361-72-8|3,5-Difluoro-2-nitroaniline| Ambeed

CAS No. :	361-72-8
Formula :	C₆H₄F₂N₂O₂
M.W :	174.11
SMILES Code :	NC1=C(C(F)=CC(F)=C1)[N+]([O-])=O
MDL No. :	MFCD07368747
InChI Key :	ZULNIHUDSFLCBT-UHFFFAOYSA-N
Pubchem ID :	223092

Safety of [ 361-72-8 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302
Precautionary Statements:	P280-P305+P351+P338

Computational Chemistry of [ 361-72-8 ] Show Less

Physicochemical Properties

Num. heavy atoms	12
Num. arom. heavy atoms	6
Fraction Csp3	0.0
Num. rotatable bonds	1
Num. H-bond acceptors	4.0
Num. H-bond donors	1.0
Molar Refractivity	39.58
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	71.84 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.03
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	1.82
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.3
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.	1.15
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	-0.14
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.23

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.37
Solubility	0.743 mg/ml ; 0.00427 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	0.196 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	-1.97
Solubility	1.85 mg/ml ; 0.0106 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	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.	-6.07 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	3.0 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)	1.97

Application In Synthesis of [ 361-72-8 ]

* 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 [ 361-72-8 ]

[ 361-72-8 ] Synthesis Path-Downstream 1~54

1
[ 404-01-3 ]
[ 361-72-8 ]

References: [1]Journal of the American Chemical Society,1951,vol. 73,p. 153.
Journal of the American Chemical Society,1959,vol. 81,p. 94,98.
[2]European Journal of Organic Chemistry,2014,vol. 2014,p. 6451 - 6466.

2
[ 315-14-0 ]
[ 361-72-8 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonia; In tetrahydrofuran; methanol;Product distribution / selectivity;	Step 1: 3,5-difluoro-2-nitroaniline Preparation A solution of the 1,3,5-trifluoro-2-nitrobenzene (7.08 g, 39.98 mmol) in tetrahydrofuran (50 mL) was stirred at 0 degrees Centigrade while a solution of 7N ammonia in methanol (23 mL) was added. The reaction turned deep red and was stirred overnight in a sealed tube. The mixture was filtered to remove NH4F and the solvent removed to give a red-orange solid which was purified by silica gel chromatography using 2:1 hexanes/ethyl acetate to give 6.27 g of 3,5-difluoro-2-nitroaniline. (M+H) 175.1, 1.89 min (LC/MS method A) Step 1: 3,5-difluoro-2-nitroaniline Preparation A solution of the 1,3,5-trifluoro-2-nitrobenzene (7.08 g, 39.98 mmol) in tetrahydrofuran (50 mL) was stirred at 0 degrees Centigrade while a solution of 7N ammonia in methanol (23 mL) was added. The reaction mixture was stirred overnight in a sealed tube. The mixture was filtered, and the solvent removed to give a red-orange solid which was purified by silica gel column chromatography using 2:1 hexanes/ethyl acetate to give 6.27 g of 3,5-difluoro-2-nitroaniline. (M+H) 175.1, 1.89 min (LC/MS method A)

References: [1]Journal of Organic Chemistry,1978,vol. 43,p. 1241 - 1243.
[2]Journal of Organic Chemistry USSR (English Translation),1988,vol. 24,p. 2267 - 2272.
Zhurnal Organicheskoi Khimii,1988,vol. 24,p. 2513 - 2518.
[3]Patent: US2009/54431,2009,A1 .Location in patent: Page/Page column 30-32.

3
[ 110-91-8 ]
[ 361-72-8 ]
[ 1035388-12-5 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran; at 50℃;	PREPARATION 1; Synthesis of 5-fluoro-3-morpholin-4-yl-benzene- 1 ,2-diamine <n="105"/>IA. 5-Fluoro-3-morpholin-4-yl-2-nitro-phenylamineA mixture of <strong>[361-72-8]2-nitro-3,5-difluoroaniline</strong> (1 g; 5.75 mmol), morpholine (600 mul; 1.2 equiv) and triethylamine (960 mul; 1.2 equiv) in THF (20 ml) was heated at 50 C overnight then evaporated. The residue was partitioned between EtOAc and brine. The ethyl acetate layer was separated, dried (Na2SO4), filtered and evaporated to give 1.34g of 5-fluoro-3- morpholin-4-yl-2-nitro-phenylamine as an orange solid. 1H NMR (DMSO-d) 6.41 (2H, d), 6.27 (IH, dd), 6.16 (IH, dd), 3.63 (4H, t), 2.89 (4H, t). MS: [M+H]+ 242.

References: [1]Patent: WO2008/75109,2008,A1 .Location in patent: Page/Page column 102-103.

4
[ 64-18-6 ]
[ 361-72-8 ]
[ 123-08-0 ]
[ 934765-58-9 ]

Yield	Reaction Conditions	Operation in experiment
		Step 2: {3-Fluoro-5-[(4-formylphenyl)oxy]-2-nitrophenyl}formamide Preparation A solution of the <strong>[361-72-8]3,5-difluoro-2-nitroaniline</strong> (0.348 g, 2.0 mmol), Cs2CO3 (1.63 g, 5 mmol), and 4-hydroxybenzaldehyde (0.268 g, 2.2 mmol) in dimethylsulfoxide (2 mL) was heated to 80 degrees Centigrade for 1 hour and then cooled. Water was added and the organics extracted using ethyl acetate (250 mL). The combined organics were then washed once in brine and dried (Na2SO4), filtered and concentrated. Chromatography on silica gel (gradient of 20%-60% ethyl acetate/hexanes) eluted the product and the fractions were concentrated. The residue was refluxed in 96% formic acid (4 mL) until the reaction was complete conversion of the aniline was observed by TLC (-1.5 h) and then cooled and poured onto ice-water. The organics were extracted with ethyl acetate (225 mL) and the combined organics washed once in water, once in brine, dried (Na2SO4), filtered and concentrated to give 0.230 g of the {3-fluoro-5-[(4-formylphenyl)oxy]-2-nitrophenyl}formamide as a solid. (M+H) 305.1, 2.15 min (LC/MS method A)

References: [1]Patent: US2009/54431,2009,A1 .Location in patent: Page/Page column 32.

5
[ 361-72-8 ]
[ 123-08-0 ]
[ 934765-55-6 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In dimethyl sulfoxide; at 80℃; for 2h;	Step 2: 4-[(3-amino-5-fluoro-4-nitrophenyl)oxy]benzaldehyde Preparation A solution of <strong>[361-72-8]3,5-difluoro-2-nitroaniline</strong> (0.400 g, 2.30 mmol), Cs2CO3 (1.87 g, 5.74 mmol), and 4-hydroxybenzaldehyde (0.309 g, 2.53 mmol) in dimethylsulfoxide (5 mL) was heated at 80 degrees Centigrade for 2 hours and then cooled. Water was added and the organics extracted using ethyl acetate (2*50 mL). The combined organics were washed once in brine and dried (Na2SO4), filtered and concentrated. Chromatography on silica gel using a gradient of 20%-60% ethyl acetate/hexanes eluted the product to give 0.536 g of 4-[(3-amino-5-fluoro-4-nitrophenyl)oxy]benzaldehyde as a yellow solid. 1H NMR (400 MHz, CDCl3) delta ppm 6.84 (d, J=8.55 Hz, 1H) 6.97 (d, J=8.79 Hz, 2H) 7.30 (d, J=8.55 Hz, 1H) 7.80 (dd, J=8.79 Hz, 2H) 8.85 (br.s, 1H) 9.82 (s, 1H)

References: [1]Patent: US2009/54431,2009,A1 .Location in patent: Page/Page column 30.

6
[ 288-13-1 ]
[ 361-72-8 ]
[ 1052686-56-2 ]

References: [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 5243 - 5263.

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[ 1052686-55-1 ]
[ 361-72-8 ]

References: [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 5243 - 5263.

8
[ 361-72-8 ]
[ 90-05-1 ]
[ 859536-42-8 ]

Yield	Reaction Conditions	Operation in experiment
		528 mg of sodium hydride was added to a tetrahydrofuran (30 ml) solution of 1.64 g of 2-methoxyphenol with cooling with ice, and the reaction liquid was stirred for 30 minutes at the same temperature. Next, 1.91 g of <strong>[361-72-8]3,5-difluoro-2-nitroaniline</strong>, which had been produced according to the method described in , was added to it, and the reaction liquid was stirred for 2 days at room temperature. The reaction liquid was poured into water, extracted with ethyl acetate, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate = 5/1 to 4/1) to obtain the entitled compound as an orange solid.

References: [1]Patent: EP1702919,2006,A1 .Location in patent: Page/Page column 65.

9
[ 1258399-08-4 ]
[ 361-72-8 ]
[ 1258399-43-7 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium phosphate;dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0); In toluene; at 100℃;Inert atmosphere;	Reference Example 36 methyl { (3S)-6-[{ (3S) -7- [ (3, 5-difluoro-2-nitrophenyl) amino] - 2, 3-dihydro-l-benzofuran-3-yl} (trifluoroacetyl) amino] -2, 3- dihydro-1-benzofuran-3-yl }acetate; [0333]To a solution of methyl [ (3S) -6-{ [ (3S) -7-bromo-2, 3- dihydro-l-benzofuran-3-yl] (trifluoroacetyl) amino}-2, 3-dihydro- l-benzofuran-3-yl] acetate (5.00 g, 10.0 mmol) and 3,5- difluoro-2-nitroaniline (2.09 g, 12.0 mmol) and tripotassium phosphate (4.25 g, 20.0 mmol) in toluene (50 mL) were added under an argon atmosphere tris (dibenzylideneacetone) dipalladium (0) (458 mg, 0.500 mmol) and dicyclohexyl [2' , 4' , 6' -tri (propan-2-yl) biphenyl-2- yl]phosphane (477 mg, 1.00 mmol), and the mixture was stirred at 100C overnight. The reaction mixture was cooled to room temperature, filtered through celite, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 60:40) to give the title compound (6.64 g, yield 100%) as a red orange oil. MS m/z 592 (M - H)".

References: [1]Patent: WO2010/143733,2010,A1 .Location in patent: Page/Page column 140.

10
[ 361-72-8 ]
4,6-difluorobenzofurazan [ No CAS ]