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Structure of 284030-58-6

Chemical Structure| 284030-58-6

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Product Details of [ 284030-58-6 ]

CAS No. :284030-58-6
Formula : C8H6F2N2O4
M.W : 232.14
SMILES Code : O=C(OC)C1=CC([N+]([O-])=O)=C(N)C(F)=C1F
MDL No. :MFCD06201870
Boiling Point : No data available
InChI Key :HOJFIOHGPQOQBF-UHFFFAOYSA-N
Pubchem ID :2759749

Safety of [ 284030-58-6 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H320-H335
Precautionary Statements:P264-P270-P301+P312-P330

Computational Chemistry of [ 284030-58-6 ] Show Less

Physicochemical Properties

Num. heavy atoms 16
Num. arom. heavy atoms 6
Fraction Csp3 0.12
Num. rotatable bonds 3
Num. H-bond acceptors 6.0
Num. H-bond donors 1.0
Molar Refractivity 50.86
TPSA ?

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

98.14 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.22
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

1.67
Log Po/w (WLOGP)?

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

2.09
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.

1.15
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

-0.22
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.18

Water Solubility

Log S (ESOL):?

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

-2.41
Solubility 0.901 mg/ml ; 0.00388 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.

-3.35
Solubility 0.105 mg/ml ; 0.000452 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

-2.06
Solubility 2.01 mg/ml ; 0.00867 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

No
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.

-6.53 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

0.0
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

3.0 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)

2.26

Application In Synthesis of [ 284030-58-6 ]

* 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 [ 284030-58-6 ]

[ 284030-58-6 ] Synthesis Path-Downstream   1~5

  • 1
  • [ 284030-57-5 ]
  • [ 18107-18-1 ]
  • [ 284030-58-6 ]
YieldReaction ConditionsOperation in experiment
92% With methanol; In tetrahydrofuran; at 0 - 20℃; for 0.5h; Step C: 4-Amino-2,3-difluoro-5-nitro-benzoic acid methyl ester 4. A 2 M solution of TMS diazomethane in hexanes (6.88 mL, 13.75 mmol) is added to a suspension of <strong>[284030-57-5]4-amino-2,3-difluoro-5-nitro-benzoic acid</strong> 3 (2.00 g, 9.17 mmol) in 25 mL of 4:1 THF:MeOH at 0 C. under nitrogen atmosphere. Upon completion of addition, reaction mixture is warmed to room temperature. After 0.5 hours, excess TMS diazomethane is destroyed by the careful addition of acetic acid. The reaction is then concentrated under reduced pressure and dried in vacuo to give 1.95 g (92%) of pure desired product: MS APCI (-) m/z 231 (M-1) detected.
92% A 2 M solution of TMS diazomethane in hexanes (6.88 ml, 13.75 mmol) is added to a suspension of <strong>[284030-57-5]4-amino-2,3-difluoro-5-nitro-benzoic acid</strong> 3 (2.00 g, 9.17 mmol) in 25 ml of 4:1 THF:MeOH at 0 C. under nitrogen atmosphere. Upon completion of addition, reaction mixture is warmed to room temperature. After 0.5 h, excess TMS diazomethane is destroyed by the careful addition of acetic acid. The reaction is then concentrated under reduced pressure and dried in vacuo to give 1.95 g (92%) of pure desired product: MS APCI (-) m/z 231 (M-1) detected.
92% In tetrahydrofuran; methanol; hexane; at 0 - 20℃; for 0.5h;Inert atmosphere; 4-Amino-2, 3-difluoro-5-nitro-benzoic acid methyl ester 4A 2 M solution of TMS diazomethane in hexanes (6.88 ml, 13.75 mmol) is added to a suspension of <strong>[284030-57-5]4-amino-2,3-difluoro-5-nitro-benzoic acid</strong> 3 (2.00 g, 9.17 mmol) in 25 ml of 4:1 THF:MeOH at 0 C under nitrogen atmosphere. Upon completion of addition, reaction mixture is warmed to room temperature. After 0.5 h, excess TMS diazomethane is destroyed by the careful addition of acetic acid. The reaction is then concentrated under reduced pressure anddried in vacuo to give 1.95 g (92%) of pure desired product: MS APCI (-) m/z 231 (M-1) detected.
84% In methanol; at 0℃; for 1h; Trimethylsilylated diazomethane (1.26 g, 11.02 mmol) was slowly added dropwise to a solution of compound 3 (2.0 g, 9.17 mmol) in methanol at 0 C, and the reaction was continued for 1 h. The reaction was quenched by the addition of a few drops of acetic acid, and then the mixture was evaporated. EtOAc (EtOAc) Methanol (10 ml) was beaten to obtain a pure product of 1.8 g in a yield of 84%.

  • 2
  • [ 186581-53-3 ]
  • [ 284030-57-5 ]
  • [ 284030-58-6 ]
YieldReaction ConditionsOperation in experiment
1.95 g (92%) With acetic acid; In tetrahydrofuran; methanol; Step C 4-Amino-2,3-difluoro-5-nitro-benzoic acid methyl ester A 2 M solution of TMS diazomethane in hexanes (6.88 ml, 13.75 mmol) is added to a suspension of <strong>[284030-57-5]4-amino-2,3-difluoro-5-nitro-benzoic acid</strong> (2.00 g, 9.17 mmol) in 25 ml of 4:1 THF:MeOH at 0 C. under nitrogen atmosphere. Upon completion of addition, reaction mixture is warmed to room temperature. After 0.5 h, excess TMS diazomethane is destroyed by the careful addition of acetic acid. The reaction is then concentrated under reduced pressure and dried in vacuo to give 1.95 g (92%) of pure desired product.
  • 3
  • [ 284030-57-5 ]
  • [ 284030-58-6 ]
YieldReaction ConditionsOperation in experiment
92% With diazomethyl-trimethyl-silane; In tetrahydrofuran; methanol; hexane; at 0 - 20℃; for 0.5h; A 2 M solution of tetramethylsilane (TMS) diazomethane in hexanes (6.88 ml, 13.75 mmol) was added to a suspension of <strong>[284030-57-5]4-amino-2,3-difluoro-5-nitrobenzoic acid</strong> (2.00 g, 9.17 mmol) in 25 ml of 4: 1 Tetrahydrofuran (THF):MeOH at 0 0C under nitrogen atmosphere. Upon completion of addition, reaction mixture was warmed to room temperature. After 0.5 hours, excess TMS diazomethane was destroyed by the careful addition of acetic acid. The reaction was then concentrated under reduced pressure and dried in vacuo 1.95 g (92%) of pure desired product: MS APCI (-) m/z 231 (M-I) detected.
70% With hydrogenchloride; In methanol; Step c Preparation of methyl 4-amino-2,3-difluoro-5-nitrobenzoate Hydrogen chloride gas was dissolved in anhydrous methanol (30 ml) until the solution was warm. The solid <strong>[284030-57-5]4-amino-2,3-difluoro-5-nitrobenzoic acid</strong> (0.47 g; 0.00215 mol) was dissolved in this solution and the reaction mixture was brought to reflux with vigorous stirring for 23 hours under a nitrogen atmosphere. The reaction mixture was allowed to cool slowly on the bench. A yellow precipitate formed and was collected by vacuum filtration and dried with suction to afford 0.35 g of yellow microfilaments; 70% yield; m.p. 183.5-184 C.; 1H-NMR (400 MHz; DMSO) delta8.36 (dd, 1H, J=7.3, 1.7 Hz), 8.06 (s, 2H), 3.78 (s, 3H); 19F-NMR (376 MHz; DMSO) delta-128.85 to -128.92 (m), -153.29 (d); MS (APCl-) 231 (M-1, 100); IR (KBr) 3433, 3322, 1700, 1650, 1549, 1343, 1285 cm-1; Anal. calcd/found for: C8H6F2N2O4 C, 41.39/41.40; H, 2.61/2.50; N, 12.07/11.98; F, 16.37/16.58.
70% With hydrogenchloride; In methanol; for 23h;Heating / reflux; Hydrogen chloride gas was dissolved in anhydrous methanol (30 ml) until the solution was warm. The solid <strong>[284030-57-5]4-amino-2,3-difluoro-5-nitrobenzoic acid</strong> (0.47 g; 0.00215 mol) was dissolved in this solution and the reaction mixture was brought to reflux with vigorous stirring for 23 hours under a nitrogen atmosphere. The reaction mixture was allowed to cool slowly on the bench. A yellow precipitate formed and was collected by vacuum filtration and dried with suction to afford 0.35 g of yellow microfilaments; 70% yield; m.p. 183.5-184 C.; 1H-NMR (400 MHz; DMSO) delta 8.36 (dd, 1H, J=7.3, 1.7 Hz), 8.06 (s, 2H), 3.78 (s, 3H); 19F-NMR (376 MHz; DMSO) delta -128.85 to -128.92 (m), -153.29 (d); MS (APCl-) 231 (M-1, 100); IR (KBr) 3433, 3322, 1700, 1650, 1549, 1343, 1285 cm-1; Anal. calcd/found for: C8H6F2N2O4 C, 41.39/41.40; H, 2.61/2.50; N, 12.07/11.98; F, 16.37/16.58.
  • 4
  • [ 67-56-1 ]
  • [ 284030-57-5 ]
  • [ 284030-58-6 ]
YieldReaction ConditionsOperation in experiment
92% With chloro-trimethyl-silane; for 15.0833h;Heating / reflux; Step C; 4-Amino-2,3-difluoro-5-nitrobenzoic acid methyl ester; TMSCl (132 g, 1.21 mol, 2.0 equiv) was added over 5 minutes to a slurry of 4-amino-2,3- difluoro-5-nitrobenzoic acid (132.3 g, 0.607 mol, 1 equiv.) in 325 mL of MeOH. The mixture was heated at reflux for 15 hours. When the reaction was complete as determined by HPLC, the mixture was cooled in an ice-water bath for 45 minutes. The reaction mixture was then filtered and the cake was washed with 65 mL of MeOH. The wet cake was dried overnight at 55 0C under high vacuum to give 128.8 g (92%) of 4-amino-2,3-difluoro-5- nitrobenzoic acid methyl ester. HPLC was 97.9 a% (220 n?i) and 99.2 a % (254 nm). 1H NMR (400 MHz, DMSO-d6) delta 3.84 (3H, s, OMe), 8.1 (2H, br s, NH2), 8.43 (IH, apparent dd, J 1.9, 7.2, Ar-H). 19F NMR (376 MHz, D6 DMSO) delta -153.6, -129.2. 13C NMR (100 MHz, DMSO-d6) delta 52 (CH3O), 105 (C, d, J 10), 125 (CH, t, J 2.7,), 128 (CH, d, J 5), 140 (C-F, dd, J 244, 15,), 141 (C, dd, J 14, 5), 152 (C-F, dd, J263, 11), 162 (COO, t, J3). IR vmjcm l 3433, 3322, 1699, 1637, 1548, 1342, 1234. MS APCI (-) m/z 231 (M-I) detected.
92% With chloro-trimethyl-silane; for 15h;Heating / reflux; TMSCl (132 g,1.21 mol, 2.0 equiv) was added over 5 minutes to a slurry of 4-amino-2,3-difluoro-5- nitrobenzoic acid (3) (132.3 g, 0.607 mol, 1 equiv) in 325 mL of MeOH. The mixture was heated at reflux for 15 hours. Once the reaction was complete by HPLC, the reaction mixture was cooled in an ice- water bath for 45 minutes. Then the reaction mixture was filtered and the cake was washed with 65 mL of MeOH. The wet cake was dried overnight at 55 C under high vacuum to provide 128.8 g (92%) of <strong>[284030-57-5]4-amino-2,3-difluoro-5-nitrobenzoic acid</strong> methyl ester (4). HPLC was 97.9 a% (220 nm) and 99.2 a % (254 nm). 1H NMR (400 MHz, d6 DMSO) delta 3.84 (3H, s, OMe)5 8.1 (2H, br s, NH2), 8.43 (IH, apparent dd, J 1.9, 7.2, Ar-H). 19F NMR (376 MHz, d6 DMSO) delta -153.6, -129.2. 13C NMR (100 MHz, d6 DMSO) delta 52 (CH3O), 105 (C, d, J 10), 125 (CH, t, J2.7,), 128 (CH5 d, J 5), 140 (C-F5 dd, J244, 15,), 141 EPO <DP n="66"/>(C, dd, J 14, 5), 152 (C-F, dd, J263, 11), 162 (COO, t, J 3). IR vmax/cm'' 3433, 3322, 1699, 1637, 1548, 1342, 1234. MS APCI (-) m/z 23.1 (M-I) detected.; TMSCl (132 g,1.21 mol, 2.0 equiv) was added over 5 minutes to a slurry of 4-amino-2,3-difluoro-5- nitrobenzoic acid (3) (132.3 g, 0.607 mol, 1 equiv) in 325 mL of MeOH. The mixture was EPO <DP n="78"/>heated at reflux for 15 hours. Once the reaction was complete by HPLC, the reaction mixture was cooled in an ice-water bath for 45 minutes. Then the reaction mixture was filtered and the cake was washed with 65 mL of MeOH. The wet cake was dried overnight at 55 C under high vacuum to provide 128.8 g (92%) of <strong>[284030-57-5]4-amino-2,3-difluoro-5-nitrobenzoic acid</strong> methyl ester (4). HPLC was 97.9 a% (220 nm) and 99.2 a % (254 nm). 1H NMR (400 MHz, d6 DMSO) delta 3.84 (3H, s, OMe), 8.1 (2H, br s, NH2), 8.43 (IH, apparent dd, J 1.9, 7.2, Ar-H). 19F NMR (376 MHz, d6 DMSO) delta -153.6, -129.2. 13C NMR (100 MHz, d6 DMSO) delta 52 (CH3O), 105 (C, d, J 10), 125 (CH, t, J2.7,), 128 (CH, d, J5), 140 (C-F, dd, J244, 15,), 141 (C, dd, J 14, 5), 152 (C-F, dd, J263, 11), 162 (COO, t, J 3). IR vmjcra l 3433, 3322, 1699, 1637, 1548, 1342, 1234. MS APCI (-) m/z 231 (M-I) detected.
  • 5
  • [ 197520-71-1 ]
  • [ 284030-58-6 ]
 

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