2338-54-7|4-Fluoro-3-methylanisole| Ambeed

CAS No. :	2338-54-7
Formula :	C₈H₉FO
M.W :	140.15
SMILES Code :	COC1=CC=C(F)C(C)=C1
MDL No. :	MFCD00042293
InChI Key :	XZBXPBDJLUJLEU-UHFFFAOYSA-N
Pubchem ID :	137546

Safety of [ 2338-54-7 ]

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

Computational Chemistry of [ 2338-54-7 ] Show Less

Physicochemical Properties

Num. heavy atoms	10
Num. arom. heavy atoms	6
Fraction Csp3	0.25
Num. rotatable bonds	1
Num. H-bond acceptors	2.0
Num. H-bond donors	0.0
Molar Refractivity	37.86
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	9.23 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.24
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	2.01
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.56
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.	2.57
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	2.7
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.42

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.35
Solubility	0.621 mg/ml ; 0.00443 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.	-1.83
Solubility	2.07 mg/ml ; 0.0148 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very 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	-3.16
Solubility	0.0961 mg/ml ; 0.000685 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.	-5.73 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)	1.11

Application In Synthesis of [ 2338-54-7 ]

* 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 [ 2338-54-7 ]

[ 2338-54-7 ] Synthesis Path-Downstream 1~55

1
[ 2338-54-7 ]
[ 367-83-9 ]

Yield	Reaction Conditions	Operation in experiment
30%		To a vigorously stirred mixture [OF 4-FLUORO-3-METHYLANISOLE] (12.0 g, 85.6 mmol) and pyri- dine (41.7 g, 527 mmol) in water (170 mL) at [50C] was added portion-wise potassium per- manganate (44.65 g, mmol) and then maintained at this temperature for 2 h. The resulting mixture was then allowed to cool to RT and allowed to stand overnight and then heated for a further 5 h at [50C.] Then the mixture was filtered over celite and then the residue was washed with sulfuric acid (conc. 100 mL). The combined filtrates were then [HALF-EVAPORA-] ted and neutralised with potasssium carbonate. Then the mixture was washed with diethyl ether and then the aqueous layer was acidified with hydrochloric acid (conc.) and the pro- duct extracted with diethyl ether. The combined extracts were then dried over sodium sul- phate. After filtration and evaporation the crude solid was [RECRYSTALLISED] from 1,2,-di- chloroethane to afford the title compound (4.4 g, 30%) as a light pink solid. MS [M/E =] 168.9 (M-H). Alternatively, a solution of 4-fluoroanisole (500 mg, 4.0 mmol) in THF (10 mL) was added to a cooled [SOLUTION (-78C) OF 2,] 2,6, 6-tetramethylpiperidine (1.1 g, 7.9 mmol) and BuLi (5 mL, 1.6 M in hexanes, 7.9 mmol) in THF (10 mL) at a slow rate to maintain the tempera- ture [BELOW-70C.] The mixture was maintained at this temperature for 12 h, and then dry C02 gas was passed into the solution. The resulting mixture was allowed to warm up to 0C and then HCl (1 M, 10 mL) was added and the product was extracted with diethyl ether. The combined organic extracts were then dried over sodium sulfate, washed with water and brine, filtered and evaporated. The crude solid was then partioned between sodium hydroxide [(1] M, 10 mL) and diethyl ether. The aqueous phase was then acidified with HCl (1 M) and the product extracted with diethyl ether. Evaporation afforded the title compound (268 mg, 40%) as a white solid. MS m/e = 168.9 (M-H).
	With potassium permanganate; In pyridine; water;	6-Fluoro-3-methoxybenzoic acid 4-Fluoro-3-methylanisol (1.0 g, 7.1 mmol) was dissolved in a mixture of pyridine (16 mL) and water (32 mL). Potassium permanganate (3.4 g, 21 mmol) was added and the reaction mixture was refluxed for 3 h and then left at room temperature over night. After filtration and extraction with CH2 Cl2 the aqueous phase was acidified with HCl precipitating the product (440 mg). 1 NMR (CD3 OD): δ7.44-7.47 (m, 1H), 7.18-7.16 (m, 2H), 3.86 (s, 3H); 13 C NMR (CD3 OD): δ167.55, 158.35 (d, J=192 Hz), 156.30, 121.65 (d, J=8.7 Hz), 120.63 (d), 118.94 (d, J=24.4 Hz), 117.03, 56.59.

References: [1]Journal of Medicinal Chemistry,1984,vol. 27,p. 577 - 585.
[2]Patent: WO2004/14856,2004,A1 .Location in patent: Page 21.
[3]Journal of Organic Chemistry,1960,vol. 25,p. 1016 - 1020.
[4]Patent: US5523475,1996,A .

2
[ 2338-54-7 ]
[ 91319-42-5 ]

Yield	Reaction Conditions	Operation in experiment
	With N-Bromosuccinimide; Perbenzoic acid; In tetrachloromethane; for 2h;Reflux;	To a solution of l-fluoro-4-methoxy-2-methylbenzene (2.0 g, 14.29 mmol) in CC , NBS (2.55 g, 14.29 mmol) and PI1CO3H (80 mg) were added. The reaction mixture was heated at reflux for 2 h, cooled to room temperature, and the solid was filtered off. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluting with PE/EA = 20/1) to give the target compound (3.0 g) as an oil. 1H NMR (CDC13): δ 6.97-6.83 (m, 3H), 4.48 (s, 2H), 3.78 (s, 3H).

References: [1]Journal of the American Chemical Society,1987,vol. 109,p. 341 - 348.
[2]Tetrahedron,1997,vol. 53,p. 5785 - 5796.
[3]Patent: WO2011/156518,2011,A2 .Location in patent: Page/Page column 126; 127.

3
[ 102-50-1 ]
[ 2338-54-7 ]

References: [1]Chimica Therapeutica,1967,vol. 2,p. 53 - 56.
[2]Journal of Medicinal Chemistry,1984,vol. 27,p. 577 - 585.
[3]Journal of the American Chemical Society,1987,vol. 109,p. 341 - 348.

4
[ 2338-54-7 ]
[ 452-70-0 ]

References: [1]Chimica Therapeutica,1967,vol. 2,p. 53 - 56.

5
[ 509-14-8 ]
[ 2338-54-7 ]
1-fluoro-4-methoxy-2-methyl-5-nitrobenzene [ No CAS ]
1-Fluoro-4-methoxy-2-methyl-3-nitro-benzene [ No CAS ]
4-fluoro-3-methyl-2,6-dinitrophenol [ No CAS ]
2-Fluoro-5-methoxy-1-methyl-3-trinitromethyl-benzene [ No CAS ]

References: [1]Journal of the Chemical Society. Perkin transactions II,1996,p. 1877 - 1888.

6
[ 509-14-8 ]
[ 2338-54-7 ]
1-fluoro-4-methoxy-2-methyl-5-nitrobenzene [ No CAS ]
4-fluoro-3-methyl-2,6-dinitrophenol [ No CAS ]
1-Fluoro-4-methoxy-2-methyl-5-trinitromethyl-benzene [ No CAS ]
1-fluoro-4-methoxy-6-methyl-c-6-nitro-r-3-trinitromethylcyclohexa-1,4-diene [ No CAS ]

References: [1]Journal of the Chemical Society. Perkin transactions II,1996,p. 1877 - 1888.

7
[ 2338-54-7 ]
[ 182880-62-2 ]
1-fluoro-4-methoxy-2-methyl-5-nitrobenzene [ No CAS ]
1-Fluoro-4-methoxy-2-methyl-3-nitro-benzene [ No CAS ]
1-Fluoro-4-methoxy-2-methyl-5-trinitromethyl-benzene [ No CAS ]

References: [1]Journal of the Chemical Society. Perkin transactions II,1996,p. 1877 - 1888.

8
[ 2338-54-7 ]
1-fluoro-4-methoxy-2-methyl-5-nitrobenzene [ No CAS ]
1-Fluoro-4-methoxy-2-methyl-3-nitro-benzene [ No CAS ]
4-fluoro-3-methyl-2,6-dinitrophenol [ No CAS ]
2-Fluoro-5-methoxy-1-methyl-3-trinitromethyl-benzene [ No CAS ]

References: [1]Journal of the Chemical Society. Perkin transactions II,1996,p. 1877 - 1888.
[2]Journal of the Chemical Society. Perkin transactions II,1996,p. 1877 - 1888.

9
[ 124-38-9 ]
[ 2338-54-7 ]
[ 447463-91-4 ]