349-58-6|3,5-Bis(trifluoromethyl)phenol| Ambeed

CAS No. :	349-58-6
Formula :	C₈H₄F₆O
M.W :	230.11
SMILES Code :	OC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1
MDL No. :	MFCD00000386
InChI Key :	ODSXJQYJADZFJX-UHFFFAOYSA-N
Pubchem ID :	67680

Safety of [ 349-58-6 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H315-H319
Precautionary Statements:	P264-P280-P302+P352-P337+P313-P305+P351+P338-P362+P364-P332+P313

Computational Chemistry of [ 349-58-6 ] Show Less

Physicochemical Properties

Num. heavy atoms	15
Num. arom. heavy atoms	6
Fraction Csp3	0.25
Num. rotatable bonds	2
Num. H-bond acceptors	7.0
Num. H-bond donors	1.0
Molar Refractivity	38.47
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	20.23 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.7
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	3.9
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	5.73
Log P_o/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.	3.59
Log P_o/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	3.44
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	3.67

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.89
Solubility	0.0298 mg/ml ; 0.00013 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.	-4.02
Solubility	0.0218 mg/ml ; 0.0000948 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	-3.6
Solubility	0.0574 mg/ml ; 0.000249 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	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.	-4.93 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	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<2.0
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)	1.38

Application In Synthesis of [ 349-58-6 ]

* 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 [ 349-58-6 ]

[ 349-58-6 ] Synthesis Path-Downstream 1~54

1
[ 34662-31-2 ]
[ 349-58-6 ]
[ 38710-84-8 ]

References: [1]Journal of Heterocyclic Chemistry,1972,vol. 9,p. 759 - 773.

2
[ 349-58-6 ]
[ 79850-12-7 ]
[ 75091-94-0 ]

References: [1]Journal of Organic Chemistry USSR (English Translation),1980,vol. 16,p. 1031 - 1038.
Zhurnal Organicheskoi Khimii,1980,vol. 16,p. 1194 - 1202.
[2]Journal of Organic Chemistry USSR (English Translation),1980,vol. 16,p. 1031 - 1038.
Zhurnal Organicheskoi Khimii,1980,vol. 16,p. 1194 - 1202.

3
[ 899807-80-8 ]
[ 349-58-6 ]
[ 899807-81-9 ]

Yield	Reaction Conditions	Operation in experiment
83%	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃;	EXAMPLE 15 (Z)-7-[(1R,2S,3R,5R)-2-(3,5-Bis-trifluoromethyl-phenoxymethyl)-5-chloro-3-hydroxy-cyclopentyl]-hept-5-enoic acid (15c, FIG. 6) Step 1: Mitsunobu Reaction of 21 and Hydroxyaryl to Give 22c DIAD (50 muL, 0.26 mmol) was added to a solution of alcohol 21 (88 mg, 0.22 mmol), triphenylphosphine (88 mg, 0.34 mmol) and 3,5-bis(trifluoromethyl)phenol (40 muL, 0.26 mmol) in CH2Cl2 (1.1 mL). After stirring overnight at rt, the solvent was removed under a stream of nitrogen. The residue was diluted with EtOAc (25 mL), washed with saturated aqueous NaHCO3 (3.x.10 mL) and brine (10 mL) then the organic phase was dried (Na2SO4) filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (10percent EtOAc/hexane) afforded 112 mg (83percent) of the desired ether 22c.
83%	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃;	EXAMPLE 15 (Z)-7-[(1R,2S,3R,5R)-2-(3,5-Bis-trifluoromethyl-phenoxymethyl)-5-chloro-3-hydroxy-cyclopentyl]-hept-5-enoic acid (15c, FIG. 6) Step 1: Mitsunobu Reaction of 21 and Hydroxyaryl to Give 22c.; DIAD (50 muL, 0.26 mmol) was added to a solution of alcohol 21 (88 mg, 0.22 mmol), triphenylphosphine (88 mg, 0.34 mmol) and 3,5-bis(trifluoromethyl)phenol (40 muL, 0.26 mmol) in CH2Cl2 (1.1 mL). After stirring overnight at rt, the solvent was removed under a stream of nitrogen. The residue was diluted with EtOAc (25 mL), washed with saturated aqueous NaHCO3 (3.x.10 mL) and brine (10 mL) then the organic phase was dried (Na2SO4) filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (10percent EtOAc/hexane) afforded 112 mg (83percent) of the desired ether 22c.
83%	With di-isopropyl azodicarboxylate; triphenylphosphine; In dichloromethane; at 20℃;	Step 4: Mitsunobu reaction of 26 and hydroxyaryl to give 27.; DIAD (50 mul_, 0.26 mmol) was added to a solution of alcohol 26 (88 mg, 0.22 mmol), thphenylphosphine (88 mg, 0.34 mmol) and 3,5-bis(thfluoromethyl)phenol (40 mul_, 0.26 mmol) in CH2CI2 (1.1 ml_). After stirring overnight at room temperature, the solvent was removed under a stream of nitrogen. The residue was diluted with EtOAc (25 ml_), washed with saturated aqueous NaHCO3 (3x10 ml_) and brine (10 ml_) then the organic phase was dried (Na2SO4) filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (10percent EtOAc/hexane) afforded 112 mg (83percent) of the desired ether 27.

References: [1]Patent: US2008/58414,2008,A1 .Location in patent: Page/Page column 15.
[2]Patent: US2007/265464,2007,A1 .Location in patent: Page/Page column 39.
[3]Patent: WO2009/146255,2009,A1 .Location in patent: Page/Page column 67.

4
[ 29823-18-5 ]
[ 349-58-6 ]
[ 1021459-88-0 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;	Preparation of Compound d1-2 Ethyl 7-bromoheptanoate and 3,5-bis(trifluoromethyl) phenol were added to dimethylformamide (DMF). The solution was added with potassium carbonate and stirred at room temperature. The solution was added with water and extracted twice with ethyl acetate. After the organic layer was washed three times with water and dried over anhydrous magnesium sulfate, the solvent was removed. The residue was purified by silica gel column chromatography to obtain ethyl 7-(3,5-bis (trifluoromethyl)phenoxy)heptanoate.

References: [1]Patent: EP1916255,2008,A2 .Location in patent: Page/Page column 30.

5
[ 349-58-6 ]
[ 75092-07-8 ]

References: [1]Journal of Organic Chemistry USSR (English Translation),1980,vol. 16,p. 1031 - 1038.
Zhurnal Organicheskoi Khimii,1980,vol. 16,p. 1194 - 1202.

6
[ 349-58-6 ]
[ 75092-08-9 ]

References: [1]Journal of Organic Chemistry USSR (English Translation),1980,vol. 16,p. 1031 - 1038.
Zhurnal Organicheskoi Khimii,1980,vol. 16,p. 1194 - 1202.

7
[ 349-58-6 ]
[ 75091-94-0 ]

References: [1]Journal of Organic Chemistry USSR (English Translation),1980,vol. 16,p. 1031 - 1038.
Zhurnal Organicheskoi Khimii,1980,vol. 16,p. 1194 - 1202.

8
[ 685892-24-4 ]
[ 349-58-6 ]

References: [1]Journal of Organic Chemistry,2005,vol. 70,p. 6404 - 6416.

9
[ 130783-02-7 ]
[ 349-58-6 ]