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Chemical Structure| 1192813-41-4 Chemical Structure| 1192813-41-4

Structure of 1192813-41-4

Chemical Structure| 1192813-41-4

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Product Details of [ 1192813-41-4 ]

CAS No. :1192813-41-4
Formula : C6H4F2N2O3
M.W : 190.10
SMILES Code : O=[N+](C1=CN=C(OC(F)F)C=C1)[O-]
MDL No. :MFCD11847317
InChI Key :WLHADOSXRICWAB-UHFFFAOYSA-N
Pubchem ID :53403752

Safety of [ 1192813-41-4 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Computational Chemistry of [ 1192813-41-4 ] Show Less

Physicochemical Properties

Num. heavy atoms 13
Num. arom. heavy atoms 6
Fraction Csp3 0.17
Num. rotatable bonds 3
Num. H-bond acceptors 6.0
Num. H-bond donors 0.0
Molar Refractivity 39.65
TPSA ?

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

67.94 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

0.76
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

2.5
Log Po/w (WLOGP)?

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

2.43
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.

0.61
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

-0.32
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.2

Water Solubility

Log S (ESOL):?

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

-2.74
Solubility 0.348 mg/ml ; 0.00183 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.

-3.57
Solubility 0.0509 mg/ml ; 0.000268 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

-1.76
Solubility 3.33 mg/ml ; 0.0175 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

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.

-5.68 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)

2.06

Application In Synthesis of [ 1192813-41-4 ]

* 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 [ 1192813-41-4 ]

[ 1192813-41-4 ] Synthesis Path-Downstream   1~8

  • 1
  • [ 1192813-41-4 ]
  • [ 317810-73-4 ]
YieldReaction ConditionsOperation in experiment
100% With hydrogen;palladium 10% on activated carbon; In methanol; under 760.051 Torr; for 1.0h; Step B: 6-(Difluoromethoxy)pyridin-3-amine To <strong>[1192813-41-4]2-(difluoromethoxy)-5-nitropyridine</strong> (4.7 g, 24.7 mmol) in degassed methanol (100 mL) was added 10% palladium on carbon (500 mg, 0.47 mmol) and the reaction was hydrogenated at atmospheric pressure for 1 hour. To this was added acetic acid (2.83 mL, 49.4 mmol) and the reaction was filtered through Celite and concentrated in vacuo to afford 6-(difluoromethoxy)pyridin-3-amine (6.33 g, 25.9 mmol, 105% yield) as an olive green liquid. 1H NMR (400 MHz, MeOD-d4) delta ppm 7.60 (d, J=2.76 Hz, 1H), 7.37 (s, 0.5H), 7.15 (dd, J=8.66, 2.89 Hz, 1H), 7.00 (s, 0.5H), 6.71 (d, J=8.78 Hz, 1H).
With hydrogenchloride; iron; In ethanol; water; at 80℃; for 20.0h; 2-Difluoromethoxy-5-nitro-pyridine obtained in Step A (1.6 g) was treated with iron (5 g) and concentrated hydrochloric acid (0.23 ml) in ethanol (15 ml) and water (2.5 ml) at 800C for 20 minutes. Filtration over Celite and evaporation of the solvent afforded 6- difluoromethoxy-pyridin-3-yl-amine (1.4 g) as an orange solid. IH NMR (400 MHz, CDCI3) 3.51 (br s, 2H), 6.89 (d, IH), 7.23 (d, IH), 7.44 (dd, IH), 7.80 (d, IH).
With hydrogenchloride; iron; In ethanol; water; at 80℃; for 0.333333h; Step B: 2-Difluoromethoxy-5-nitro-pyridine obtained in Step A (1.6 g) was treated with iron (5 g) and concentrated hydrochloric acid (0.23 ml) in ethanol (15 ml) and water (2.5 ml) at 800C for 20 minutes. Filtration over Celite and evaporation of the solvent afforded 6- difluoromethoxy-pyridin-3-yl-amine (1.4 g) as an orange solid. IH NMR (400 MHz, CDCl3) 3.51 (br s, 2H), 6.89 (d, IH), 7.23 (d, IH), 7.44 (dd, IH), 7.80 (d, IH).
With hydrogen;palladium 10% on activated carbon; In methanol; under 760.051 Torr; for 1.0h; Step B: 6-(difluoromethoxy)pyridin-3-amine To <strong>[1192813-41-4]2-(difluoromethoxy)-5-nitropyridine</strong> (4.7 g, 24.7 mmol) in degassed methanol (100 mL) was added 10% palladium on carbon (500 mg, 0.47 mmol) and the reaction was hydrogenated at atmospheric pressure for 1 hour. To this was added acetic acid (2.83 mL, 49.4 mmol) and the reaction was filtered through Celite and concentrated in vacuo to afford 6-(difluoromethoxy)pyridin-3-amine (6.33 g, 25.9 mmol, 105 % yield) as an olive green liquid. XH NMR (400 MHz, MeOD-d4) delta ppm 7.60 (d, J=2.76 Hz, 1 H), 7.37 (s, 0.5 H), 7.15 (dd, J=8.66, 2.89 Hz, 1 H), 7.00 (s, 0.5 H), 6.71 (d, J=8.78 Hz, 1 H).
Step-2 -Preparation of 6-(difluoromethoxy)pyridin-3-amine To a solution of <strong>[1192813-41-4]2-(difluoromethoxy)-5-nitropyridine</strong> (0.900 g, 2.35 mmol) in ethanol (5.0 mL), was added iron powder (0.400 g, 7.14 mmol) and conc. HCl (0.2 mL). The reaction mass was refluxed for 1/2 h. Ethanol was removed under vacuum. To the reaction mass, water was added, basified with NaHCO3 and extracted with DCM. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated to afford 0.400 g of the desired product. 1HNMR (DMSO-d6): delta 7.65 (s, 1H), 7.52-7.03 (t, J=72.0 Hz, 1H), 7.27 (s, 1H), 6.73 (d, J=8.4 Hz, 1H); MS [M-H]-: 159.14.
6.33 g With palladium 10% on activated carbon; hydrogen; In methanol; under 760.051 Torr; for 1.0h; To <strong>[1192813-41-4]2-(difluoromethoxy)-5-nitropyridine</strong> (4.7 g, 24.7mmol) in degassed methanol (100 mL) was added 10% palladium on carbon (500 mg, 0.47 mmol) and the reaction was hydrogenated at atmospheric pressure for 1 hour. To this was added acetic acid (2.83 ml., 49.4 mmol) and the reaction wasfiltered through Celite and concentrated in vacuo to afford6-(difluoromethoxy)pyridin-3-amine (6.33 g, 25.9 mmol,105% yield) as an olive green liquid.
With hydrogenchloride; iron; In ethanol; water; at 80℃; for 0.333333h; Step B: 2-Difluoromethoxy-5-nitro-pyridine obtained in Step A (1.6 g) was treated with iron (5 g) and concentrated hydrochloric acid (0.23 ml) in ethanol (15 ml) and water (2.5 ml) at 800C for 20 minutes. Filtration over Celite and evaporation of the solvent afforded 6-difluoromethoxy-pyridin-3-yl-amine (1.4 g) as an orange solid. IH NMR (400 MHz, CDCl3) 3.51 (br s, 2H), 6.89 (d, IH), 7.23 (d, IH), 7.44 (dd, IH), 7.80 (d, IH).

  • 2
  • [ 5418-51-9 ]
  • [ 1717-59-5 ]
  • [ 1192813-41-4 ]
YieldReaction ConditionsOperation in experiment
74.4% With sodium carbonate; In acetonitrile; at 0 - 20℃; for 16.0h; To a solution of 5-nitropyridin-2-ol (XCVIII) (1 g, 7.14 mmol) in acetonitrile (10 mL) at 0 C. was added sodium carbonate (1.513 g, 14.28 mmol), and 2,2-difluoro-2-(fluorosulfonyl)acetic acid (XCIX) (1.107 mL, 10.71 mmol). The reaction was allowed to stir from 0 C. to room temperature over 16 h. The reaction was quenched with saturated aqueous sodium bicarbonate and extracted with EtOAc, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified on a silica gel column (0%?10% EtOAc/hexane) to give 2-(difluoromethoxy)-5-nitropyridine (C) as a light brown oil (1.01 g, 5.31 mmol, 74.4% yield). 1H NMR (DMSO-d6, 500 MHz) delta ppm 7.36 (d, J=9.61 Hz, 1H), 7.82 (t, J=71.70 Hz, 1H), 8.70 (dd, J=9.06, 2.74 Hz, 1H), 9.15 (d, J=2.74 Hz, 1H); ESIMS found for C6H4F2N2O3 m/z 191.0 (M+H).
49% With sodium sulfate; In acetonitrile; at 20℃; for 16.0h; Step A: 2-(Difluoromethoxy)-5-nitropyridine To 2-hydroxy-5-nitropyridine (7 g, 50 mmol) in acetonitrile (500 mL) was added sodium sulfate (1.5 g, 10.6 mmol), and 2,2-difluoro-2-(fluorosulfonyl)acetic acid (6.2 mL, 60 mmol) and the reaction was allowed to stir at room temperature for 16 hours. The reaction was quenched with saturated aqueous sodium bicarbonate and the acetonitrile was removed in vacuo. The remaining aqueous component was extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The pale brown oily solid was triturated with ether/hexanes, filtered and the filtrate concentrated to afford 2-(difluoromethoxy)-5-nitropyridine (4.7 g, 24.7 mmol, 49% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) delta ppm 9.14 (d, J=2.76 Hz, 1H), 8.68 (dd, J=9.03, 2.76 Hz, 1H), 7.98 (s, 0.5H), 7.62 (s, 0.5H), 7.34 (d, J=9.03 Hz, 1H).
49% With sodium sulfate; In acetonitrile; at 20℃; for 16.0h; Step A: 2-(Difluoromethoxy)-5-nitropyridineTo 2-hydroxy-5-nitropyridine (7 g, 50 mmol) in acetonitrile (500 niL) was added sodium sulfate (1.5 g, 10.6 mmol), and 2,2-difluoro-2-(fluorosulfonyl)acetic acid (6.2 mL, 60 mmol) and the reaction was allowed to stir at room temperature for 16 hours. The reaction was quenched with saturated aqueous sodium bicarbonate and the acetonitrile was removed in vacuo. The remaining aqueous component was extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The pale brown oily solid was triturated withether/hexanes, filtered and the filtrate concentrated to afford 2-(difluoromethoxy)-5- nitropyridine (4.7 g, 24.7 mmol, 49 % yield) as a yellow oil. XH NMR (400 MHz, DMSO-de) delta ppm 9.14 (d, J=2.76 Hz, 1 H), 8.68 (dd, J=9.03, 2.76 Hz, 1 H), 7.98 (s, 0.5 H), 7.62 (s, 0.5 H), 7.34 (d, J=9.03 Hz, 1 H).
49% With sodium sulfate; In acetonitrile; at 20℃; for 16.0h; To 2-hydroxy-5-nitropyridine (7 g, 50 mmol) inacetonitrile (500 mL) was added sodium sulfate (1.5 g, 10.6mmol), and 2,2-difluoro-2-(fluorosulfonyl)acetic acid (6.2ml., 60 mmol) and the reaction was allowed to stir at roomtemperature for 16 hours. The reaction was quenched withsaturated aqueous sodium bicarbonate and the acetonitrilewas removed in vacuo. The remaining aqueous componentwas extracted with ethyl acetate, washed with brine, driedover sodium sulfate, filtered and concentrated in vacuo. Thepale brown oily solid was triturated with ether/hexanes, filteredand the filtrate concentrated to afford 2-(difluoromethoxy)-5-nitropyridine (4.7 g, 24.7 mmol, 49% yield) asa yellow oil.

  • 3
  • [ 5418-51-9 ]
  • [ 1895-39-2 ]
  • 1-(difluoromethyl)-5-nitropyridin-2(1H)-one [ No CAS ]
  • [ 1192813-41-4 ]
YieldReaction ConditionsOperation in experiment
1.5%; 15% In acetonitrile; for 48.0h;Reflux; 2-Hydroxy-5-nitro-pyridine (5 g) was treated with sodium chlorodifluoro- acetate (11.5 g) in refluxing acetonitrile (186 ml) for 2 days. The solvent was evaporated, the residue poured into ethyl acetate, washed with brine, dried over sodium sulfate and then concentrated in vacuo. Chromatography on silica gel (eluent: hexane / ethyl acetate 1 :1) afforded 2-difluoromethoxy-5-nitro-pyridine (1 g, 15%) and l-difluoromethyl-5-nitro-lH- pyridin-2-one (90 mg, 1.5%). 2-Difluoromethoxy-5-nitro-pyridine: MS (ES+) 191 (MEta+); IH NMR (400 MHz, CDCl3) 7.05 (d, IH), 7.51 (t, IH), 8.53 (dd, IH), 9.09 (d, IH). 1-Difluoromethyl-5-nitro-lH-pyridin-2-one: MS (ES+) 191 (MEta+); 6.65 (d, IH), 7.63 (t, IH), 8.14 (dd, IH), 8.73 (d, IH).
1.5%; 15% In acetonitrile; for 48.0h;Reflux; Step A: 2-Hydroxy-5-nitro-pyridine (5 g) was treated with sodium chlorodifluoro- acetate (1 1.5 g) in refluxing acetonitrile (186 ml) for 2 days. The solvent was evaporated, the residue poured into ethyl acetate, washed with brine, dried over sodium sulfate and then concentrated in vacuo. Chromatography on silica gel (eluent: hexane / ethyl acetate 1 :1) afforded 2-difluoromethoxy-5-nitro-pyridine (I g, 15%) and l-difluoromethyl-5-nitro-lH- pyridin-2-one (90 mg, 1.5%). 2-Difluoromethoxy-5-nitro-pyridine: MS (ES+) 191 (MH+); IH NMR (400 MHz, CDCl3) 7.05 (d, IH), 7.51 (t, IH), 8.53 (dd, IH), 9.09 (d, IH). 1-Difluoromethyl-5-nitro-l//-pyridin-2-one: MS (ES+) 191 (MH+); 6.65 (d, IH), 7.63 (t, IH), 8.14 (dd, IH), 8.73 (d, IH).
In acetonitrile; for 48.0h;Reflux; This example illustrates the preparation of 2-chloro-N-{r-[4-(5-chloro-pyrirnidin-2- yl)-benzyl]-6-difluoromethoxy- 1 ',2',3',4',5',6'-hexahydro-[2,4']bipyridinyl-3-yl} - isonicotinamide (Compound B6 of Table B).The title compound was obtained from 2-bromo-6-difluoromethoxy-pyridin-3-yl- amine following the procedures described in Example 5. 2-Bromo-6-difluoromethoxy-pyridin- 3-yl-amine was prepared as follows:Step A: 2-Hydroxy-5-nitro-pyridine (5 g) was treated with sodium chlorodifluoro- acetate (11.5 g) in refluxing acetonitrile (186 ml) for 2 days. The solvent was evaporated, the residue poured into ethyl acetate, washed with brine, dried over sodium sulfate and then concentrated in vacuo. Chromatography on silica gel (eluent: hexane / ethyl acetate 1 :1) afforded 2-difluoromethoxy-5-nitro-pyridine (1 g) and l-difluoromethyl-5-nitro-lH-pyridin-2- one (90 mg). 2-Difluoromethoxy-5-nitro-pyridine: MS (ES+) 191 (MH+); IH NMR (400 MHz, CDCl3) 7.05 (d, IH), 7.51 (t, IH), 8.53 (dd, IH), 9.09 (d, IH). l-Difluoromethyl-5- nitro-lH-pyridin-2-one: MS (ES+) 191 (MEta+); IH NMR (400 MHz, CDCl3) 6.65 (d, IH), 7.63 (t, IH), 8.14 (dd, IH), 8.73 (d, IH).
  • 4
  • [ 1192813-41-4 ]
  • [ 1196698-52-8 ]
  • 5
  • [ 1192813-41-4 ]
  • [ 1192813-44-7 ]
  • 6
  • [ 1192813-41-4 ]
  • [ 1192813-47-0 ]
  • 7
  • [ 5418-51-9 ]
  • [ 1895-39-2 ]
  • [ 1192813-41-4 ]
YieldReaction ConditionsOperation in experiment
In acetonitrile; for 72.0h;Reflux; Step-1 -Preparation of 2-(difluoromethoxy)-5-nitropyridine To a solution of 2-hydroxy-5-nitro pyridine (10 g, 0.071 mol) in acetonitrile (100 mL) was added sodium chlorodifluoroacetate (11.5 g, 0.075 mol). The reaction mass was refluxed for 72 h. The excess of solvent was removed under vacuum and the reaction mass was diluted with ethyl acetate and water. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated. The obtained crude was purified by column chromatography on neutral alumina eluting with 10% EtOAc: Pet.ether to afford 0.900 g of the desired product. 1HNMR (DMSO-d6): delta 7.05 (d, J=8.7 Hz, 1H), 7.53 (d, J=71.4 Hz, 1H), 8.54 (dd, J=8.1 Hz & 5.4 Hz, 1H), 7.91 (s, 1H); MS [M-]: 190.83.
  • 8
  • [ 1192813-41-4 ]
  • [ 1192807-47-8 ]
 

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