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Chemical Structure| 391-77-5 Chemical Structure| 391-77-5
Chemical Structure| 391-77-5

4-Chloro-6-fluoroquinoline

CAS No.: 391-77-5

4.5 *For Research Use Only !

Cat. No.: A298367 Purity: 97%

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Product Details of [ 391-77-5 ]

CAS No. :391-77-5
Formula : C9H5ClFN
M.W : 181.59
SMILES Code : C1=C(F)C=CC2=C1C(=CC=N2)Cl
MDL No. :MFCD00278783
InChI Key :CKTQPWIDUQGUGG-UHFFFAOYSA-N
Pubchem ID :2736586

Safety of [ 391-77-5 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Calculated chemistry of [ 391-77-5 ] Show Less

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 46.71
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

12.89 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

2.09
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

2.92
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

3.45
Log Po/w (MLOGP)?

MLOGP: Topological method implemented from
Moriguchi I. et al. 1992 Chem. Pharm. Bull.
Moriguchi I. et al. 1994 Chem. Pharm. Bull.
Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.

2.83
Log Po/w (SILICOS-IT)?

SILICOS-IT: Hybrid fragmental/topological method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

3.5
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.96

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-3.42
Solubility 0.0687 mg/ml ; 0.000378 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-2.85
Solubility 0.255 mg/ml ; 0.00141 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble
Log S (SILICOS-IT)?

SILICOS-IT: Fragmental method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-4.59
Solubility 0.00461 mg/ml ; 0.0000254 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Moderately soluble

Pharmacokinetics

GI absorption?

Gatrointestinal absorption: according to the white of the BOILED-Egg

High
BBB permeant?

BBB permeation: according to the yolk of the BOILED-Egg

Yes
P-gp substrate?

P-glycoprotein substrate: SVM model built on 1033 molecules (training set)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

No
CYP1A2 inhibitor?

Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.83 / AUC=0.90
External: ACC=0.84 / AUC=0.91

Yes
CYP2C19 inhibitor?

Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.80 / AUC=0.86
External: ACC=0.80 / AUC=0.87

No
CYP2C9 inhibitor?

Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set)
and tested on 2075 molecules (test set)
10-fold CV: ACC=0.78 / AUC=0.85
External: ACC=0.71 / AUC=0.81

No
CYP2D6 inhibitor?

Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set)
and tested on 1068 molecules (test set)
10-fold CV: ACC=0.79 / AUC=0.85
External: ACC=0.81 / AUC=0.87

No
CYP3A4 inhibitor?

Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)
and tested on 2579 molecules (test set)
10-fold CV: ACC=0.77 / AUC=0.85
External: ACC=0.78 / AUC=0.86

No
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-5.33 cm/s

Druglikeness

Lipinski?

Lipinski (Pfizer) filter: implemented from
Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev.
MW ≤ 500
MLOGP ≤ 4.15
N or O ≤ 10
NH or OH ≤ 5

0.0
Ghose?

Ghose filter: implemented from
Ghose AK. et al. 1999 J. Comb. Chem.
160 ≤ MW ≤ 480
-0.4 ≤ WLOGP ≤ 5.6
40 ≤ MR ≤ 130
20 ≤ atoms ≤ 70

None
Veber?

Veber (GSK) filter: implemented from
Veber DF. et al. 2002 J. Med. Chem.
Rotatable bonds ≤ 10
TPSA ≤ 140

0.0
Egan?

Egan (Pharmacia) filter: implemented from
Egan WJ. et al. 2000 J. Med. Chem.
WLOGP ≤ 5.88
TPSA ≤ 131.6

0.0
Muegge?

Muegge (Bayer) filter: implemented from
Muegge I. et al. 2001 J. Med. Chem.
200 ≤ MW ≤ 600
-2 ≤ XLOGP ≤ 5
TPSA ≤ 150
Num. rings ≤ 7
Num. carbon > 4
Num. heteroatoms > 1
Num. rotatable bonds ≤ 15
H-bond acc. ≤ 10
H-bond don. ≤ 5

2.0
Bioavailability Score?

Abbott Bioavailability Score: Probability of F > 10% in rat
implemented from
Martin YC. 2005 J. Med. Chem.

0.55

Medicinal Chemistry

PAINS?

Pan Assay Interference Structures: implemented from
Baell JB. & Holloway GA. 2010 J. Med. Chem.

0.0 alert
Brenk?

Structural Alert: implemented from
Brenk R. et al. 2008 ChemMedChem

0.0 alert: heavy_metal
Leadlikeness?

Leadlikeness: implemented from
Teague SJ. 1999 Angew. Chem. Int. Ed.
250 ≤ MW ≤ 350
XLOGP ≤ 3.5
Num. rotatable bonds ≤ 7

No; 1 violation:MW<1.0
Synthetic accessibility?

Synthetic accessibility score: from 1 (very easy) to 10 (very difficult)
based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties,
trained on 12'782'590 molecules and tested on 40 external molecules (r2 = 0.94)

1.43

Application In Synthesis [ 391-77-5 ]

* 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.

  • Downstream synthetic route of [ 391-77-5 ]

[ 391-77-5 ] Synthesis Path-Downstream   1~6

  • 1
  • [ 391-78-6 ]
  • [ 391-77-5 ]
YieldReaction ConditionsOperation in experiment
With trichlorophosphate; In dichloromethane; (b) 4-Chloro-6-fluoroquinoline A mixture of 52 g (0.319 mol) of <strong>[391-78-6]6-fluoro-4-hydroxyquinoline</strong> and 100 ml of phosphorus oxychloride was stirred and heated under reflux for 3 hr. The reaction mixture was concentrated in vacuo. A slurry of the residue in methylene chloride was poured into ice-water, and the mixture neutralized with 3N sodium hydroxide. The organic phase was separated, and the aqueous phase was extracted with 250 ml of methylene chloride twice. The organic phases were combined, washed with water, dired over sodium sulfate, and concentrated in vacuo. The residue was crystallized from hexane to give 27.95 g of product, mp 71°-74°.
  • 3
  • [ 391-77-5 ]
  • [ 1166829-70-4 ]
  • ethyl 2-(4-(6-fluoroquinolin-4-yl)cyclohex-3-en-1-yl)acetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
95% With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 100℃; for 16h;Sealed tube; Inert atmosphere; Ethyl 2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-3-en-l- yl)acetate (Intermediate 154E) (5 g, 17.00 mmol) was taken up in dioxane (28.3 ml) and water (7.08 ml). 4-Chloro-6-fluoroquinoline (2.57 g, 14.15 mmol) was added followed by K2C03 (5.87 g, 42.5 mmol). Mixture was bubble with nitrogen gas for 5 minutes before the addition of Pd(Ph3P)4 (0.327 g, 0.283 mmol). After addition, reaction was vacated and backfilled with N2 three times and then sealed (sealed vial parafilmed) and heated to 100 C for 16 hours. The reaction was concentrated in vacuo and purified directly via silica gel flash column chromatography to give Intermediate 154F (4.22 g, 13.47 mmol, 95% yield). LC-MS Anal. Calc'd for C19H20FNO2 313.15, found [M+H]+ 314.1 Tr = 0.75 min (Method A
95% With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 100℃; for 16h;Inert atmosphere; Sealed tube; Ethyl 2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-3-en-l- yl)acetate (WO 2016/073774, PCT/US 2015/059316 Intermediate 164E) (5 g, 17.00 mmol) was taken up in dioxane (28.3 ml) and water (7.08 ml). 4-chloro-6-fluoroquinoline (2.57 g, 14.15 mmol) was added followed by K2CO3 (5.87 g, 42.5 mmol). The reaction mixture was bubble with nitrogen gas for 5 minutes before the addition of Pd(Ph3P)4 (0.327 g, 0.283 mmol). After addition, reaction was vacated and backfilled with N2 three times and then sealed (sealed vial parafilmed) and heated to 100 C for 16 hours. The reaction was concentrated in vacuo and purified directly via silica gel flash column chromatography to give Intermediate 10A (4.22 g, 13.47 mmol, 95 % yield). LC-MS Anal. Calc'd for C19H20FNO2 313.15, found [M+H] 314.1 Tr = 0.75 min (Method A).
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 100℃; for 16h;Inert atmosphere; Sealed tube; Ethyl 2-(4-(4,4,5 ,5 -tetramethyl- 1,3 ,2-dioxaborolan-2-yl)cyclohex-3 -en-i - yl)acetate (Intermediate 164E) (5 g, 17.00 mmol) was taken up in dioxane (28.3 ml) and water (7.08 ml). 4-Chloro-6-fluoroquinoline (2.57 g, 14.15 mmol) was added followed by K2C03 (5.87 g, 42.5 mmol). Mixture was bubbled with nitrogen gas for 5 minutesbefore the addition of Pd(Ph3P)4 (0.327 g, 0.283 mmol). After the addition, the reaction was evacuated and backfilled with N2 three times and then sealed (sealed vial parafilmed) and heated to 100 C for 16 hours. The reaction was concentrated in vacuo and purified directly via silica gel flash colunm chromatography to give Intermediate 164F (4.22 g,13.47 mmol, 95% yield). LC-MS Anal. Calc’d for C,9H20FN02 313.15, found [M+H]314.1 T = 0.75 mm (Method A).
  • 4
  • [ 391-77-5 ]
  • [ 271-73-8 ]
  • 6-fluoro-4-(1H-pyrazolo[3,4-b]pyridin-1-yl)quinolone [ No CAS ]
  • 5
  • [ 198211-38-0 ]
  • [ 391-77-5 ]
  • tert-butyl (3-(6-fluoroquinolin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
22% With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 60℃; To a solution of <strong>[198211-38-0]tert-butyl 3-azabicyclo[3.1.0]hexan-6-ylcarbamate</strong> (300 mg, 1.51 mmol) in DMF (7.566 mL) were added DIEA (529 mu, 3.03 mmol) and 4-chloro-6-fluoroquinoline (330 mg, 1.82 mmol) and the resulting mixture was stirred at RT for 3 days. Then the reaction mixture was heated to 60 C and stirred for 18 h. The reaction mixture was diluted with EtOAc (50 mL) and washed with H20 (50 mL). The layers were separated, and the organic layer was washed with sat. NaCl (50 mL), dried over Na2S04, filtered, and concentrated and purified via silica gel chromatography (0 - 10% MeOH in DCM) to give tert-butyl (3-(6- fluoroquinolin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (115 mg, 0.35 mmol, 22 % yield) as a yellow solid. MS(ES+) C19H22FN3O2 requires: 343, found: 344 [M+H]+.
  • 6
  • [ 391-77-5 ]
  • [ 25602-68-0 ]
  • 8-(6-fluoroquinolin-4-yl)-8-azabicyclo[3.2.1]oct-3-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
26% With copper(l) iodide; In dimethyl sulfoxide; at 100℃; for 6h;Inert atmosphere; Under nitrogen protection,To <strong>[25602-68-0]nortropinone hydrochloride</strong> (1.6 g, 9.9 mmol),4-chloro-6-fluoroquinoline (1.8 g, 9.9 mmol) and TEA (2.0 g, 20.0 mmol)GuI (0.2 g, 1.0 mol) was added to a 20 mL DMSO solution.After the addition, the reaction mixture was stirred at 100 ° C for 6 h under nitrogen.The reaction system was poured into 200 mL of water.Extract with EA (10 mL x 3). The organic phase is washed with saturated brine.The anhydrous Na2SO4 was sufficiently dried and concentrated under reduced pressure.Column chromatography with residue (PE: EA = 2:1)Purification yielded 0.7 g (yield: 26percent) of the title compound.It is a yellow solid.
 

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