314298-13-0|1-Fluoro-5-methoxy-2-methyl-4-nitrobenzene| Ambeed

CAS No. :	314298-13-0
Formula :	C₈H₈FNO₃
M.W :	185.15
SMILES Code :	O=[N+](C1=C(OC)C=C(F)C(C)=C1)[O-]
MDL No. :	MFCD15527524
InChI Key :	JQNHPTUQNTUAJC-UHFFFAOYSA-N
Pubchem ID :	18468141

Safety of [ 314298-13-0 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H317-H319
Precautionary Statements:	P280-P305+P351+P338

Computational Chemistry of [ 314298-13-0 ] Show Less

Physicochemical Properties

Num. heavy atoms	13
Num. arom. heavy atoms	6
Fraction Csp3	0.25
Num. rotatable bonds	2
Num. H-bond acceptors	4.0
Num. H-bond donors	0.0
Molar Refractivity	46.68
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	55.05 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.76
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	2.19
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.47
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.	2.18
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	0.56
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.83

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.58
Solubility	0.49 mg/ml ; 0.00265 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.	-2.98
Solubility	0.194 mg/ml ; 0.00105 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	-2.57
Solubility	0.495 mg/ml ; 0.00267 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.	-5.87 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	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)	1.93

Application In Synthesis of [ 314298-13-0 ]

* 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 [ 314298-13-0 ]

[ 314298-13-0 ] Synthesis Path-Downstream 1~35

1
[ 106579-00-4 ]
[ 314298-13-0 ]

Yield	Reaction Conditions	Operation in experiment
76%	With pyridine; sodium nitrite; In n-heptane; water; ethyl acetate;	Step 1: 1-Fluoro-5-methoxy-2-methyl-4-nitro-benzene: Under nitrogen in a nalgene bottle, a stirring solution of pyridine (17.1 mL, 3.2 M, -70 C.) was treated dropwise with HF-pyridine (51.91 mL). Next, 5-methoxy-2-methyl-4-nitro-phenylamine (10.0 g, 54.9 mmol) was added followed by sodium nitrite (6.4 g, 92.76 mmol). The dry ice/acetone bath was removed and the reaction was allowed to warm to room temperature. The solution was then heated at 60 C. for 2 h (or until nitrogen evolution stops.) After cooling to room temperature, the nalgene bottle was placed in an ice bath and 375 mL of water was slowly added to the solution. The resulting orange precipitate was collected by suction filtration and washed with 250 mL of water. Purification of the solid via silica gel flash chromatography (30% ethyl acetate in heptane) provided 1-fluoro-5-methoxy-2-methyl-4-nitro-benzene (7.69 g, 76%) as a light orange solid: mp 71-74C. Rf 0.56 (30% ethyl acetate in heptane); 1H NMR (CDCl3, 300 MHz) delta 7.82 (d, J=7.5 Hz, 1H), 6.75 (d, J=10.5 Hz, 1H), 3.93 (s, 3H), 2.25 (d, J=2.1 Hz, 3H); ESI-LC/MS m/z calcd for C8H8FNO3: 185.1; Found 186.0 (M+1)+. Anal. calcd for C8H8FNO3: C, 51.90; H, 4.36. Found C, 52.11; H, 4.47.
63%		Intermediate 7 1-Fluoro-5-methoxy-2-methyl-4-nitrobenzene Hydrogen fluoride (70%) in pyridine (47.4 ml, 0.48 mol) in a plastic separatory funnel was added dropwise over 20 min. to pyridine (16 mL) in a plastic bottle at -78 C. (dry ice/acetone bath) under nitrogen. Note: reaction was exothermic. After the addition was complete, the reaction was stirred for 10 min. at -78 C. 5-Methoxy-2-methyl-4-nitroaniline (9.11 g, 0.05 mol) was then added and the reaction mixture was stirred for an additional 10 min. at -78 C. Sodium nitrite (5.8 g, 0.08 mol) was then added and the reaction mixture was stirred an additional 10 min. at -78 C. The reaction mixture was allowed to warm to RT and then heated to 60 C. for 2 h. The reaction mixture was then allowed to cool to RT and an ice/water mixture (300 mL) was added. The resultant precipitates were collected by vacuum filtration, washed with water and dried under vacuum. The solid product was recrystallized from methylcyclohexane to give yellow crystals as the title product (5.8 g, 63%).1H NMR (300 MHz, CHLOROFORM-d) delta ppm 7.82 (d, 1H), 6.75 (d, 1H), 3.93 (s, 3H), 2.25 (d, 3H).

References: [1]Bioorganic and Medicinal Chemistry,2004,vol. 12,p. 5661 - 5675.
[2]Patent: US6420426,2002,B1 .
[3]Patent: US2012/28924,2012,A1 .Location in patent: Page/Page column 25.

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[ 314298-13-0 ]
[ 314298-14-1 ]

Yield	Reaction Conditions	Operation in experiment
99%	Pd-C; In ethanol;	Step 2: 4-Fluoro-2-methoxy-5-methyl-phenylamine: A solution of <strong>[314298-13-0]1-fluoro-5-methoxy-2-methyl-4-nitro-benzene</strong> (5.5 g, 29.3 mmol) and 10% Pd-C (1.56 g) in ethanol (300 mL, 0.1 M) was hydrogenated at 1 atm. After stirring overnight, the solution was flushed through a pad of silica gel using 400 mL of ethanol as the eluant. The filtrate was concentrated under reduced pressure to afford 4-fluoro-2-methoxy-5-methyl-phenylamine (4.5 g, 99%) as a pale purple solid: mp 108-110 C.; Rf 0.35 (30% ethyl acetate in heptane); 1H NMR (DMSO-d6, 300 MHz) delta 6.62 (d, J=11.4 Hz, 1H)', 6.43 (d, J=7.8 Hz, 1H), 3.70 (s, 3H), 2.02 (d, J=1.8 Hz, 3H); ESI-LC/MS m/z calcd for C8H10FNO: 155.1; Found 156.0 (M+1)+. Anal. calcd for C8H10FNO: C, 61.92; H, 6.50. Found: C, 61.64; H, 6.53.

References: [1]Bioorganic and Medicinal Chemistry,2004,vol. 12,p. 5661 - 5675.
[2]Patent: US6420426,2002,B1 .

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[ 314298-13-0 ]
[ 314298-15-2 ]