonate; In acetonitrile; at 80℃; for 3h;Inert atmosphere;	3-Bromo-6-hydroxyquinoline (760 mg, 3.39 mmol)Potassium carbonate (563 mg, 4.07 mmol)Placed in a 100 mL round bottom flask, 15 ml of acetonitrile was added,Benzyl bromide (0.44 mL) was added with stirring,The mixture was then heated to 80 C for 3 hours,After the reaction, the reaction solvent was removed,The crude product was purified by column chromatography to give 3-bromo-6-benzyloxyquinoline (760 mg, yield 68%).

Reference： [1]Patent: WO2012/107500,2012,A1 .Location in patent: Page/Page column 64
[2]Patent: WO2013/38362,2013,A1 .Location in patent: Page/Page column 75; 76
[3]Patent: US2013/245002,2013,A1 .Location in patent: Paragraph 0703
[4]Patent: US2013/324526,2013,A1 .Location in patent: Paragraph 0456; 0460
[5]Patent: CN104250252,2017,B .Location in patent: Paragraph 0168; 0170; 0171; 0172

14
[ 580-16-5 ]
[ 13669-57-3 ]

Reference： [1]Patent: WO2012/107500,2012,A1
[2]Patent: WO2013/38362,2013,A1
[3]Patent: US2013/245002,2013,A1
[4]Patent: US2013/324526,2013,A1

15
[ 13669-57-3 ]
[ 1393352-89-0 ]

Reference： [1]Patent: WO2012/107500,2012,A1
[2]Patent: WO2013/38362,2013,A1
[3]Patent: US2013/245002,2013,A1
[4]Patent: US2013/324526,2013,A1

16
[ 13669-57-3 ]
[ 1393352-90-3 ]

Reference： [1]Patent: WO2012/107500,2012,A1
[2]Patent: WO2013/38362,2013,A1
[3]Patent: US2013/245002,2013,A1
[4]Patent: US2013/324526,2013,A1

17
[ 13669-57-3 ]
[ 1393352-91-4 ]

Reference： [1]Patent: WO2012/107500,2012,A1
[2]Patent: WO2013/38362,2013,A1
[3]Patent: US2013/245002,2013,A1
[4]Patent: US2013/324526,2013,A1

18
[ 13669-57-3 ]
[ 1393352-92-5 ]

Reference： [1]Patent: WO2012/107500,2012,A1
[2]Patent: US2013/324526,2013,A1

19
[ 13669-57-3 ]
[ 1393352-93-6 ]

Reference： [1]Patent: WO2012/107500,2012,A1
[2]Patent: US2013/324526,2013,A1

20
[ 13669-57-3 ]
[ 1393352-94-7 ]

Reference： [1]Patent: WO2012/107500,2012,A1
[2]Patent: US2013/324526,2013,A1

21
[ 24306-33-0 ]
[ 13669-57-3 ]

Reference： [1]Patent: WO2012/107500,2012,A1
[2]Patent: WO2013/38362,2013,A1
[3]Patent: US2013/245002,2013,A1
[4]Patent: US2013/324526,2013,A1

22
[ 1022151-47-8 ]
[ 13669-57-3 ]

Yield	Reaction Conditions	Operation in experiment
86%	With methanol; potassium carbonate; In water; at 20℃; for 2h;	A solution of J.ii (1 g, 3.76 mmol) and K2C03 (1.04 g, 7.52 mmol) in MeOH/H20 (5 mL/3 mL) was stirred at rt for 2 hours. The reaction mixture was concentrated under reduced pressure to afford a crude solid which was further purified by washing with water, dried under vaccum to give the title compound J.iii as white solid (760 mg, yield 86%). LCMS (method B): [M+H]+ = 224, tR = 2.29 min
86%	With water; potassium carbonate; In methanol; at 20℃; for 2h;	A solution of Intermediate A (1 g, 3.76 mmol) and K2C03 (1.04 g, 7.52 mmol) in MeOH/H20 (5 mL/3 ml.) was stirred at rt for 2 hours. The reaction mixture was concentrated under reduced pressure to afford a crude solid which was further purified by washing with water, dried under vaccum to give the title compound as white solid (760 mg, yield 86%). LCMS (method N): [M+H]+ = 224, tR = 2.29 min.
86%	With water; potassium carbonate; In methanol; at 20℃; for 1h;	A solution of Intermediate A (1 g, 3.76 mmol) and K2CO3 (1.04 g, 7.52 mmol) in MeOH/H2O (5 mL/3 mL) was stirred at rt for 2 hours. The reaction mixture was concentrated under reduced pressure to afford a crude solid which was further purified by washing with water, dried under vacuum to give the title compound as white solid (760 mg, yield 86%). LCMS (method N): [M+H]+=224, tR=2.29 min.

86%

With potassium carbonate; In methanol; water; at 20℃; for 2h;

A solution of J.ii (1 g, 3.76 mmol) and K2CO3 (1.04 g, 7.52 mmol) in MeOH/H2O (5 mL/3 mL) was stirred at rt for 2 hours. The reaction mixture was concentrated under reduced pressure to afford a crude solid which was further purified by washing with water, dried under vacuum to give the title compound J.iii as white solid (760 mg, yield 86%). LCMS (method B): [M+H]+=224, tR=2.29 min.

Reference： [1]Patent: WO2012/107500,2012,A1 .Location in patent: Page/Page column 63; 64
[2]Patent: WO2013/38362,2013,A1 .Location in patent: Page/Page column 75
[3]Patent: US2013/245002,2013,A1 .Location in patent: Paragraph 0702
[4]Patent: US2013/324526,2013,A1 .Location in patent: Paragraph 0456; 0459

23
[ 13669-57-3 ]
[ 96-32-2 ]
[ 1057691-99-2 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 80℃; for 2h;	3-Bromo-quinolin-6-ol (10.0g ) was dissolved in dry DMF (100 ml). Bromo-acetic acid methyl ester (7.51 g) and dry potassium carbonate (18.5 g) were added to the mixture at RT. The resulting suspension was stirred at 80c for 2 hours. The reaction mixture was poured onto brine and the resulting mixture was extracted twice with ethyl acetate (2x100 ml). The organic layers were combined, washed with brine, dried over magnesium sulphate, filtered and evaporated. The crude mixture was recrystallized in isopropanol to give (3-bromo-quinolin-6-yloxy) acetic acid methyl ester (11.5g) as a pale yellow solid.1H NMR (CDCI3) delta ppm: 8.78 (1 H,d); 8.20 (1H,d), 8.0 (1H,d); 7.44 (1H,dxd); 6.92 (1 H,d); 4.76 (2H, s); 3.85 (3H,s).

Reference： [1]Patent: WO2008/110355,2008,A1 .Location in patent: Page/Page column 78

24
[ 13669-57-3 ]
[ 533-68-6 ]
[ 1057691-93-6 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 70℃; for 1h;	3-Bromo-quinolin-6-ol (11.3 g) (preparation described in Liebigs Ann Chem 1966, 98- 106) was dissolved in dry DMF (100 ml). 2-Bromo-butyhc acid ethyl ester (11.05 g) and dry potassium carbonate (20.9 g) were added to the mixture at RT. The resulting suspension was stirred at 70c for 1 hour. The reaction mixture was poured into brine. <n="77"/>After removal of the precipitate and separation of the two phases, the aqueous layer was extracted twice with ethyl acetate (2x100ml). The organic layers were combined, washed with brine, dried over magnesium sulphate, filtered and evaporated to give 2-(3- bromo-quinolin-6-yloxy)-butyric acid ethyl ester as a oil (17.8) which was used in the next step without further purification.1H NMR (CDCI3) delta ppm: 8.78 (1 H,d); 8.15 (1 H,d); 7.98 (1 H,d); 7.42 (1 H,dxd); 6.90 (1 H,d); 4.70 (1 H,t); 4.25 (2H,q); 2.08 (2H,m); 1.25 (3H,t); 1.13 (3H,t).

Reference： [1]Patent: WO2008/110355,2008,A1 .Location in patent: Page/Page column 75-76

25
[ 13669-57-3 ]
[ 1057686-28-8 ]

Reference： [1]Patent: WO2008/110355,2008,A1

26
[ 13669-57-3 ]
[ 1057685-53-6 ]

Reference： [1]Patent: WO2008/110355,2008,A1

27
[ 13669-57-3 ]
[ 1057692-01-9 ]

Reference： [1]Patent: WO2008/110355,2008,A1

28
[ 13669-57-3 ]
[ 1057692-04-2 ]

Reference： [1]Patent: WO2008/110355,2008,A1

29
[ 13669-57-3 ]
[ 1057692-06-4 ]

Reference： [1]Patent: WO2008/110355,2008,A1

30
[ 13669-57-3 ]
[ 1268367-63-0 ]

Reference： [1]Patent: WO2008/110355,2008,A1

31
[ 13669-57-3 ]
[ 1057692-13-3 ]

Reference： [1]Patent: WO2008/110355,2008,A1

32
[ 13669-57-3 ]
[ 1057692-14-4 ]

Reference： [1]Patent: WO2008/110355,2008,A1

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[ 13669-57-3 ]
[ 1057691-96-9 ]

Reference： [1]Patent: WO2008/110355,2008,A1

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[ 13669-57-3 ]
[ 1427473-83-3 ]