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Chemical Structure| 455-18-5 Chemical Structure| 455-18-5

Structure of 455-18-5

Chemical Structure| 455-18-5

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Product Details of [ 455-18-5 ]

CAS No. :455-18-5
Formula : C8H4F3N
M.W : 171.12
SMILES Code : N#CC1=CC=C(C(F)(F)F)C=C1
MDL No. :MFCD00001826
InChI Key :DRNJIKRLQJRKMM-UHFFFAOYSA-N
Pubchem ID :67995

Safety of [ 455-18-5 ]

GHS Pictogram:
Signal Word:Danger
Hazard Statements:H301+H311+H331-H315-H319
Precautionary Statements:P501-P261-P270-P271-P264-P280-P337+P313-P305+P351+P338-P361+P364-P332+P313-P301+P310+P330-P302+P352+P312-P304+P340+P311-P403+P233-P405
Class:6.1
UN#:3439
Packing Group:

Computational Chemistry of [ 455-18-5 ] Show Less

Physicochemical Properties

Num. heavy atoms 12
Num. arom. heavy atoms 6
Fraction Csp3 0.12
Num. rotatable bonds 1
Num. H-bond acceptors 4.0
Num. H-bond donors 0.0
Molar Refractivity 36.16
TPSA ?

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

23.79 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.81
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

2.79
Log Po/w (WLOGP)?

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

3.73
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.

2.52
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

2.8
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.73

Water Solubility

Log S (ESOL):?

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

-2.96
Solubility 0.186 mg/ml ; 0.00109 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.

-2.95
Solubility 0.194 mg/ml ; 0.00113 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

-3.36
Solubility 0.074 mg/ml ; 0.000433 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.

-5.36 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)

1.54

Application In Synthesis of [ 455-18-5 ]

* 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.

  • Downstream synthetic route of [ 455-18-5 ]

[ 455-18-5 ] Synthesis Path-Downstream   1~8

  • 1
  • [ 455-18-5 ]
  • [ 38980-96-0 ]
YieldReaction ConditionsOperation in experiment
72% With ammonium chloride; sodium methylate; In methanol; diethyl ether; 4-(Trifluoromethyl)benzamidine Hydrochloride A solution of 4-(trifluoromethyl)benzonitrile (Avocado 14514, 15 g) in anhydrous methanol (90 ml) was treated with sodium methoxide (0.50 g) and the resulting solution stirred for 4 d at ambient temperature. After this time, ammonium chloride (4.7 g) was added and the mixture stirred for a further day. The mixture was subsequently evaporated and the residual white solid triturated in diethyl ether, filtered and dried to afford of 4-(trifluoromethyl)benzamidine hydrochloride as a white solid (14.2 g, 72%). Mass spectrum 188 [M]+.
With hydrogenchloride; NaNH2; In ethanol; ethyl acetate; toluene; EXAMPLE 1 Preparation of p-(Trifluoromethyl)benzamidine Hydrochloride STR13 A stirred solution of p-(trifluoromethyl)-benzonitrile (100 g, 0.585 mol)in toluene is treated with NaNH2 (38 g, 0.878 mol. 90% pure) and dibenzo-18-crown-6 (1.5 g), heated at reflux temperatures for 4 hours, cooled to 10 C. and treated slowly with 175 ml of concentrated HCl over a 30 minute period. The resultant reaction mixture is filtered and the filtercake is washed with toluene and dried to give a powdery yellowish solid. The solid is dissolved in ethanol and filtered. The filtrate is concentrated in vacuo to give a yellow solid residue. The residue is slurried in ethyl acetate and filtered. The filtercake is washed with ether and dried to give the title product as a yellow solid, 132.3 g (quantitative yield), identified by 1 H-NMR, 13 C-NMR and 19 FNMR analyses.
4-(trifluoromethyl)benzimidamide hydrochloride To a 3-neck flask equipped with a reflux condenser was added 4-(trifluoromethyl)benzonitrile (80 g, 0.468 mol), NaNH2 (27.4 g, 0.701 mol), 18-Crown-6 (1.2 g) and toluene (350 mL). The solution was heated to reflux for 4 h. The mixture was cooled to 0 C. and concentrated aqueous HCl (140 mL) was added slowly. The precipitated solid was collected by filtration and washed with 1:2 methanol:dichloromethane (1:2, 250 mL) to provide 4-(trifluoromethyl)benzimidamide hydrochloride (53 g) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) delta 9.83 (s, 2H), 9.62 (s, 2H), 8.09 (d, J=8.0 Hz, 2H), 7.90 (d, J=8.0 Hz, 2H).
General procedure: A 100 mL flask was charged with 30 mL of anhydrous MeOH, 10 mmol of the arylnitrile, and 1.0 mmol of sodium methoxide. The complex was protected from moisture and stirred for 48 h. Then, 10 mmol of NH4Cl was added and stirring was continued for 24 h. Unreacted NH4Cl was filtered, and methanol was stripped from the filtrate to afford the product aryl amidine hydrochlorides, which was dissolved in 2.5 mL 8M sodium hydroxide aqueous solution and stirred for 1 h. Then chloroform (20 ml x 3) and H2O (20 ml x 3) were added successively to extract the product, and the combined organic layer was dried with anhydrous MgSO4 and then evaporated under vacuum to remove the organic solvent to give the desired arylamidine.

  • 2
  • [ 455-18-5 ]
  • [ 75-16-1 ]
  • [ 306761-54-6 ]
YieldReaction ConditionsOperation in experiment
1.81 g Reference Example 27-3 2-[4-(Trifluoromethyl)phenyl]propane-2-amine To a solution of 4-(trifluoromethyl)benzonitrile (3.01 g) in diethyl ether (88.0 mL), methylmagnesium bromide (about 3.0 mol/L, solution in diethyl ether, 17.6mL) was added and the mixture was stirred at room temperature for 40 minutes. To the reaction mixture, tetraisopropyl orthotitanate (5.15 mL) was added slowly and thereafter the mixture was refluxed for 6 hours. After cooling the mixture to 0C, an aqueous solution of 20% sodium hydroxide was added and the mixture was stirred at room temperature for an hour. After phase separation, the aqueous layer was extracted with diethyl ether twice. The combined organic layers were passed through a phase separator and thereafter concentrated under reduced pressure. The resulting residue was dissolved in 5% hydrochloric acid and washed with diethyl ether twice. The aqueous layer was rendered basic with an aqueous solution of 20% sodium hydroxide and extracted with diethyl ether three times. The combined organic layers were washed with saturated brine and thereafter passed through a phase separator to be concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 95:5-10:90) to give the titled compound as a yellow oil (1.81 g). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.51 (s, 6 H) 7.54 - 7.69 (m, 4 H). MS ESI/APCI Dual posi: 204[M+H]+.
  • 3
  • [ 455-18-5 ]
  • [ 75-16-1 ]
  • [ 15996-84-6 ]
  • 4
  • [ 455-18-5 ]
  • [ 157869-15-3 ]
  • [ 1208259-10-2 ]
  • 5
  • [ 455-18-5 ]
  • 2-((4-ethoxyphenyl)ethynyl)-5-methylaniline [ No CAS ]
  • [ 157869-15-3 ]
  • (Z)-4-(1-(4-ethoxyphenyl)-2-(4-methoxyphenyl)-2-(2-(4-(trifluoromethyl)phenyl)quinazolin-4-yl)vinyl)-7-methyl-2-(4-(trifluoromethyl)phenyl)quinazoline [ No CAS ]
  • 6
  • [ 455-18-5 ]
  • [ 157869-15-3 ]
  • (Z)-1,2-bis(4-methoxyphenyl)-1,2-bis(2-(4-(trifluoromethyl)phenyl)quinazolin-4-yl)ethene [ No CAS ]
  • 7
  • [ 455-18-5 ]
  • [ 917-54-4 ]
  • [ 306761-54-6 ]
YieldReaction ConditionsOperation in experiment
Step A: Anhydrous CeCl3 (0.84 g, 3.4 mmol) was stirred in dry THF (10 mL), at room temperature, under a N2 atmosphere for 2 h. Then, the solution was cooled at -78 C, followed by dropwise addition of MeLi (2.2 mL, 3.4 mmol, 1.6 M), and allowed to stir for 30 min at -78 C. Then, a solution of 4-methoxybenzonitrile (0.15 g, 1.1 mmol) in dry THF (5 mL) was added dropwise to the above solution. The crude reaction was stirred at room temperature overnight, quenched by adding 1.5 mL of concentrated NH4OH, and allowed to stir for 1 h at room temperature. The organic layer was filtered, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was used for next reaction without further purification.
  • 8
  • [ 57772-50-6 ]
  • [ 455-18-5 ]
  • 8-methyl-2-(4-(trifluoromethyl)phenyl)quinazoline [ No CAS ]
YieldReaction ConditionsOperation in experiment
38% With C39H32Cl2N5PRu; potassium tert-butylate; In tert-Amyl alcohol; at 130℃; for 2h;Sealed tube; General procedure: To an oven-dried 15 mL sealed tube were added 2-aminophenylmethanol 1 (0.425 mmol), benzonitrile 2(0.25 mmol), Ru cat. b (1.94 mg, 1 mol%), and KOtBu (14.02 mg, 0.5equiv) intamyl alcohol (1 mL) under an air atmosphere. The sealedtube was capped and heated at 130C for 2 h. The reaction mixturewas cooled down to room temperature and directly concentratedunder vacuum. The crude mixture was puried by preparative thin-layer-chromatography (petroleum ether/ethyl acetate 20/1) togive the desired product 3 or 4.
 

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