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Structure of 120103-19-7

Chemical Structure| 120103-19-7

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Product Details of [ 120103-19-7 ]

CAS No. :120103-19-7
Formula : C6H5F2NO
M.W : 145.11
SMILES Code : OC1=CC(F)=C(N)C=C1F
MDL No. :MFCD03094492
InChI Key :RPNPSBJBVUOFBH-UHFFFAOYSA-N
Pubchem ID :2778762

Safety of [ 120103-19-7 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319
Precautionary Statements:P261-P305+P351+P338

Computational Chemistry of [ 120103-19-7 ] Show Less

Physicochemical Properties

Num. heavy atoms 10
Num. arom. heavy atoms 6
Fraction Csp3 0.0
Num. rotatable bonds 0
Num. H-bond acceptors 3.0
Num. H-bond donors 2.0
Molar Refractivity 32.79
TPSA ?

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

46.25 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.26
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

1.09
Log Po/w (WLOGP)?

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

2.1
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.

1.68
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

1.5
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.53

Water Solubility

Log S (ESOL):?

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

-1.87
Solubility 1.96 mg/ml ; 0.0135 mol/l
Class?

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

Very soluble
Log S (Ali)?

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

-1.65
Solubility 3.22 mg/ml ; 0.0222 mol/l
Class?

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

Very 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

-2.0
Solubility 1.45 mg/ml ; 0.01 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.

-6.41 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

1.0
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

2.0 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)

1.15

Application In Synthesis of [ 120103-19-7 ]

* 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 [ 120103-19-7 ]
  • Downstream synthetic route of [ 120103-19-7 ]

[ 120103-19-7 ] Synthesis Path-Upstream   1~3

  • 1
  • [ 868736-12-3 ]
  • [ 120103-19-7 ]
YieldReaction ConditionsOperation in experiment
99% With hydrogen In methanol at 20℃; for 24.3333 h; 10percent palladium on carbon (921 mg) was added to a solution of 1-(benzyloxy)-2,5-difluoro-4-nitrobenzen (9.21 g) in methanol (300 ml), followed by stirring at room temperature under hydrogen atmosphere for 24 hours and 20 minutes. The air of the flask was replaced with nitrogen to stop the reaction, and the catalyst was removed by filtration using celite. The filtrate was distilled off under reduced pressure to give the title compound (4.96 g, 99percent) as a pale brown solid.1H-NMR Spectrum (DMSO-d6) δ (ppm): 4.67 (1H, s), 6.53-6.64 (1H, m), 9.03 (1H, s).
99% With hydrogen In methanol at 20℃; for 24.33 h; (Reference Example C-2) 4-Amino-2,5-difluorophenol
To a solution of 1-(benzyloxy)-2,5-difluoro-4-nitrobenzene (9.21 g) in methanol (300 ml) was added 10 percent palladium on carbon (921 mg), followed by stirring under a hydrogen atmosphere at room temperature for 24 hr and 20 min.
The atmosphere in the reaction vessel was replaced with nitrogen to stop the reaction, and the catalyst was filtered through Celite.
The filtrate was removed under reduced pressure to provide the titled compound as a brown solid (4.96 g, 99 percent).
1H-NMR Spectrum (DMSO-d6) δ (ppm): 4.67 (1H, s), 6.53-6.64 (1H, m), 9.03 (1H, s).
99% With hydrogen In methanol at 20℃; for 24.3333 h; (Production Example 95) 4-Amino-2,5-difluorophenol
To a solution of 1-(benzyloxy)-2,5-difluoro-4-nitrobenzene (9.21 g) in methanol (300 ml) was added 10 percent palladium on carbon (921 mg), followed by stirring under a hydrogen atmosphere at room temperature for 24 hr and 20 min.
The atmosphere in the reaction vessel was replaced with nitrogen to stop the reaction, and the catalyst was filtered through Celite.
The filtrate was removed under reduced pressure to provide the titled compound as a brown solid (4.96 g, 99 percent).
1H-NMR Spectrum (DMSO-d6) δ (ppm): 4.67 (1H, s), 6.53-6.64 (1H, m), 9.03 (1H, s).
86% With palladium 10% on activated carbon In tetrahydrofuran; methanol at 32℃; for 10 h; To a suspension of l-(benzyloxy)-2,5-difluoro-4-nitrobenzene (1.06 g, 4 mmol) in CH3OH (25 mL) and THF (5 mL) was added Pd/C (185 mg, 17percent). The reaction was stirred at 32 °C under atmosphere for 10 hours, and then filtered through a CELITE® pad. The organic phase was washed with MeOH (10 mL) and concentrated in vacuo. The residue was stirred in DCM (15 mL), filtered and washed with DCM (20 mL) to give the title compound as a dark brown solid (500 mg, 86percent). MS (ESI, pos. ion) m/z: 146.2 [M+H]+; IH NMR (400 MHz, DMSO-i): δ 4.68 (s, 2H), 6.53-6.65 (m, 2H), 9.06 (br s, IH).
86% With 50% palladium on charcoal; hydrogen In tetrahydrofuran; methanol at 32℃; for 10 h; Step 2) 4-amino-2,5-difluorophenol [0181] To a suspension of l-(benzyloxy)-2,5-difluoro-4-nitrobenzene (1.06 g, 4 mmol) in CH3OH (25 mL) and THF (5 mL) was added Pd/C (50 percent Pd content, 185 mg). The reaction was stirred at 32 °C under atmosphere for 10 hours. The mixture was filtered through a CELITE® pad and the filtrate was concentrated in vacuo. The residue was washed with DCM (15 mL) to give the title compound as a dark brown solid (500 mg, 86 percent). MS (ESI, pos. ion) m/z: 146.2 [M+H]+; NMR (400 MHz, DMSO-i): δ (ppm) 4.68 (s, 2H), 6.53-6.65 (m, 2H), 9.06 (br, 1H).
86% With 50% palladium on charcoal; hydrogen In tetrahydrofuran; methanol at 32℃; for 10 h; Step 2)
4-amino-2,5-difluorophenol
To a suspension of 1-(benzyloxy)-2,5-difluoro-4-nitrobenzene (1.06 g, 4 mmol) in CH3OH (25 mL) and THF (5 mL) was added Pd/C (50percent Pd content, 185 mg).
The reaction was stirred at 32° C. under H2 atmosphere for 10 hours.
The mixture was filtered through a CELITE® pad and the filtrate was concentrated in vacuo.
The residue was washed with DCM (15 mL) to give the title compound as a dark brown solid (500 mg, 86percent).
MS (ESI, pos. ion) m/z: 146.2 [M+H]+;
1H NMR (400 MHz, DMSO-d6): δ (ppm) 4.68 (s, 2H), 6.53-6.65 (m, 2H), 9.06 (br, 1H).

References: [1] Patent: US2008/214815, 2008, A1, . Location in patent: Page/Page column 18.
[2] Patent: EP2119706, 2009, A1, . Location in patent: Page/Page column 45.
[3] Patent: EP1889836, 2008, A1, . Location in patent: Page/Page column 82.
[4] Patent: WO2013/180949, 2013, A1, . Location in patent: Paragraph 0183.
[5] Patent: WO2014/22116, 2014, A2, . Location in patent: Paragraph 0181.
[6] Patent: US2015/37280, 2015, A1, . Location in patent: Paragraph 0315.
[7] Patent: EP1889836, 2008, A1, . Location in patent: Page/Page column 84.
  • 2
  • [ 847872-05-3 ]
  • [ 120103-19-7 ]
References: [1] Patent: EP1514865, 2005, A1, . Location in patent: Page/Page column 9.
  • 3
  • [ 2105-61-5 ]
  • [ 120103-19-7 ]
References: [1] Patent: WO2014/22116, 2014, A2, .
[2] Patent: US2015/37280, 2015, A1, .
[3] Patent: EP1889836, 2008, A1, .
 

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