128562-95-8|4-(Trifluoromethyl)-1H-indole| Ambeed

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Quality Control of [ 128562-95-8 ] Purity: 98% SDS Specification

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Product Details of [ 128562-95-8 ]

CAS No. :	128562-95-8
Formula :	C₉H₆F₃N
M.W :	185.15
SMILES Code :	FC(C1=CC=CC2=C1C=CN2)(F)F
MDL No. :	MFCD09954766
InChI Key :	YTVBZSLUNRYKID-UHFFFAOYSA-N
Pubchem ID :	19803703

Safety of [ 128562-95-8 ]

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

Computational Chemistry of [ 128562-95-8 ] Show Less

Physicochemical Properties

Num. heavy atoms	13
Num. arom. heavy atoms	9
Fraction Csp3	0.11
Num. rotatable bonds	1
Num. H-bond acceptors	3.0
Num. H-bond donors	1.0
Molar Refractivity	43.3
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	15.79 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.68
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	2.93
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	4.34
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.	2.61
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	3.48
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	3.01

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.28
Solubility	0.0971 mg/ml ; 0.000525 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.	-2.92
Solubility	0.221 mg/ml ; 0.00119 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	-4.17
Solubility	0.0125 mg/ml ; 0.0000676 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately 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.	-5.35 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)	1.44

Application In Synthesis of [ 128562-95-8 ]

* 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 [ 128562-95-8 ]

[ 128562-95-8 ] Synthesis Path-Downstream 1~25

1
[ 128562-95-8 ]
[ 98-09-9 ]
[ 1018974-87-2 ]

Yield	Reaction Conditions	Operation in experiment
89%		[0118] Step 3. l-Benzenesulfonyl-4-trifluoromethyl-lH-indole[0119] To a slurry of 60 % sodium hydride (2.4 g, 61 mmol) in dimethylformamide (125 mL) at 00C was added 4-trifluoromethyl-lH-indole (4.5 g, 24 mmol). The reaction was stirred at 00C for thirty minutes and then benzenesulfonyl chloride (3.8 mL, 30 mmol) was added drop wise to the reaction. The reaction was stirred for three hours allowing it to warm to room temperature and then poured onto ice/water and extracted with ethyl acetate. Washed the organic layer with sodium bicarbonate, ammonium chloride, and sodium chloride. Dried the organic layer with magnesium sulfate and concentrated onto silica gel. Purified using automated flash chromatography with a gradient mobile phase consisting of ethyl acetate and hexane resulting in the isolation of l-benzenesulfonyl-4-trifluoromethyl-lH-indole (7.0 g, 89 %).
1.08 g		Step 3d: 1-Benzenesulfonyl-<strong>[128562-95-8]4-trifluoromethyl-1H-indole</strong> 370 mg of NaH at 60% in oil are added to a solution of 0.85 g of <strong>[128562-95-8]4-trifluoromethyl-1H-indole</strong> in 15 ml of tetrahydrofuran, under an inert atmosphere. The reaction mixture is stirred at ambient temperature for one hour and then 0.88 ml of benzenesulfonyl chloride is added dropwise and the stirring is continued for 16 hours. The reaction mixture is then poured into a 10% ammonium chloride solution, extracted with ethyl acetate and dried over magnesium sulfate. After filtration and concentration under reduced pressure, the residue is purified by silica column chromatography, elution being carried out with a mixture of heptane and diisopropyl ether (98/2, then 95/5: v/v), so as to give 1.08 g of 1-benzenesulfonyl-<strong>[128562-95-8]4-trifluoromethyl-1H-indole</strong> in the form of a pale yellow oil which is used as it is in the next step.

References: [1]Patent: WO2008/60998,2008,A1 .Location in patent: Page/Page column 36.
[2]Patent: US2013/274253,2013,A1 .Location in patent: Paragraph 2946-2947.
[3]Journal of Medicinal Chemistry,2015,vol. 58,p. 9480 - 9497.

2
[ 905274-06-8 ]
[ 128562-95-8 ]

Yield	Reaction Conditions	Operation in experiment
100%	With iron; acetic acid;Heating / reflux;	[0116] Step 2. 4-Trifluoromethyl-lH-indole[0117] To a solution of dimethyl-[2-(2-nitro-6-trifluoromethyl-phenyl)-vinyl]-amine (6.3 g, 24 mmol) in acetic acid (150 mL) was added iron powder (4.3 g, 77 mmol). The reaction was heated to reflux overnight under nitrogen. Upon cooling, the reaction mixture was diluted with 2.0 M HCl and the aqueous phase was extracted with ethyl acetate. The organic layer was neutralized with a saturated solution of potassium carbonate and extracted. Washed <n="37"/>organic layer with sodium bicarbonate followed by sodium chloride. Dried with magnesium sulfate and concentrated to give 4-trifluoromethyl-lH-indole (4.5 g, 100%).
959 mg	With iron; acetic acid; for 16h;Reflux;	Step 2d: 4-Trifluoromethyl-1H-indole 850 mg of powdered iron are added to a solution of 1.2 g of dimethyl[(E)-2-(2-nitro-6-trifluoromethylphenyl)vinyl]amine in 30 ml of acetic acid. The reaction mixture is refluxed for 16 hours and then poured into a solution of hydrochloric acid (HCl, 2N), and extracted with ethyl acetate. The organic phases are washed with a 10% sodium carbonate solution and then with a saturated NaCl solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure so as to give 959 mg of 4-trifluoromethyl-1H-indole which is used in the next step.

References: [1]Patent: WO2008/60998,2008,A1 .Location in patent: Page/Page column 35-36.
[2]Bioscience, Biotechnology and Biochemistry,2008,vol. 72,p. 2025 - 2033.
[3]Patent: US2013/274253,2013,A1 .Location in patent: Paragraph 2944-2945.

3
[ 50-00-0 ]
[ 128562-95-8 ]
[ 124-40-3 ]
[ 1143584-17-1 ]

Yield	Reaction Conditions	Operation in experiment
	With acetic acid; In ethanol; water; at 0 - 20℃;	(1150) A solution of aqueous formaldehyde (37%, 0.465 ml, 6.24 mmol) and dimethylamine (40%, 0.79 ml, 6.25 mmol) in 10 ml EtOH was cooled to 0 C. <strong>[128562-95-8]4-trifluoromethylindole</strong> (0.77 g, 4.16 mmol) (compound 128) was dissolved in a HOAc:EtOH mixture (1:1, 10 ml) and added dropwise to the reaction mixture. After stirring at this temperature for 2 hrs, the mixture was allowed to warm to room temperature and stirred overnight. (1151) The mixture was cautiously added to a sat'd solution of NaHCO3. 1N NaOH was added until the pH was between 9-10. The resulting mixture was extracted with CH2Cl2 (3×). The organic extracts were combined and washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give 1.0 g of N,N-dimethyl-1-(4-(trifluoromethyl)-1H-indol-3-yl)methanamine (compound 129). This was used as-is without further purification.

References: [1]Bioscience, Biotechnology and Biochemistry,2008,vol. 72,p. 2025 - 2033.
[2]Patent: US2016/168140,2016,A1 .Location in patent: Paragraph 1150; 1151.

4
[ 128562-95-8 ]
[ 6482-24-2 ]
[ 1313043-30-9 ]

Yield	Reaction Conditions	Operation in experiment
72%		A. 1 -(2-Methoxy-ethyl)-4-trifluoromethyl-1 H-indole A mixture of 4-trifluoromethyl-1 H-indole (105 mg, 0.57 mmol), powder KOH (159 mg, 2.83 mmol) in DMSO (6 mL) is stirred at r.t. for 5 min. 2-Methoxyethyl bromide (80 muIota_, 0.85 mmol) is added. After the reaction mixture is stirred at r.t. overnight, it is partitioned between H2O and Et2O. The two layers are separated, and the aqueous layer is extracted with Et2O (3x). The combined organic extracts are washed with H2O and brine, dried over MgSO , filtered, and concentrated in vacuo. The crude material is purified on silica gel with heptane/EtOAc (100/0 to 70/30) as eluent to yield the product (100 mg, 72%) as a clear colorless liquid.1 H NMR (300 MHz, CDCI3) delta 7.53 (d, J = 8.2 Hz, 1 H), 7.40 (d, J = 7.3 Hz, 1 H), 7.35- 7.20 (m, 2H), 6.69 (s, 1 H), 4.32 (t, J = 5.4 Hz, 2H), 3.71 (t, J = 5.4 Hz, 2H), 3.31 (s, 3H);19F NMR (300 MHz, CDCI3) delta -60.99 (s, 3F);LC Rt: 3.21 min; MS 244 (M+H, 100%).

References: [1]Patent: WO2011/79102,2011,A1 .Location in patent: Page/Page column 188-189.

5
[ 128562-95-8 ]
[ 1313043-31-0 ]

References: [1]Patent: WO2011/79102,2011,A1 .

6
[ 128562-95-8 ]
[ 1313043-32-1 ]

References: [1]Patent: WO2011/79102,2011,A1 .

7
[ 128562-95-8 ]
[ 1313043-33-2 ]

References: [1]Patent: WO2011/79102,2011,A1 .

8
[ 128562-95-8 ]
[ 1313040-69-5 ]

References: [1]Patent: WO2011/79102,2011,A1 .

9
[ 6656-49-1 ]
[ 128562-95-8 ]

References: [1]Patent: US2013/274253,2013,A1 .
[2]Patent: US2016/9706,2016,A1 .
[3]Patent: US2016/168140,2016,A1 .

10
[ 128562-95-8 ]
[ 1018974-88-3 ]