[ CAS No. 21269-34-1 ] {[proInfo.proName]}

Name: 21269-34-1|4-Hydroxy-8-methoxyquinoline|98%
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Quality Control of [ 21269-34-1 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 21269-34-1 ]

Product Details of [ 21269-34-1 ]

CAS No. :	21269-34-1	MDL No. :	MFCD02684163
Formula :	C₁₀H₉NO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	DJVLMLGPDKKYJW-UHFFFAOYSA-N
M.W :	175.18	Pubchem ID :	243291
Synonyms :

Calculated chemistry of [ 21269-34-1 ]

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	10
Fraction Csp3 :	0.1
Num. rotatable bonds :	1
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	50.26
TPSA :	42.35 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) :	-6.69 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.52
Log Po/w (XLOGP3) :	0.95
Log Po/w (WLOGP) :	1.95
Log Po/w (MLOGP) :	0.88
Log Po/w (SILICOS-IT) :	1.94
Consensus Log Po/w :	1.45

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.03
Solubility :	1.64 mg/ml ; 0.00938 mol/l
Class :	Soluble
Log S (Ali) :	-1.43
Solubility :	6.56 mg/ml ; 0.0375 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-3.25
Solubility :	0.0985 mg/ml ; 0.000562 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.62

Safety of [ 21269-34-1 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 21269-34-1 ]

* 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 [ 21269-34-1 ]
Downstream synthetic route of [ 21269-34-1 ]

[ 21269-34-1 ] Synthesis Path-Upstream 1~1

1
[ 21269-34-1 ]
[ 139399-63-6 ]

Reference： [1] Monatshefte fuer Chemie, 1991, vol. 122, # 11, p. 935 - 942
[2] Journal of Fluorescence, 2018, vol. 28, # 5, p. 1121 - 1126

[ 21269-34-1 ] Synthesis Path-Downstream 1~51

2
[ 28027-18-1 ]
[ 21269-34-1 ]

Yield	Reaction Conditions	Operation in experiment
	With diphenylether Erhitzen auf Siedetemperatur;
	With dowtherm A at 240℃; for 1h;	3.1.1. Preparation of the Intermediates 1II-1VI General procedure: Diethyl (ethoxymethylene) malonate (6.48 g, 30.00 mmol) and m-fluroaniline (2.78 g, 25.00 mmol) was stirred in refluxing ethanol (10 mL) for 1.5 h. The mixture was concentrated under reduced pressure. The residue was crystallized in petroleum ether, filtered off, and air-dried to get 1II. Compound 1II (2.80 g, 9.96 mmol) was stirred in Dowtherm-A (8 mL) for 0.5 h at 260 °C. After the reaction was over by TLC, the mixture was cooled to room temperature and petroleum ether was added to get the crude ester, which was further washed with petroleum ether to afford 1III, as a white solid. 1III was hydrolyzed in refluxing NaOH solution (10%, 20 mL) for 1.5 h to give 1IV. Compound 1IV (1.24 g, 6 mmol) was stirred in Dowtherm-A (10 mL) for 1 h at 240 °C. After the reaction was over as monitored by TLC, the reaction mixture was cooled to room temperatureand the crude was washed with petroleum ether to afford 1V as a white solid. To a solution of 1V (1.20 g, 7.36 mmol) in 1,2-dichloroethane (30 mL), POCl3 (1.35 g, 8.83 mmol) was added dropwise. The mixture was refluxed for 1 h. Saturated NaHCO3 solution was added to neutralize the reaction mixture, which was worked up with 1,2-dichloroethane. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel) using petroleum ether/ethyl acetate as an eluent (5:1) to produce 1VI as a white solid [17].

Reference： [1]Lauer et al. [Journal of the American Chemical Society, 1946, vol. 68, p. 1268]
[2]Liu, Dan; Luan, Tian; Kong, Jian; Zhang, Ying; Wang, Hai-Feng [Molecules, 2016, vol. 21, # 1]

3
[ 21269-34-1 ]
[ 103028-31-5 ]

Yield	Reaction Conditions	Operation in experiment
91%	With phosphorus tribromide In N,N-dimethyl-formamide at 65℃; for 5h;	9.1 Step 1) Preparation of 4-bromo-8-methoxyquinoline (9b) At room temperature, 4-hydroxy-8-methoxyquinoline (9a) (3.0g, 17.14mmol), phosphorus tribromide (9.3g, 34.2mmol) were added to N,N dimethylformamide (25.0 mL), the reaction solution was raised to 65°C and stirred for 5 hours.Cool to room temperature, add ice water (50.0 mL), and adjust the pH of the aqueous phase to about 9 with ammonia.The resulting mixture was extracted with ethyl acetate (100.0 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 7/3) to obtain 4-bromo-8-methoxyquinoline (9b) (3.7 g, yield 91%) ).
87%	With phosphorus(V) oxybromide In chloroform for 4h; Heating;
76%	With phosphorus tribromide In N,N-dimethyl-formamide at 45 - 60℃; for 0.75h;	1.I 4-Bromo-8-methoxyquinoline 34: Following an adapted procedure from Pulley et al.3 for the synthesis of bromo-quinolines from quinolinols; toa solution of 8-methoxyquinolin-4-ol 33 (2.50 g, 14.3 mmol) in DMF (20 mL) was added phosphorus tribromide (1.54mL, 16.4 mmol) at 60 °C and the mixture was stirred at 45 °C for 45 min. After cooling to rt, H2O (25 mL) was addedand a saturated solution of aqueous Na2CO3 was added to adjust the pH of the solution to 10. The resulting creamcolouredcrystals were filtered and washed with H2O (10 mL) giving 4-bromo-5-fluoroquinoline 34 (2.58 g, 10.8 mmol,76%) as cream solid. mp = 99-101 °C; IR (neat) vmax 1252, 1085 cm-1; 1HNMR (400MHz, CDCI3) δ (ppm) 8.69 (d, J=4.6Hz, 1H, NCH), 7.78 (d, J=8.1 Hz, 1H, BrCCCH), 7.75 (d, J=4.8 Hz, 1H, BrCCH), 7.58 (t, J=8.2 Hz, 1H, ArH), 7.14 (d,J=8.0 Hz, 1H, ArH), 4.12 (s, 3H, OMe); 13C NMR (101 MHz, CDCI3) δ (ppm) 155.5, 148.5, 134.1, 129.0, 128.0, 125.8,118.5, 108.5, 56.3; HRMS (ESI)+ m/z for C10H9BrNO+calculated 237.9862, found 237.9865.

74%	With phosphorus tribromide In N,N-dimethyl-formamide at 20℃; for 1h;	61.1; 62.1; 63.1; 64.1 Step 1. 4-bromo-8-methoxyquinoline Into a lOO-mL round-bottom flask, was placed 8-methoxyquinolin-4-ol (2 g, 11.42 mmol, 1.00 equiv), N,N-dimethylformamide (20 mL). This was followed by the addition of PBr3 (3.4 g, 12.56 mmol, 1.10 equiv) dropwise with stirring at room temperature. The resulting solution was stirred for 1 h at room temperature. The reaction was then quenched by the addition of water (70 mL). The pH value of the solution was adjusted to 7-8 with potassium hydroxide. The resulting solution was extracted with ethyl acetate (80 mL x 3) and the organic layers combined and concentrated under vacuum. This resulted in 2 g (74%) of 4-bromo-8-methoxyquinoline as a gray solid. MS (ES, m/z) [M+H]+: 238.
70.6%	With phosphorus(V) oxybromide at 60 - 120℃; for 1.5h; Inert atmosphere;	3 Synthesis of 4-bromo-8-methoxyquinoline 4-Hydroxy-8-methoxyquinoline (220 mg, 1 mmol), Ρ0 Β γ3 (1.44 g, 5 mmol) was added to the reaction mixture, and the atmosphere of the reaction flask was replaced with nitrogen. The mixture was preheated at 60 ° C until P0Br3 melted, then the temperature was heated to 120 ° C and maintained for 1.5 h. The mixture was cooled to room temperature, poured into ice water and extracted, extracted with CH 2 C 2, and combined organics. Filtration, concentration and column chromatography gave 16811^ dark brown product, yield 70.6%.
67%	With phosphorus tribromide In N,N-dimethyl-formamide at 45℃; for 0.75h;	3 Synthesis of 4-bromo-8-methoxyquinoline (15): To a solution of 8-methoxyquinolin-4-ol (2.67 g, 15.2 mmol, 1 equiv) in N,N- dimethylformamide (20 mL) at 60 °C was added phosphorus tribromide (1.65 mL, 17.5 mmol, 1.2 equiv). The mixture was cooled to 45 °C for 45 mins. After cooling to room temperature, the reaction was diluted with water (25 mL) and the pH was adjusted to ~ 10 with saturated aqueous NaHCCb. The resulting solid was washed in water, filtered and taken up in EtOAc and concentrated in vacuo, to afford 8-methoxy-4- bromoquinoline (2.44 g, 10.3 mmol, 67%). The analyses were consistent with the data reported in the literature. Ref: WO2010/152603 (2008) TLC Rf 0.51 (EtOAc/ MeOH 75:25) H MR (400MHz, CDCb) δ (ppm) 8.69 (d, J=4.6 Hz, 1H, NCH), 7.78 (d, J=8.1 Hz, 1H, BrCCCH), 7.75 (d, J=4.8 Hz, 1H, BrCCH), 7.58 (t, J=8.2 Hz, 1H, ArH), 7.14 (d, J=8.0 Hz, 1H, ArH), 4.12 (s, 3H, OMe) ppm 13CNMR (101 MHz, CDCb) δ (ppm) 155.5 (4), 148.5 (10), 134.1 (2), 129.0 (7), 128.0 (1), 125.8 (5,8), 118.5 (3), 108.5 (6), 56.3 (13) ppm IR (neat) v max 1252 (s), 1085 (s) cm"1 LCMS (ESI+) m/z 238.0 [M79Br+H]+, 340.0 [M81Br+H]+ (ESI+) m/z 260.0 [M79Br+Na]+, 262.0 [M81Br+Na]+ 11 RMS (ESI+) m/z calcd. 237.9862 meas. 237.9865 [M+H]+ Mpt 99 - 101 °C
	With phosphorus(V) oxybromide for 1.5h; Reflux;

Reference： [1]Current Patent Assignee: SHANGHAI YAHONG PHARMACEUTICAL TECH; SHANGHAI YAHONG MEDITECH; JIANGSU YAHONG MEDICINE SCIENCE TECH; JIANGSU YAHONG MEDITECH - CN111960998, 2020, A Location in patent: Paragraph 0287-0291
[2]Gershon, Herman; Clarke, Donald D. [Monatshefte fur Chemie, 1991, vol. 122, # 11, p. 935 - 942]
[3]Current Patent Assignee: GOVERNMENT OF FRANCE; ETAT FRANCAIS MINI DES ARMEES REPRESENTE PAR LA DIRECTION CENTRALE DU SERVICE DE SANTE DES ARMEES; UNIVERSITY OF STRASBOURG; CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE; ETAT FRANCAIS MINI DES ARMEES REPRESENTE PAR LA DIRECTION CENTRALE DU SERVICE DE SANTE DES - EP3696170, 2020, A1 Location in patent: Paragraph 0095; 0153; 0156-0157
[4]Current Patent Assignee: THE ROCKEFELLER UNIVERSITY - WO2019/108565, 2019, A1 Location in patent: Paragraph 0377; 0378
[5]Current Patent Assignee: AAC ACOUSTIC TECHNOLOGIES HOLDINGS INC.; NANJING TECH UNIVERSITY - CN108947898, 2018, A Location in patent: Paragraph 0074; 0079; 0080
[6]Current Patent Assignee: CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE; UNIVERSITY OF STRASBOURG - WO2017/21319, 2017, A1 Location in patent: Page/Page column 26
[7]Jianbo, He; Tingting, Zhou; Yongjing, Cao; Yuanyuan, Zhang; Weiqing, Yang; Menglin, Ma [Journal of Fluorescence, 2018, vol. 28, # 5, p. 1121 - 1126]

4
[ 21269-34-1 ]
[ 25542-62-5 ]
6-(8-Methoxy-quinolin-4-yloxy)-hexanoic acid ethyl ester [ No CAS ]
6-(8-Methoxy-4-oxo-4H-quinolin-1-yl)-hexanoic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1: 23% 2: 48%	With potassium carbonate In ethanol for 6h; Heating;

Reference： [1]Desideri, Nicoletta; Sestili, Isabella; Stein, Maria Luisa; Manarini, Stefano; Dell'Elba, Giuseppe; Cerletti, Chiara [Archiv der Pharmazie, 1997, vol. 330, # 4, p. 100 - 106]

5
[ 21269-34-1 ]
6-(8-Methoxy-quinolin-4-yloxy)-hexanoic acid; hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 48 percent / K₂CO₃ / ethanol / 6 h / Heating 2: 71 percent / 2 N HCl / 2 h / Heating

Reference： [1]Desideri, Nicoletta; Sestili, Isabella; Stein, Maria Luisa; Manarini, Stefano; Dell'Elba, Giuseppe; Cerletti, Chiara [Archiv der Pharmazie, 1997, vol. 330, # 4, p. 100 - 106]

6
[ 21269-34-1 ]
[ 57334-36-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 95 percent / POCl₃ / 3 h / Heating 2: 89 percent / 76percent H₂SO₄

Reference： [1]Gershon, Herman; Clarke, Donald D. [Monatshefte fur Chemie, 1991, vol. 122, # 11, p. 935 - 942]

7
[ 21269-34-1 ]
[ 139399-63-6 ]

Reference： [1]Monatshefte fur Chemie,1991,vol. 122,p. 935 - 942
[2]Journal of Fluorescence,2018,vol. 28,p. 1121 - 1126

8
[ 27568-04-3 ]
[ 21269-34-1 ]

Reference： [1]Journal of the American Chemical Society,1946,vol. 68,p. 1268
[2]Molecules,2016,vol. 21

9
[ 21269-34-1 ]
4-hydroxy-3-hydroxymethyl-8-methoxyquinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With formaldehyd In sodium hydroxide	14.a EXAMPLE 14 (a) 4-Hydroxy-8-methoxyquinoline was reacted with formaldehyde in aqueous sodium hydroxide to give the novel compound 4-hydroxy-3-hydroxymethyl-8-methoxyquinoline, m.p. >350°.

Reference： [1]Current Patent Assignee: WALGREENS BOOTS ALLIANCE, INC., - US4442109, 1984, A

10
[ 25165-68-8 ]
[ 21269-34-1 ]

Yield	Reaction Conditions	Operation in experiment
62.7%	In diphenylether at 250℃; for 0.5h;	3 Synthesis of 4-hydroxy-8-methoxyquinoline: To a 100 ml round bottom flask was added the starting material (1.4g, 5mmol) and Ph20 (20mL), and the mixture was heated to reflux for 30min, when the reaction mixture turned from pale yellow to dark brown The reaction reached the end. After cooling to room temperature, petroleum ether (20 mL) was added, the product was precipitated, filtered, washed with petroleum ether (20 mL X2) and dried in air to yield 1.22 g of dark yellow product, yield 62.7%.
2.65 g	In diphenylether at 300℃; for 0.25h;
	In diphenylether at 210℃; for 1h; Microwave irradiation;	10 General procedure: Referring to Fig. 9, the synthesis of the instantly disclosed small molecule antagonists of the kinase domain of PFKFB4 (including various compounds of Formulae (I), (II), and (III), (IV), (V), (VI), and (VII) began with the condensation of Meldrum's acid (1) with aniline 2 in the presence of trimethyl orthoformate to afford adduct 3 in excellent yield (Dutta, A. K.; et al. Discovery of 4-(4-(2-((5-Hydroxy- 1,2,3,4- tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)piperazin- l-yl)quinolin-8-ol and Its Analogues as Highly Potent Dopamine D2/D3 Agonists and as Iron Chelator: In Vivo Activity Indicates Potential Application in Symptomatic and Neuroprotective Therapy for Parkinson's Disease. J. Med. Chem. 2010, 53, 2114-2125). Cyclization was facilitated by heating 3 in diphenyl ether to produce 8-methoxyquinolin-4-ol (4) core, which was subsequently converted to chloride 5 by refluxing in phosphoryl chloride (Id.). The carbon linker was installed by heating chloride 5 with a commercially available primary amine (Perez, B. C; et al. N-Cinnamoylated Chloroquine Analogues as Dual-Stage Antimalarial Leads. J. Med. Chem. 2013, 56, 556-567). In the final step, several conditions were surveyed for nitric acid ester formation and many were sluggish or produced multiple byproducts. Ultimately, treating alcohol 6 with concentrated nitric acid, acetic acid, and acetic anhydride in ethyl acetate produced the desired product (Kourounakis, P. N. et al. Nitric oxide releasing derivatives of tolfenamic acid with anti- inflammatory activity and safe gastrointestinal profile. Bioorg. Med. Chem. 2005, 13, 6485-6492.)

In diphenylether at 210℃; for 1h; Microwave irradiation;

Reference： [1]Current Patent Assignee: AAC ACOUSTIC TECHNOLOGIES HOLDINGS INC.; NANJING TECH UNIVERSITY - CN108947898, 2018, A Location in patent: Paragraph 0074; 0077; 0078
[2]Location in patent: experimental part Ghoshs, Balaram; Antonio, Tamara; Reith, Maarten E. A.; Dutta, Aloke K. [Journal of Medicinal Chemistry, 2010, vol. 53, # 5, p. 2114 - 2125]
[3]Current Patent Assignee: UNIVERSITY OF LOUISVILLE - WO2016/172499, 2016, A1 Location in patent: Page/Page column 61
[4]Current Patent Assignee: UNIVERSITY OF LOUISVILLE - US2019/127329, 2019, A1 Location in patent: Paragraph 0032; 0176

11
[ 90-04-0 ]
[ 21269-34-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: ethanol / Reflux 2: dowtherm A / 0.5 h / 260 °C 3: sodium hydroxide / ethanol / 1.5 h / Reflux 4: dowtherm A / 1 h / 240 °C
	Multi-step reaction with 2 steps 1: N,N-dimethyl-formamide / 3 h 2: diphenylether / 1 h / 210 °C / Microwave irradiation
	Multi-step reaction with 2 steps 1.1: 3 h / 100 °C 1.2: 3 h / 30 - 100 °C 2.1: diphenylether / 0.5 h / 250 °C

Reference： [1]Liu, Dan; Luan, Tian; Kong, Jian; Zhang, Ying; Wang, Hai-Feng [Molecules, 2016, vol. 21, # 1]
[2]Current Patent Assignee: UNIVERSITY OF LOUISVILLE - WO2016/172499, 2016, A1 Current Patent Assignee: UNIVERSITY OF LOUISVILLE - US2019/127329, 2019, A1
[3]Current Patent Assignee: AAC ACOUSTIC TECHNOLOGIES HOLDINGS INC.; NANJING TECH UNIVERSITY - CN108947898, 2018, A

12
[ 104007-09-2 ]
[ 21269-34-1 ]