[ CAS No. 661463-17-8 ] {[proInfo.proName]}

Name: 661463-17-8|4-Bromo-6-fluoroquinoline|98%
Brand: Ambeed
SKU: A489314
Price: 10.0 USD
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Quality Control of [ 661463-17-8 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 661463-17-8 ]

Product Details of [ 661463-17-8 ]

CAS No. :	661463-17-8	MDL No. :	MFCD09261094
Formula :	C₉H₅BrFN	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	HIWPTYUKGHNQCU-UHFFFAOYSA-N
M.W :	226.05	Pubchem ID :	17976318
Synonyms :

Calculated chemistry of [ 661463-17-8 ]

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 :	0.0
Molar Refractivity :	49.4
TPSA :	12.89 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) :	2.18
Log Po/w (XLOGP3) :	2.98
Log Po/w (WLOGP) :	3.56
Log Po/w (MLOGP) :	2.98
Log Po/w (SILICOS-IT) :	3.54
Consensus Log Po/w :	3.05

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.74
Solubility :	0.0416 mg/ml ; 0.000184 mol/l
Class :	Soluble
Log S (Ali) :	-2.91
Solubility :	0.275 mg/ml ; 0.00122 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.84
Solubility :	0.00327 mg/ml ; 0.0000145 mol/l
Class :	Moderately soluble

Medicinal Chemistry

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

Safety of [ 661463-17-8 ]

Signal Word:	Danger	Class:	N/A
Precautionary Statements:	P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H318	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 661463-17-8 ]

* 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 [ 661463-17-8 ]
Downstream synthetic route of [ 661463-17-8 ]

[ 661463-17-8 ] Synthesis Path-Upstream 1~3

1
[ 391-78-6 ]
[ 661463-17-8 ]

Yield	Reaction Conditions	Operation in experiment
79%	With phosphorus tribromide In N,N-dimethyl-formamide at 45 - 60℃; for 0.75 h;	To a solution of intermediate A.i (20 g, 122.58 mmol) in DMF (130 niL), heated to 60⁰C, was added phosphorous tribromide (13 mL, 1.15 eq.). The reaction was heated at 45°C for 45 min. After cooling to rt, the reaction was diluted with water (200 mL). Sat. Na₂CO₃ was added until pH 10 was reached. The solid was formed was filtered off. The solid was taken up in EA (200 mL) and the solution was concentrated to dryness. The residue was chromatographed (EA) to afford the title bromide as a yellowish solid (22 g, 79percent yield). ¹H NMR (CDCl₃) δ: 8.70 (d, J = 4.7 Hz, IH); 8.14 (m, IH); 7.96 (d, J = 4.7 Hz, IH); 7.81-7.73 (m, 2H).

Reference： [1] Patent: WO2008/152603, 2008, A1, . Location in patent: Page/Page column 36
[2] Patent: WO2017/21319, 2017, A1, . Location in patent: Page/Page column 32

2
[ 21873-50-7 ]
[ 661463-17-8 ]

Yield	Reaction Conditions	Operation in experiment
76%	With phosphorus tribromide In DMF (N,N-dimethyl-formamide); water at 0 - 20℃; for 1.08333 h;	To a solution of (10b) (11.3 g, 69.3 mmol) in DMF (350 ml) was added dropwisephosphorous tribromide (7.1 ml, 76.3 mmol) over five minutes (slightly exothermic). The reaction was allowed to cool to room temperature and was then diluted with ice water and stirred 1 hour then diluted with additional water. The product was filtered off, washed with water and dried in vacuo to afford the product as a white solid (12.0 g, 76percent). MS (+ve ion electrospray) m/z 226 (MH+).

Reference： [1] Patent: WO2004/14361, 2004, A1, . Location in patent: Page/Page column 41

3
[ 371-40-4 ]
[ 661463-17-8 ]

Reference： [1] Patent: WO2017/21319, 2017, A1,
[2] Patent: WO2008/152603, 2008, A1,

[ 661463-17-8 ] Synthesis Path-Downstream 1~88

1
[ 21873-50-7 ]
[ 661463-17-8 ]

Yield	Reaction Conditions	Operation in experiment
76%	With phosphorus tribromide; In DMF (N,N-dimethyl-formamide); water; at 0 - 20℃; for 1.08333h;	To a solution of (10b) (11.3 g, 69.3 mmol) in DMF (350 ml) was added dropwisephosphorous tribromide (7.1 ml, 76.3 mmol) over five minutes (slightly exothermic). The reaction was allowed to cool to room temperature and was then diluted with ice water and stirred 1 hour then diluted with additional water. The product was filtered off, washed with water and dried in vacuo to afford the product as a white solid (12.0 g, 76%). MS (+ve ion electrospray) m/z 226 (MH+).

Reference： [1]Patent: WO2004/14361,2004,A1 .Location in patent: Page/Page column 41

2
[ 661463-17-8 ]
[ 6783-05-7 ]
[ 1093219-05-6 ]

Yield	Reaction Conditions	Operation in experiment
87%	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃;	To a hot (100 0C) solution of intermediate A.ii (18.5 g, 81.8 mmol), K2CO3 (14.7 g, 106 mmol), trans-2-phenylboronic acid (13.7 g, 90 mmol) in dioxane (320 mL) and water (80 mL) was added Pd(PPh3 )4 (4.77 g, 5 mol%). The resulting mixture was stirred at 1000C over night. After cooling, the reaction mixture was diluted with water (300 mL). The volatiles were removed in vacuo and the residue was taken up in EA (300 mL). The two layers were separated and the aq. layer was extracted one more with EA (300 mL). The combined org. layers were washed with brine, dried over MgSO4, filtered and <n="39"/>concentrated to dryness. The residue was chromatographed (EA-Hept 1 :2) to afford the title compound as a yellow solid (17.79 g, 87% yield).1H NMR (CDCl3) delta: 8.89 (d, J = 4.6 Hz, IH); 8.16 (dd, J = 9.5, 5.5 Hz, IH); 7.83 (dd, J = 2.7, 9.5 Hz, IH); 7.70-7.63 (m, 4H); 7.55-7.34 (m, 5H).

Reference： [1]Patent: WO2008/152603,2008,A1 .Location in patent: Page/Page column 36-37

3
[ 391-78-6 ]
[ 661463-17-8 ]

Yield	Reaction Conditions	Operation in experiment
79%	With phosphorus tribromide; In N,N-dimethyl-formamide; at 45 - 60℃; for 0.75h;	To a solution of intermediate A.i (20 g, 122.58 mmol) in DMF (130 niL), heated to 600C, was added phosphorous tribromide (13 mL, 1.15 eq.). The reaction was heated at 45°C for 45 min. After cooling to rt, the reaction was diluted with water (200 mL). Sat. Na2CO3 was added until pH 10 was reached. The solid was formed was filtered off. The solid was taken up in EA (200 mL) and the solution was concentrated to dryness. The residue was chromatographed (EA) to afford the title bromide as a yellowish solid (22 g, 79percent yield). 1H NMR (CDCl3) delta: 8.70 (d, J = 4.7 Hz, IH); 8.14 (m, IH); 7.96 (d, J = 4.7 Hz, IH); 7.81-7.73 (m, 2H).
	With phosphorus tribromide; In N,N-dimethyl-formamide; at 45 - 60℃; for 0.75h;	To a solution of AMI0015 (2.30 g, 14.1 mmol, 1 equiv) in N,N-dimethylformamide (20 mL) at 60 °C was added phosphorus tribromide (1.52 mL, 16.2 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 NaHCCte. The resulting solid was washed in water, filtered and taken up in EtOAc and concentrated in vacuo, to afford 4-bromo-6-fluoroquinoline (3.12 g, 13.8 mmol, 98percent). The analyses were consistent with the data reported in the literature. Ref: WO2010/152603 (2008) TLC Rf 0.64 (EtOAc/MeOH 8:2) FontWeight="Bold" FontSize="10" H MR (400MHZ, DMSO-de) delta (ppm) 8.73 (d, J=4.6 Hz, 1H, NCH), 8.18 (m, 1H, NCCH), 8.00 (d, J=4.6 Hz, 1H, BrCCH), 7.77-7.88 (m, 2H, FCCH, FCCH) ppm 13CNMR (101 MHz, DMSO-de) delta (ppm) 162.5 (5), 150.5 (10), 146.0 (2), 133.5 (6), 128.6 (7), 128.5 (4), 126.6 (1), 121.2 (8), 1 10.5 (3) ppm IR (neat) v max 1585 (m) cm"1 LCMS (ESI+) m/z 227.0 [M79Br+H]+, 229.0 [M81Br+H]+ 11 RMS (ESI+) m/z calcd. 225.9662 m/z meas. 225.9962 [M+H]+

Reference： [1]Patent: WO2008/152603,2008,A1 .Location in patent: Page/Page column 36
[2]Patent: WO2017/21319,2017,A1 .Location in patent: Page/Page column 32

4
[ 661463-17-8 ]
[ 31180-85-5 ]
ethyl 2-(4-(6-fluoroquinolin-4-yl)-4-hydroxycyclohexyl)propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44%		To a solution of <strong>[661463-17-8]4-bromo-6-fluoroquinoline</strong> (163 mg, 0.721 mmol) in THF (5 mL) at -78C was added t-BuLi (1.7M-3.2M in Heptane) (0.849 mL, 1.443 mmol) drop wise. It turned from clear to dark brown color. The reaction was stirred at -78C for 3 min. Then ethyl 2-(4-oxocyclohexyl) propanoate (130 mg, 0.656 mmol) in THF (1 mL) was added drop wise. The reaction was stirred at -78C for lh. The reaction was diluted with saturated NH4C1 and EtOAc. Organic was separated and washed with brine, dried over MgS04, filtered and concentrated to give a crude material. This material was purified with ISCO 40g, 40 mL/min. 0-100% EtOAc/Hexane in 35 min. The desired product was eluted with 55% EtOAc/Hexane to give 234A (100 mg, 0.290 mmol, 44%) as the mixture of the diastereomers.

Reference： [1]Patent: WO2016/73770,2016,A1 .Location in patent: Paragraph 0503

5
[ 371-40-4 ]
[ 661463-17-8 ]

Reference： [1]Patent: WO2017/21319,2017,A1
[2]Patent: WO2008/152603,2008,A1

6
[ 661463-17-8 ]
methyl 3-(benzyloxy)-6-(4-((6-fluoroquinolin-4-yl)amino)but-1-yn-1-yl)picolinate [ No CAS ]

Reference： [1]Patent: WO2017/21319,2017,A1

7
[ 661463-17-8 ]
methyl 6-(4-((6-fluoroquinolin-4-yl)amino)butyl)-3-hydroxypicolinate [ No CAS ]

Reference： [1]Patent: WO2017/21319,2017,A1

8
[ 661463-17-8 ]
(E)-6-(4-((6-fluoroquinolin-4-yl)amino)butyl)-3-hydroxypicolinaldehyde oxime [ No CAS ]

Reference： [1]Patent: WO2017/21319,2017,A1

9
[ 661463-17-8 ]
C₂₆H₃₄FN₃O₃Si [ No CAS ]

Reference： [1]Patent: WO2017/21319,2017,A1

10
[ 661463-17-8 ]
C₁₉H₁₈FN₃O₂ [ No CAS ]

Reference： [1]Patent: WO2017/21319,2017,A1

11
[ 661463-17-8 ]
[ 14044-63-4 ]
N-(but-3-yn-1-yl)-6-fluoroquinolin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	at 80 - 140℃;	3-Butyn-l -amine (764 mg, 0.91 mL, 1 1.1 mmol, 5 eq.) was mixed with 4-bromo-6- fluoroquinoline (500 mg, 2.21 mmol, 1 eq.) to form a paste, which was heated to 80 C for 1 hour without stirring, the temperature was raised to 140 C and the reaction was left overnight with stirring. After cooling to room temperature, NaOH (1M, 2 mL) was added. The organic product was basified (10% NaOH) and extracted with CH2CI2. The organic extracts were combined, dried (MgS04), filtered and concentrated in vacuo. The crude product was purified by column chromatography (AI2O3, 10%> MeOH in EtOAc), affording N-(but-3-yn-l-yl)-6-fluoroquinolin-4-amine (465 mg, 2.17 mmol, 98%>). Ref: Austin et al, J ACS, 1489-1497 (1958) TLC Rf 0.75 (MeOH/ EtOAc 1 :9, AI2O3) FontWeight="Bold" FontSize="10" H MR (400MHZ, DMSO-de) delta (ppm) 8.41 (d, J=5.1 Hz, 1H, NCH), 7.89-8.08 (m, 1H, FCCHCH), 7.85 (dd, J=9.3, 5.9 Hz, 1H, FCCHCH), 7.53 (td, J=8.7, 2.8 Hz, 1H, FCCHC), 6.54 (d, J=5.4 Hz, 1H, NCHCH), 3.42-3.51 (m, 2H, CH2CH2CCH), 2.90 (t, J=2.6 Hz, 1H, CH2CH2CCH), 2.56 (td, J=7.1 , 2.7 Hz, 2H, CH2CH2CCH) ppm 13CNMR (101 MHz, DMSO-de) delta (ppm) 150.5 (4), 150.2 (7), 149.1 (9), 140.0 (1), 124.6 (2), 1 19.9 (3), 1 13.6 (6), 108.8 (5), 99.4 (8), 72.9 (16), 56.0 (13), 41.8 (11), 18.3 (12) ppm IR (neat) v max 3387 (m), 2830 (m), 663 (s) cm"1 LCMS (ESI+) m/z 215.1 [M+H]+ 11 RMS (ESI+) m/z calcd. 215.0979 m/z meas. 215.0982 [M+H]+ Mpt 148 - 150 C

Reference： [1]Patent: WO2017/21319,2017,A1 .Location in patent: Page/Page column 32-33

12
[ 661463-17-8 ]
(1S,5S,6R)-ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[3.1.0]hex-2-ene-6-carboxylate [ No CAS ]
(1S,5S,6R)-ethyl 3-(6-fluoroquinolin-4-yl)bicyclo[3.1.0]hex-2-ene-6-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
37.6%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 105℃; for 2h;Inert atmosphere;	A solution of (l S,5S,6R)-ethyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)bicyclo[3.1.0]hex-2-ene-6-carboxylate (343 mg, 1.233 mmol), <strong>[661463-17-8]4-bromo-6-fluoroquinoline</strong> (307 mg, 1.356 mmol) and K2C03 (528 mg, 3.82 mmol) in Dioxane (5605 mu I Water (561 was degassed with N2 for 2 minutes, PdCl2(dppf)-CH2Cl2 Adduct (201 mg, 0.247 mmol) was added, and the mixture was degassed with N2 for an additional 2 minutes. The reaction mixture was heated to 105 C and stirred for 6 h. The reaction mixture was allowed to cool to room temperature and filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified via silica gel chromatography (0 - 70 % EtOAc in hexanes) to give (l S,5S,6R)-ethyl 3-(6-fluoroquinolin-4-yl)bicyclo[3.1.0]hex-2-ene-6- carboxylate (138 mg, 0.464 mmol, 37.6 % yield) as a colorless liquid. MS (ES+) Ci8Hi6FN02 requires: 297, found: 298 [M+H]+.

Reference： [1]Patent: WO2018/136437,2018,A2 .Location in patent: Page/Page column 284; 285

13
[ 661463-17-8 ]
[ 482586-86-7 ]

Reference： [1]Patent: WO2008/152603,2008,A1

14
[ 661463-17-8 ]
[ 1093219-22-7 ]

Reference： [1]Patent: WO2008/152603,2008,A1

15
[ 661463-17-8 ]
2-(5-(6-fluoroquinolin-4-yl)thiophen-2-ylthio)-2-methylpropionic acid [ No CAS ]

Reference： [1]Patent: CN109608432,2019,A

16
[ 661463-17-8 ]
1-(5-(6-fluoroquinolin-4-yl)thiophen-2-ylthio)cyclobutyl-1-carboxylic acid [ No CAS ]

Reference： [1]Patent: CN109608432,2019,A

17
[ 661463-17-8 ]
ethyl 2-(5-(6-fluoroquinolin-4-yl)thiophen-2-ylthio)-2-methylpropanoate [ No CAS ]

Reference： [1]Patent: CN109608432,2019,A

18
[ 661463-17-8 ]
ethyl 1-(5-(6-fluoroquinolin-4-yl)thiophen-2-ylthio)cyclobutyl-1-carboxylate [ No CAS ]

Reference： [1]Patent: CN109608432,2019,A

19
[ 661463-17-8 ]
[ 5419-55-6 ]
(6-fluoroquinolin-4-yl)boronic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
2.8 g		4-Bromo-6-fluoroquinoline (5.0 g, 22.12 mmol) and THF (100 ml) were added to the reactor, nitrogen-protected, and then cooled to -78 C, and n-butyllithium (16.6 ml, 26.56 mmol) was slowly added dropwise. After the completion of the dropwise addition, the reaction was kept for 2 hours, and then triisopropyl borate (6.70 g, 33.15 mmol) was added dropwise. After the completion of the dropwise addition, the mixture was slowly stirred to room temperature and stirred until the reaction was completed. It was quenched by the addition of 6M diluted hydrochloric acid (10 ml) and stirred at room temperature for 3 hours.It is then extracted with ethyl acetate (100 ml), dried over anhydrous sodiumColumn chromatography (ethyl acetate / n-hexane system) was purified to give compound 10b:6-Fluoroquinolin-4-yl-boronic acid 2.8 g.

Reference： [1]Patent: CN109608432,2019,A .Location in patent: Paragraph 0206; 0208; 0209; 0210

20
[ 661463-17-8 ]
[ 856900-26-0 ]
3-(6-fluoroquinolin-4-carbonyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46%		Under nitrogen protection and -70 C,Dissolve in 20 mL of THF containing <strong>[661463-17-8]4-bromo-6-fluoroquinoline</strong> (1.4 g, 6.2 mmol)n-Butyllithium (1.6 M in n-hexane solution, 3.9 mL, 6.2 mmol) was added dropwise to the solution.The reaction mixture is stirred at -70 CAfter 30 min, a solution of 3-cyano-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.4 g, 5.6 mmol) in 5 mL THF was added dropwise.The system was stirred at 70 C for 2 h.Pour into 100mL of saturated ammonium chloride solution,Then extract with EA (50mL x 3),The organic phase is washed with saturated brine.The anhydrous Na2SO4 was sufficiently dried.Concentration under reduced pressure and column chromatography (DCM:MeOH = 30:1)Purification afforded 1.1 g (yield: 46%) of title compound.It is a yellow solid.

Reference： [1]Patent: CN109575022,2019,A .Location in patent: Paragraph 0589-0590; 0593-0594

21
[ 661463-17-8 ]
[ 1024038-48-9 ]
C₂₀H₂₃FN₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; for 4h;Inert atmosphere;	To a stirred solution of 320 mg (1 .82 mmol) of compound 18-1 hydrochloride and 790 mg (6.12 mmol) of DIEA in 10 mL of NMP was added 200 mg (1 .22 mmol) of 4-chloro-1 ,6- naphthyridine. The mixture was stirred at for 4 h under nitrogen atmosphere. The mixture was diluted with 10 mL of water and extracted with three 20 mL portions of ethyl acetate. The combined organic extracts were washed with 20 mL of brine and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated to afford a residue, which was purified by chromatography on silica gel column eluting with 0 to 6 % gradient of methanol in dichloromethane to afford a residue, which was purified by C18 silica gel eluting with 0 to 40 % gradient of acetonitrile in water (0.05% NH4HCO3) to afford compound 22-1. LC-MS: m/e = 268 [M+H]+.

Reference： [1]Patent: WO2019/78968,2019,A2 .Location in patent: Page/Page column 80; 81; 89-91

22
[ 661463-17-8 ]
[ 73183-34-3 ]
6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline [ No CAS ]