947144-26-5|3-Nitro-6-(trifluoromethyl)pyridine-2,4-diol| Ambeed

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Quality Control of [ 947144-26-5 ] Purity: 95% SDS Specification

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Product Details of [ 947144-26-5 ]

CAS No. :	947144-26-5
Formula :	C₆H₃F₃N₂O₄
M.W :	224.09
SMILES Code :	OC1=NC(C(F)(F)F)=CC(O)=C1[N+]([O-])=O
MDL No. :	MFCD14706616
InChI Key :	RNRDDIRUBACPKU-UHFFFAOYSA-N
Pubchem ID :	54726807

Safety of [ 947144-26-5 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H332-H335
Precautionary Statements:	P280-P305+P351+P338-P310

Computational Chemistry of [ 947144-26-5 ] Show Less

Physicochemical Properties

Num. heavy atoms	15
Num. arom. heavy atoms	6
Fraction Csp3	0.17
Num. rotatable bonds	2
Num. H-bond acceptors	8.0
Num. H-bond donors	2.0
Molar Refractivity	42.11
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	99.17 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.0
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	2.33
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.57
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.	-0.31
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	-0.57
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.0

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.86
Solubility	0.308 mg/ml ; 0.00138 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.	-4.05
Solubility	0.0199 mg/ml ; 0.0000888 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	-1.15
Solubility	15.9 mg/ml ; 0.0708 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.	-6.01 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	2.0 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)	2.11

Application In Synthesis of [ 947144-26-5 ]

* 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 [ 947144-26-5 ]

[ 947144-26-5 ] Synthesis Path-Downstream 1~10

1
[ 947144-26-5 ]
[ 358-23-6 ]
C₈HF₉N₂O₈S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; at 0 - 20℃; for 1.0h;Product distribution / selectivity;	PREPARATION 17; N2,N4-Dibenzyl-3-nitro-6-trifluoromethyl-pyridine-2,4-diamine; <strong>[947144-26-5]3-Nitro-6-trifluoromethyl-pyridine-2,4-diol</strong> (5.0 g, 22.3 mmol) was dissolved in DCM (50 mL) and Et3N (6.22 ml, 44.6 mmol) was added. The mixture was cooled to 0 C. and Tf2O (7.32 ml, 44.6 mmol) was added dropwise. The mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was concentrated in vacuo and the residue was dissolved in THF (50 ml). BnNH2 (7.3 ml, 66.9 mmol) was added and the mixture was stirred at 50 C. for 24 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was treated with water (50 ml) and extracted with EtOAc (150 ml). The extract was washed with brine (50 ml), dried over MgSO4 and concentrated in vacuo to give the crude (27 g).A second batch of <strong>[947144-26-5]3-Nitro-6-trifluoromethyl-pyridine-2,4-diol</strong> (11.06 g, 49.4 mmol) was dissolved in DCM (100 mL) and Et3N (13.8 ml, 98.7 mmol) was added. The mixture was cooled to 0 C. and Tf2O (16.2 ml, 98.7 mmol) was added dropwise. The mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was concentrated in vacuo and the residue was dissolved in THF (100 ml). BnNH2 (16.2 ml, 148 mmol) was added and the mixture was stirred at 50 C. for 24 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was treated with water (100 ml) and extracted with EtOAc (200 ml). The extract was washed with brine (50 ml), dried over MgSO4 and concentrated in vacuo to give the crude (53 g). The two crudes were combined. Column chromatography through silica eluting with 95:5→90:10 Pentane:EtOAc gave the title compound (15.93 g) as a yellow solid.1H NMR (CDCl3) 9.68-9.64 (m, 1H), 9.36-9.32 (m, 1H), 7.43-7.29 (m, 10H), 6.38 (s, 1H), 4.81 (d, 2H), 4.55 (d, 2H); LRMS (APCI and ES) m/z 403 [MH]+.

References: [1]Patent: US2007/197478,2007,A1 .Location in patent: Page/Page column 47.

2
[ 947144-26-5 ]
[ 947144-53-8 ]

Yield	Reaction Conditions	Operation in experiment
		<strong>[947144-26-5]3-Nitro-6-trifluoromethyl-pyridine-2,4-diol</strong> (5.8 gm, 26 mmol) was heated in phenylphosphonic dichloride (3OmL) at 1000C for 19 hours. Cooled and poured on to ice (60 gm), extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with aqueous sodium hydrogen carbonate solution (10%w/v) until the washings remained basic (pH ~8). The deep yellow organic layer was then washed with saturated brine, dried over sodium sulphate, filtered and evaporated to give a yellow gum. Trituration of the gum with dichloromethane gave a yellow solid which was filtered off and dried (4.65gm). The solid was dissolved in water (25mL) and acidified with 2N hydrochloric acid (7.5mL) to give a thick white precipitate which was filtered off and washed with water. The precipitate was dissolved in ethyl acetate, dried over sodium sulphate, filtered and evaporated to give 4-chloro-3-nitro-6-trifluoromethyl- pyridin-2-as a white solid (3.75gm).
		PREPARATION 34; 4-Chloro-3-nitro-6-trifluoromethyl-pyridin-2-ol; <strong>[947144-26-5]3-Nitro-6-trifluoromethyl-pyridine-2,4-diol</strong> (5.8 gm, 26 mmol) was heated in phenylphosphonic dichloride (30 mL) at 100 C. for 19 hours. The resulting mixure was then cooled and poured on to ice (60 gm), and then extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with aqueous sodium hydrogen carbonate solution (10% w/v) until the washings remained basic (pH 8). The deep yellow organic layer was then washed with saturated brine, dried over sodium sulphate, filtered and evaporated to give a yellow gum. Trituration of the gum with dichloromethane gave a yellow solid which was filtered off and dried (4.65 gm). The solid was dissolved in water (25 mL) and acidified with 2N hydrochloric acid (7.5 mL) to give a thick white precipitate which was filtered off and washed with water. The precipitate was dissolved in ethyl acetate, dried over sodium sulphate, filtered and evaporated to give the title compound as a white solid (3.75 gm).1H NMR (DMSOd6) 7.78 (s, 1H). 13C NMR (DMSOd6) 157.2 (s) 145.2 (q) 138.1 (s) 136.98 (s) 120.6 (q) 113.86 (s). LRMS (ES-) m/z 241/243 [MH]-

References: [1]Patent: WO2008/47201,2008,A2 .Location in patent: Page/Page column 32.
[2]Patent: US2007/197478,2007,A1 .Location in patent: Page/Page column 50.

3
[ 947144-32-3 ]
[ 947144-26-5 ]

Yield	Reaction Conditions	Operation in experiment
71%	With sulfuric acid; nitric acid; In water; at 20 - 50℃; for 4.5h;	6-Trifluoromethyl-pyridine-2,4-diol (56 g, 310 mmol) was added in 3- 5 gm portions to concentrated sulphuric acid (140 mL) with stirring to give a pale brown solution. The temperature increased to ~50C during the addition. Nitric acid(21.1 mL 328 mmol, 70% HNO3 d=1.4 gm/ml) was added drop wise at such a rate as to maintain a reaction temperature of between 45 and 5O0C which took approximately 90 minutes. Once all the nitric acid had been added the reaction was allowed to cool to ambient temperature over 3 hours. Poured into ice/water (-1.3 kg) with stirring, after a few minutes a pale yellow precipitate formed which was filtered off, dissolved in ethyl acetate and dried over sodium sulphate, filtered and evaporated. A second crop of material was obtained by extraction of the aqueous filtrate with ethyl acetate. Combined batches and purified by crystallization from ethyl acetate/ n-heptane gave 3- nitro-6-trifluoromethyl-pyridine-2,4-diol as a white 'fluffy' solid (49.5 gm 71% yield).
71%	With sulfuric acid; nitric acid; In water; at 45 - 50℃; for 4.5h;	PREPARATION 35; 3-Nitro-6-trifluoromethyl-pyridine-2,4-diol; 6-Trifluoromethyl-pyridine-2,4-diol (56 gm, 310 mmol) was added in 3-5 gm portions to conc. sulphuric acid (140 mL) with stirring to give a pale brown solution. The temperature increased to 50 C. during the addition. Nitric acid (21.1 mL 328 mmol, 70% HNO3 d=1.4 gm/ml) was added drop wise at such a rate as to maintain a reaction temperature of between 45 and 50 C. which took approximately 90 minutes. Once all the nitric acid had been added the reaction was allowed to cool to ambient temperature over 3 hours. The reaction mixture was then poured into ice/water (1.3 kg) with stirring, and after a few minutes a pale yellow precipitate formed which was filtered off, dissolved in ethyl acetate and dried over sodium sulphate, filtered and evaporated. A second crop of material was obtained by extraction of the aqueous filtrate with ethyl acetate. Combined batches and purified by crystallization from ethyl acetate/ n-heptane gave the title compound as a white ‘fluffy’ solid (49.5 gm 71% yield).1H NMR (DMSOd6) 6.82 (s, 1H). 13C NMR (DMSOd6) 159.82 (s) 157.58 (s) 143.10 (broad s) 127.26 (s) 120.85 (q) 102.83 (s).

References: [1]Patent: WO2008/47201,2008,A2 .Location in patent: Page/Page column 32.
[2]Patent: US2007/197478,2007,A1 .Location in patent: Page/Page column 50.

4
[ 947144-26-5 ]
[ 1211534-13-2 ]