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Chemical Structure| 35480-52-5 Chemical Structure| 35480-52-5

Structure of Flecainide Impurity D
CAS No.: 35480-52-5

Chemical Structure| 35480-52-5

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Product Details of [ 35480-52-5 ]

CAS No. :35480-52-5
Formula : C11H8F6O4
M.W : 318.17
SMILES Code : OC(=O)C1=C(OCC(F)(F)F)C=CC(OCC(F)(F)F)=C1
MDL No. :MFCD00221424
InChI Key :YPGYLCZBZKRYQJ-UHFFFAOYSA-N
Pubchem ID :2736078

Safety of [ 35480-52-5 ]

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

Computational Chemistry of [ 35480-52-5 ] Show Less

Physicochemical Properties

Num. heavy atoms 21
Num. arom. heavy atoms 6
Fraction Csp3 0.36
Num. rotatable bonds 7
Num. H-bond acceptors 10.0
Num. H-bond donors 1.0
Molar Refractivity 56.38
TPSA ?

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

55.76 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.0
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

3.5
Log Po/w (WLOGP)?

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

5.79
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.

2.47
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

3.27
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

3.4

Water Solubility

Log S (ESOL):?

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

-3.77
Solubility 0.0544 mg/ml ; 0.000171 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.

-4.35
Solubility 0.0141 mg/ml ; 0.0000442 mol/l
Class?

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

Moderately 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

-3.81
Solubility 0.0487 mg/ml ; 0.000153 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

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

Yes
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.

-5.76 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.

0.56

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<0.0
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)

2.0

Application In Synthesis of [ 35480-52-5 ]

* 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.

  • Upstream synthesis route of [ 35480-52-5 ]

[ 35480-52-5 ] Synthesis Path-Upstream   1~6

  • 1
  • [ 75-89-8 ]
  • [ 35480-52-5 ]
YieldReaction ConditionsOperation in experiment
75.3%
Stage #1: With sodium t-butanolate In DMF (N,N-dimethyl-formamide) at 0 - 25℃; for 1 h;
Stage #2: at 100℃; for 10 h;
To a solution of 2,2,2-trifluoroethanol (14.7 g) and DMF (125 ml) was added sodium tert-butoxide (12.8 g) at 0° C.
The solution was stirred at 20 to 25° C. for 1 hour at which point 5-bromo-2-(2,2,2-trifluoroethoxy)benzoic acid (20 g) was added followed by cupric bromide (2.0 g).
The mixture was stirred at 100° C. for 10 hours, cooled to 10° C., and water (30 ml) was added followed by 20percent HCl solution (90 ml).
The solution was extracted with dichloromethane (3*80 ml), and the combined organic layers were washed with water (3*60 ml).
The solution was concentrated to one-third of the original volume and hexane (200 ml) was added.
The resulting suspension was stirred at room temperature for 2 hours, filtered and the damp cake was rinsed with hexane (2*40 ml).
The damp cake was dried in vacuo at 40° C. for 5 hours to give the product as a white solid (16.02 g, yield 75.3percent).
References: [1] Patent: US2005/59825, 2005, A1, . Location in patent: Page/Page column 4.
  • 2
  • [ 75-89-8 ]
  • [ 21739-92-4 ]
  • [ 35480-52-5 ]
YieldReaction ConditionsOperation in experiment
45% With potassium <i>tert</i>-butylate In tetrahydrofuran; water EXAMPLE 1
300 ml of THF are initially introduced at room temperature, and 84.7 g of potassium tert-butoxide are added with stirring 76.0 g of 2,2,2-trifluoroethanol are added dropwise to this reaction mixture, with the temperature being kept below 35° C.
When the addition is complete, stirring is continued, and 29.6 g of 5-bromo-2-chlorobenzoic acid are subsequently introduced.
After the subsequent addition of 27.3 g of copper(I) bromide, the reaction mixture is heated to reflux.
After 43 hours, the reaction mixture is cooled to 5° C. and allowed to run into dilute hydrochloric acid at 5° C.
The organic phase is separated from the aqueous phase,.
and the solvent is distilled off, during which the product precipitates.
100 ml of water are added to the residue and then filtered.
For purification, the crude product is taken up in MTB ether (methyl tert-butyl ether).
Undissolved components are separated off by filtration through neutral aluminium oxide, and the solvent is subsequently removed.
Recrystallisation from an ethanol/water mixture gives 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid in a yield of 45percent.
Melting point: 120-122° C., purity>98percent (HPLC).
References: [1] Patent: US2003/176721, 2003, A1, .
  • 3
  • [ 1023951-32-7 ]
  • [ 35480-52-5 ]
YieldReaction ConditionsOperation in experiment
81.6%
Stage #1: With pyridine; sodium hydroxide In water at 18 - 81℃; for 1 h;
Stage #2: With sodium permanganate In water at 81 - 93℃; for 7.75 h;
Stage #3: With hydrogenchloride In water
Example 2
Preparation of 2,5-bis(2,2,2-trifluorethoxy)benzoic acid (III)
The 2,5-bis(2,2,2-trifluoroethoxy)toluene (II) (220 g, 0.986 mol) was added to magnetically stirred pyridine (1550 mL) at 18-23°C.
The reaction mixture was stirred under a reflux.
Thereafter a 10 percent aqueous NaOH solution (20 mL, 0.050 mol) and copper (II) sulphate (0.27 g, 0.0017 mol) were added to the reaction mixture.
The reaction mixture was heated at 81 °C for 1 hour at which point a 40percent aqueous sodium permanganate solution (2290 g, 6.45 mol) was added in portions within a time period of 6.5 hours.
After the addition of an aqueous sodium permanganate solution the reaction mixture was stirred at 83 to 93°C for 75 minutes.
A precipitate of manganese oxides was separated by filtration at 80-95°C, the manganese oxides was rinsed on the filter with 5 liters of hot (80°C) water.
The combined filtrates were cooled to 9°C in 50 minutes.
The crystallization suspension was filtered to obtain damp cake of unreacted 2,5-bis(2,2,2-trifluoroethoxy)toluene (II), which was removed thereafter.
The filtrate of reaction mixture was mixed with activated charcoal (20.0 g) and stirred for 75 minutes; the precipitate of charcoal was separated by filtration and liquid phase was acidified to pH=1-2 using concentrated HCl.
The crystallization solution was filtrated and the product cake on the filter was rinsed with 200 mL of water.
The intermediate 2,5-bis(2,2,2-trifluorethoxy)benzoic acid (III) was dried at reduced pressure for 18 hours.
The 2,5-bis(2,2,2-trifluorethoxy)benzoic acid was obtained as an off-white powder (210.2 g, 81.6percent) having a melting point of 121°C to 125°C.
75.2%
Stage #1: With pyridine; sodium hydroxide; potassium permanganate In water at 85 - 100℃; for 1 h;
Stage #2: With hydrogenchloride In water
Example 3
Pyridine (310 mL), water (175 mL) and 2,5-bis(2,2,2-trifluoroethoxy)toluene (44.4 g, 0.154 mol) were mixed in a 1 liter round bottom flask, the pH was adjusted to 11-12 with sodium hydroxide.
The mixture was heated to 85°C and treated with potassium permanganate in 6 portions of 34 grams each, for a total of 204 g (1.29 mol).
The permanganate addition rate was such as to maintain the temperature at 90-100°C.
The reaction mixture was maintained at 85-95°C for an additional hour and filtered while hot.
The manganese oxide precipitate was washed with water and the washings were combined with the pyridine-water filtrate, then cooled to 5-10°C and filtered to remove the unreacted starting material.
The product was isolated by acidifying the filtrate with concentrated hydrochloric acid to pH=1-2 and removing the white precipitate by filtration.
After washing on the filter with water and drying under reduced pressure 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid was obtained as white powder in 37.2 g (0.116 mol, 75.2percent) yield having a melting point of 121°C to 125°C.
References: [1] Patent: EP1918280, 2008, A1, . Location in patent: Page/Page column 7.
[2] Patent: EP1918280, 2008, A1, . Location in patent: Page/Page column 4; 7.
  • 4
  • [ 35480-31-0 ]
  • [ 35480-52-5 ]
References: [1] British Journal of Pharmacology, 2016, p. 2446 - 2459.
  • 5
  • [ 106-37-6 ]
  • [ 35480-52-5 ]
References: [1] Research on Chemical Intermediates, 2016, vol. 42, # 3, p. 2525 - 2537.
  • 6
  • [ 2150-46-1 ]
  • [ 35480-52-5 ]
References: [1] British Journal of Pharmacology, 2016, p. 2446 - 2459.
 

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