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Chemical Structure| 367-27-1 Chemical Structure| 367-27-1

Structure of 2,4-Difluorophenol
CAS No.: 367-27-1

Chemical Structure| 367-27-1

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Product Details of [ 367-27-1 ]

CAS No. :367-27-1
Formula : C6H4F2O
M.W : 130.09
SMILES Code : OC1=CC=C(F)C=C1F
MDL No. :MFCD00009715
InChI Key :NVWVWEWVLBKPSM-UHFFFAOYSA-N
Pubchem ID :123051

Safety of [ 367-27-1 ]

GHS Pictogram:
Signal Word:Danger
Hazard Statements:H228-H302+H312+H332-H314
Precautionary Statements:P264-P270-P271-P280-P304+P340-P305+P351+P338-P310-P330-P331-P363-P370+P378-P403-P501
Class:8(4.1)
UN#:2921
Packing Group:

Computational Chemistry of [ 367-27-1 ] Show Less

Physicochemical Properties

Num. heavy atoms 9
Num. arom. heavy atoms 6
Fraction Csp3 0.0
Num. rotatable bonds 0
Num. H-bond acceptors 3.0
Num. H-bond donors 1.0
Molar Refractivity 28.38
TPSA ?

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

20.23 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.62
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

2.06
Log Po/w (WLOGP)?

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

2.51
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.

2.34
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

2.23
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.15

Water Solubility

Log S (ESOL):?

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

-2.44
Solubility 0.475 mg/ml ; 0.00365 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.

-2.11
Solubility 1.0 mg/ml ; 0.0077 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

-2.34
Solubility 0.591 mg/ml ; 0.00454 mol/l
Class?

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

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

No
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.

-5.63 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)

1.1

Application In Synthesis of [ 367-27-1 ]

* 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.

  • Downstream synthetic route of [ 367-27-1 ]

[ 367-27-1 ] Synthesis Path-Downstream   1~15

  • 2
  • [ 367-27-1 ]
  • [ 34662-29-8 ]
  • [ 116686-91-0 ]
  • 3
  • [ 13195-50-1 ]
  • [ 367-27-1 ]
  • [ 190966-72-4 ]
  • 4
  • [ 367-27-1 ]
  • [ 113512-71-3 ]
  • 5
  • [ 367-27-1 ]
  • [ 364-31-8 ]
  • 2,4-Difluoro-6-aminophenol Hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; H2; nitrogen;palladium; In methanol; 2,4-Difluoro-6-aminophenol Hydrochloride (715) A mixture of 2,4-Difluoro-6-nitrophenol (28.4 g, 0.162 mol; prepared by a similar method as 711 except replacing 2-chloro-4-fluorophenol with 2,4-difluorophenol) and 10% palladium on carbon (3.5 g) in absolute MeOH (120 mL) was placed under 1 atm of H2 and stirred until complete reduction had occurred. The H2 was replaced with nitrogen and the reaction was filtered through Celite. Gaseous HCl was bubbled through the filtrate and the resulting solution concentrated. The residue was taken up into H2 O, washed with Et2 O (2*), neutralized with solid NaHCO3 and the product extracted with Et2 O. The extracts were combined dried over MgSO4 and filtered. The filtrate was treated with gaseous HCl and resulting precipitate collected and dried under vacuum to provide 12.9 g of compound 715 as a beige solid. STR94
  • 6
  • [ 367-27-1 ]
  • [ 364-31-8 ]
YieldReaction ConditionsOperation in experiment
93% With nitric acid; acetic acid; at 10.0℃; for 1.5h; Step 1: To a solution of 2A (100.0 g, 0.769 mol) in AcOH (800 mL) was added dropwise HNO3/AcOH (200 mL, v/v=1/1). The mixture was stirred at 10 C. for 90 min and then poured into ice-water (4 L). The solid was collected by filtration and washed by small amount of water to afford 2B (125 g, 93%), which was used in the next step without further purification.
With nitric acid; In acetic acid; C.1 2,4-Difluoro-6-nitrophenol To a mixture of nitric acid (100 ml) and acetic acid (100 ml) was added a solution of 2,4-difluorophenol (13 g, 100 mmoles) in acetic acid (100 ml) dropwise at -5 under stirring. Stirring continued for 2 hours. The reaction mixture was poured into ice. The precipitate was collected, washed with water and dried to leave 11.26 g of a yellow solid. The material was used in the next step without further purification. 1H NMR: 11.15 (br.s., 1H), 7.68-7.79 (m, 2H).
  • 7
  • [ 890315-75-0 ]
  • [ 367-27-1 ]
  • [ 131274-22-1 ]
  • [ 564483-19-8 ]
  • [ 890316-65-1 ]
YieldReaction ConditionsOperation in experiment
With citric acid;tris-(dibenzylideneacetone)dipalladium(0); palladium diacetate; In ethyl acetate; toluene; Example 557 0.018 mL of 2,4-difluorophenol was added to 1 mL of toluene suspension containing 10 mg of 60percent sodium hydride at room temperature, and the resulting mixture was heated to reflux under nitrogen atmosphere for 15 minutes. After the reaction mixture was cooled to room temperature, 0.5 mL of toluene solution containing 4.7 mg of 2-(di-tert-butylphosphino)-2',4',6'-triisopropylbiphenyl, 1.7 mg of palladium acetate and 70 mg of tert-butyl 2-(benzamido)-4-bromobenzoate was added and the resulting mixture was heated to reflux under nitrogen atmosphere for 4 hours. After the reaction mixture was cooled to room temperature, 4.5 mg of 60percent sodium hydride, 4.7 mg of 2-(di-tert-butylphosphino)-2',4',6'-triisopropylbiphenyl and 1.7 mg of palladium acetate were added and the resulting mixture was heated to reflux under nitrogen atmosphere for 2 hours. After the reaction mixture was cooled to room temperature, 0.018 mL of 2,4-difluorophenol, 7.4 mg of 60percent sodium hydride, 4.7 mg of 2-(di-tert-butylphosphino)-2',4',6'-triisopropylbiphenyl and 1.7 mg of palladium acetate were added and the resulting mixture was heated to reflux under nitrogen atmosphere for 2 hours. After the reaction mixture was cooled to room temperature, 1.6 mg of tri-tert-butylphosphine tetrafluoroborate and 5.1 mg of tris(dibenzylideneacetone)dipalladium(0) were added, and the resulting mixture was heated to reflux under nitrogen atmosphere for 1 hour and 30 minutes. 10percent citric acid aqueous solution and ethyl acetate were added after the reaction mixture was cooled to room temperature. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane: ethyl acetate = 4:1] to obtain tert-butyl 2-(benzamido)-4-(2,4-difluorophenoxy)benzoate.
  • 8
  • [ 57641-66-4 ]
  • [ 367-27-1 ]
  • [ 1249176-47-3 ]
  • 9
  • [ 367-27-1 ]
  • [ 84851-56-9 ]
  • methyl 4-(1-(2,4-difluorophenoxy)ethyl)benzoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
33% Methyl 4-(l-(2,4-dtfluorophenoxy)ethyl)benzoate. To the solution of 4-(l- hydroxyethyl)benzoate (300 mg.1.67 mmol) in tetrahydrofuran (80 mL) was added triphenylphosphine (570 mg, 2.2 mmol) and 2,4-difluorophenol (159 mg,1.67 mmol) , the mixture was stirred for 30 minutes at room temperature, then diisopropylazodicarboxylate (568.3 mg, 2.2 mmol) was added dropwise to the solution at 0 C. The mixture was stirred at room temperature for 12 hours. Then the mixture was concentrated and the residue was purified by column chromatography (silica gel, Petroleum ether / ethyl acetate = 20: 1) to give methyl 4-(l-(2,4-difhiorophenoxy)ethyl)benzoate (151 mg, 33%) as oil. 1H-NMR (300 MHz, CD3OD) delta 8.03 (d, J = 8.1 Hz, 2H,), 7.460 (d, J = 8.1 Hz, 2H), 6.86-6.72 (m, 3H), 5.29 (q, 1H), 3.91(s, 3H), 1.67 (d, J = 6.3 Hz, 2H).
33% To the solution of 4-(1-hydroxyethyl)benzoate (300 mg. 1.67 mmol) in tetrahydrofuran (80 mL) was added triphenylphosphine (570 mg, 2.2 mmol) and 2,4-difluorophenol (159 mg, 1.67 mmol), the mixture was stirred for 30 minutes at room temperature, then diisopropylazodicarboxylate (568.3 mg, 2.2 mmol) was added dropwise to the solution at 0 C. The mixture was stirred at room temperature for 12 hours. Then the mixture was concentrated and the residue was purified by column chromatography (silica gel, Petroleum ether/ethyl acetate=20:1) to give methyl 4-(1-(2,4-difluorophenoxy)ethyl)benzoate (151 mg, 33%) as oil. 1H-NMR (300 MHz, CD3OD) delta 8.03 (d, J=8.1 Hz, 2H), 7.460 (d, J=8.1 Hz, 2H), 6.86-6.72 (m, 3H), 5.29 (q, 1H), 3.91 (s, 3H), 1.67 (d, J=6.3 Hz, 2H).
  • 10
  • [ 1520-70-3 ]
  • [ 367-27-1 ]
  • 5-(2,6-dichloropyrimidin-4-yl)-1,3-dimethylpyridin-2-one [ No CAS ]
  • N-[4-(2,4-difluorophenoxy)-6-(1,5-dimethyl-6-oxopyridin-3-yl)pyrimidin-2-yl]ethanesulfonamide [ No CAS ]
  • N-[2-(2,4-difluorophenoxy)-6-(1,5-dimethyl-6-oxopyridin-3-yl)pyrimidin-4-yl]ethanesulfonamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
8% A mixture of 2,4-difluorophenol (25 mg, 0.19 mmol) and 5-(2,6-dichloropyrimidin-4-yl)- 1 ,3-dimethylpy- ridin-2-one (50 mg, 0.19 mmol) in DMF (0.5 mE) and THF (0.5 mE) was treated with K2C03 (304 mg, 0.23 mmol). The mixture was stirred at rt for 3 h. The resulting suspension was diluted with water and extracted with EtOAc (10 mEx3). The combined organic layers were washed with iN NaOH (aq) (5 mE), water (15 mE), brine, dried over Mg504, and concentrated in vacuo. The crude solid was purified by silica gel column chromatography using a gradient of EtOAc (0 to 50percent) in DCM to afford an unseparated mixture of regioisomeric title compounds (66 mg, 96percent combined) as a white solid. ECMS (M+H)=364 for both regioisomers.11315] A solution of <strong>[1520-70-3]ethanesulfonamide</strong> (80 mg, 0.73 mmol) in DMF (2 mE) was treated with NaH (27 mg, 0.68 mmol, 60percent by weight). Afier 15 mm, the mixture was treated with a DMF (1 mE) solution of title compounds obtainedfrom Step 2. The reaction mixture was stirred at 500 C. for 14 h. The resulting suspension was diluted with water and extracted with EtOAc (10 mEx3). The combined organic layers were washed with brine, dried over Na2504, and concentrated in vacuo. Preparative HPEC isolated both regioisomers as Examples 346 and 347. The title compound (6 mg, 8percent) was obtained as a white solid. ?H NMR (400 MHz, DMSO-d5) oe ppm 1.08 (t, J=7.1 Hz, 3H) 2.07 (s, 3H) 3.11 (q, J=7.1 Hz, 2H) 3.54 (s, 3H) 6.81 (s, 1H) 7.17 (m, 1H) 7.47 (s, 2H) 7.79 (s, 1H) 8.37 (s, 1H) 11.37 (bs, 1H). ECMS (M+H7 =437.
  • 11
  • [ 367-27-1 ]
  • [ 116457-91-1 ]
  • (R)-methyl 3-(2,4-difluorophenoxy)-2-(tritylamino)propanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
74% With azodicarboxylic acid bis(2-methoxyethyl) ester; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 2h; To a stirred solution of (R)-methyl3-hydroxy-2-(tritylamino)propanoate (800 mg, 2.2 mmol), 2,4-difluorophenol (370 mg, 2.9 mmol), and triphenylphosphine (760 mg, 2.9 mmol) in THF (15 mL) was added dropwise a solution of bis(2-methoxyethyl) azodicarboxylate (670 mg, 2.9 mmol) in THF (2 mL) at 0 C. The mixture was stirred at room temperature for 2 hrs. The mixture was concentrated, and the residue was diluted with EtOAc (50 mL). The diluted mixture was washed with a saturated aqueous NaHC03 solution and then brine, and was dried over Na2S04. After filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluted with 3% to 13% EtOAc in hexane) to give the title compound as a colorless gum (771 mg, 74% yield).‘H NMR (300 MHz, CDC13) delta 7.52(6H, d, J = 7.3 Hz), 7.30-7.16 (9H, m), 6.99-6.72 (3H, m), 4.29 (1H, d, J =9.5, 5.2 Hz), 4.02 (1H, dd, J = 9.5, 6.9 Hz), 3.78-3.71 (1H, m), 3.24 (3H, s),2.88 (1H, d, J = 10.3 Hz). MS (ESI)m/z: fragment signal of 243 (positive ion) was observed.
  • 12
  • [ 918340-51-9 ]
  • [ 367-27-1 ]
  • [ 1613479-37-0 ]
  • 13
  • [ 21560-29-2 ]
  • [ 367-27-1 ]
  • [ 1613479-58-5 ]
  • 14
  • [ 367-27-1 ]
  • [ 1352244-77-9 ]
  • 1-bromo-2-(2,4-difluorophenoxy)-4-methoxy-5-nitrobenzene [ No CAS ]
YieldReaction ConditionsOperation in experiment
48% With potassium carbonate; In dimethyl sulfoxide; at 20℃; 1-bromo-2-fluoro-4-methyl-5-nitrobenzene (2.0 g, 8.55 mmol) was dissolved in dimethyl sulfoxide (20 mL) at room temperature, then 2,4-difluorophenol (1.67 g, 12.82 mmol) and potassium carbonate (2.36 g, 17.10 mmol) were added to the reaction mixture, and stirred at room temperature overnight. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (40 mL). The organic phase was washed with saturated brine (10 mL*2), dried over anhydrous sodium sulfate, filtered and evaporated. 2,4-Difluorophenoxy)-4-methoxy-5-nitrobenzene (2.90 g, white solid, yield: 99%).
  • 15
  • [ 367-27-1 ]
  • [ 19064-24-5 ]
  • 1-(2,4-difluorophenoxy)-3-fluoro-2-nitrobenzene [ No CAS ]
YieldReaction ConditionsOperation in experiment
9.4 g To a solution of 2,4-difluorophenol (5.00 g, 38.4 mmol) in DMF (50 mL) was added NaH (1.84 g, 46.1 mmol, 60% purity) at 0 C. The mixture was stirred at 25 C for 1 h. Then <strong>[19064-24-5]1,3-difluoro-2-nitrobenzene</strong> (6.11 g, 38.4 mmol) in DMF (10 mL) was added to the reaction mixture. The mixture was stirred at 25 C for 16 h. The resulting soluiton was diluted with water (100 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over anhydrous Na2SO4, filtered and concentrated to give a residue. The residue was purified by column chromatography to give 1-(2,4- difluorophenoxy)-3-fluoro-2-nitrobenzene (I-178) (9.40 g) as a yellow oil.
 

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