103877-80-1|2,5-Difluoro-4-methylbenzoic acid| Ambeed

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Quality Control of [ 103877-80-1 ] Purity: 97% SDS Specification

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Product Details of [ 103877-80-1 ]

CAS No. :	103877-80-1
Formula :	C₈H₆F₂O₂
M.W :	172.13
SMILES Code :	O=C(O)C1=CC(F)=C(C)C=C1F
MDL No. :	MFCD08063230
InChI Key :	PWWMQUUDAAWEBK-UHFFFAOYSA-N
Pubchem ID :	13657451

Safety of [ 103877-80-1 ]

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

Computational Chemistry of [ 103877-80-1 ] Show Less

Physicochemical Properties

Num. heavy atoms	12
Num. arom. heavy atoms	6
Fraction Csp3	0.12
Num. rotatable bonds	1
Num. H-bond acceptors	4.0
Num. H-bond donors	1.0
Molar Refractivity	38.28
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	37.3 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.47
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.	2.81
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.	2.79
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	2.52
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.32

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.48
Solubility	0.573 mg/ml ; 0.00333 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.	-2.42
Solubility	0.654 mg/ml ; 0.0038 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	-2.71
Solubility	0.334 mg/ml ; 0.00194 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.	-5.92 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.	0.56

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)	1.33

Application In Synthesis of [ 103877-80-1 ]

* 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 [ 103877-80-1 ]

[ 103877-80-1 ] Synthesis Path-Downstream 1~35

1
[ 103877-80-1 ]
[ 103877-56-1 ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride;	Preparation of 2,5-difluoro-4-methyl-benzoyl chloride 250 ml of thionyl chloride are taken and 120 g of <strong>[103877-80-1]2,5-difluoro-4-methyl-benzoic acid</strong> are introduced in portions at room temperature, with brisk evolution of gas. When the evolution of gas has subsided, the mixture is heated slowly to the reflux temperature and stirred until the evolution of gas has ended. The excess thionyl chloride is distilled off, the reaction product is coarsely distilled over and the distillate is fractionated on a small column. Yield: 97 g (72.9% of theory) of 2,5-difluoro-4-methylbenzoyl chloride of boiling point b.p.: 103/20 mbar, nD20: 1.5232.

References: [1]Patent: US4762844,1988,A .

2
[ 103877-80-1 ]
[ 3144-09-0 ]
[ 1355070-69-7 ]

Yield	Reaction Conditions	Operation in experiment
87%	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; for 18h;Inert atmosphere; Reflux;	Preparation 32,5-Difluoro-4-methyl-N-(methylsulfonyl)benzamideA mixture of <strong>[103877-80-1]2-5-difluoro-4-methylbenzoic acid</strong> (6.0 g, 34.9 mmol), diisopropylethylamine (13.5 g, 105.0 mmol), propanephosphonic acid cyclic anhydride (50 mL, 50% w/w solution in ethyl acetate, 84.0 mmol) and methyl sulphonamide (6.6 g, 69.7 mmol) in tetrahydrofuran (200 mL) was heated under reflux with stirring under N2 for 18 hours. After cooling, the solution was evaporated in vacuo and the residue suspended in water. The mixture was extracted with ethyl acetate (300 mL) and the organic extract then washed with brine (2 x 80 mL). The organic solution was then dried over sodium sulphate and evaporated in vacuo to give a solid. Trituration with hexane gave the title compound (7.6 g, 87%) as an off white solid after drying.1H NMR (400 MHz, d6-DMSO): delta 2.26 (s, 3H), 3.34 (s, 3H), 7.33 (m, 1 H), 7.44 (m, 1 H). LCMS Rt = 1 .24 minutes MS m/z 248 [M-H]-
87%	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; ethyl acetate; for 18h;Reflux; Inert atmosphere;	Preparation 92,5-Difluoro- -methyl-N-(methylsulfonyl)benzamideA mixture of <strong>[103877-80-1]2-5-difluoro-4-methylbenzoic acid</strong> (6.0 g, 34.9 mmol), diisopropylethylamine (1 3.5 g, 1 05.0 mmol), propanephosphonic acid cyclic anhydride (50 mL, 50% w/w solution in ethyl acetate, 84.0 mmol) and methyl sulphonamide (6.6 g, 69.7 mmol) in THF (200 ml_) was heated under reflux with stirring under N2 for 18 hours. After cooling, the solution was evaporated in vacuo and the residue suspended in water. The mixture was extracted with ethyl acetate (300 ml_) and the organic extract then washed with brine (2 x 80 ml_). The organic solution was then dried over sodium sulphate and evaporated in vacuo to give a solid. Trituration with hexane gave the title compound (7.6 g, 87%) as an off white solid after drying.1H NMR (400 MHz, DMSO-d6): delta 2.26 (s, 3H), 3.34 (s, 3H), 7.33 (m, 1 H), 7.44 (m, 1 H). LCMS Rt = 1 .24 minutes. MS m/z 248 [M-H]-

References: [1]Patent: WO2012/7868,2012,A2 .Location in patent: Page/Page column 72.
[2]Patent: WO2012/7869,2012,A2 .Location in patent: Page/Page column 68-69.

3
[ 103877-80-1 ]
[ 1355070-71-1 ]

References: [1]Patent: WO2012/7869,2012,A2 .
[2]Patent: WO2012/7868,2012,A2 .

4
[ 103877-80-1 ]
[ 64-17-5 ]
[ 1355488-96-8 ]

Yield	Reaction Conditions	Operation in experiment
95%	With sulfuric acid; for 18h;Reflux;	Preparation 18Ethyl 2 ,5-difl uoro-4-meth yl benzoateTo a solution of <strong>[103877-80-1]2,5-difluoro-4-methylbenzoic acid</strong> (5 g, 2.904 mmol) in ethanol (100 ml_) was added concentrated sulfuric acid (1 ml_). The reaction mixture was stirred at reflux for 18 hours. LCMS showed complete consumption of starting material, so the solvents were removed in vacuo and the resulting residue redissolved in EtOAc (50 ml_), and washed with saturated aqueous sodium bicarbonate. The organic layer was separated, and the aqueous layer extracted with EtOAc (2 x 50 ml_). The combined organics were dried over sodium sulfate and evaporated to yield the title compound as a pale yellow oil (5.502 g, 95%).1H NMR (CDCIs, 400 MHz): delta 1 .38 (t, 3H), 2.30 (d, 3H), 4.37 (q, 2H), 6.95 (dd, 1 H), 7.55 (dd, 1 H).LCMS Rt = 3.06 minutes. MS m/z molecular ion not observed.
	With thionyl chloride; at 70℃; for 18h;	To a solution of <strong>[103877-80-1]2,5-difluoro-4-methylbenzoic acid</strong> (595 mg, 3.89 mmol) in ethanol (30 ml_) was added a catalytic amount of thionyl chloride (2 drops). The reaction was stirred for 18 hours at 70 C, and cooled to room temperature. The solvent was removed in vacuo to afford the title compound as a clear oil (500 mg, 86%). No further purification undertaken. 1H NMR (400 MHz, CDCI3): delta 1 .30 (t, 3H), 2.30 (s, 3H), 4.40 (q, 2H), 6.90 (m, 1 H), 7.60 (m, 1 H). LCMS Rt = 3.53 minutes MS no mass ion observed.

References: [1]Patent: WO2012/7869,2012,A2 .Location in patent: Page/Page column 74.
[2]Patent: WO2013/88315,2013,A1 .Location in patent: Page/Page column 71.

5
[ 103877-80-1 ]
[ 1355488-98-0 ]

References: [1]Patent: WO2012/7869,2012,A2 .
[2]Patent: WO2013/88315,2013,A1 .

6
[ 103877-80-1 ]
[ 1355489-16-5 ]

References: [1]Patent: WO2012/7869,2012,A2 .

7
[ 103877-80-1 ]
[ 1355489-18-7 ]

References: [1]Patent: WO2012/7869,2012,A2 .

8
[ 103877-80-1 ]
[ 1355487-52-3 ]

References: [1]Patent: WO2012/7869,2012,A2 .

9
[ 103877-80-1 ]
[ 1355488-72-0 ]

References: [1]Patent: WO2015/103317,2015,A1 .
[2]Patent: WO2012/7868,2012,A2 .

10
[ 103877-80-1 ]
[ 1355631-28-5 ]

References: [1]Patent: WO2012/7868,2012,A2 .

11
[ 103877-80-1 ]
[ 1355636-86-0 ]

References: [1]Patent: WO2012/7868,2012,A2 .

12
[ 103877-80-1 ]
[ 1355636-87-1 ]

References: [1]Patent: WO2012/7868,2012,A2 .

13
[ 67-56-1 ]
[ 103877-80-1 ]
[ 1355488-71-9 ]

Yield	Reaction Conditions	Operation in experiment
98%	With sulfuric acid; for 18h;Inert atmosphere; Reflux;	Preparation 26Methyl 2,5-difluoro-4-methylbenzoateTo a suspension of 4-methyl-2,5-difluorobenzoic acid (comm, 52 g, 0.3 mol) in methanol (1 .0 L) was added concentrated sulphuric acid (3 mL) with stirring and the reaction heated to reflux under nitrogen for 18 hours. The reaction was quenched with aqueous sodium bicarbonate solution (10 %, 150 mL), concentrated in vacuo and the resulting residue partitioned between EtOAc (800 mL) and water (400 mL). The organic layer was washed with water (250 mL) and brine (100 mL), dried with sodium sulphate and concentrated in vacuo to yield the title compound as a clear oil that solidified on standing (54.7 g, 98%).1H NMR (400 MHz, CDCI3): delta 2.33 (s, 3H), 3.92 (s, 3H), 6.98 (m, 1 H), 7.58 (m, 1 H).
83%	With thionyl chloride; at 20℃; for 3h;	To a solution of <strong>[103877-80-1]2,5-difluoro-4-methyl-benzoic acid</strong> (5 g, 29.0 mmol, 1.0 eq) in MeOH (200 mL) was added SOCb (17.2 g, 145 mmol, 5 eq). The mixture was stirred at rt for 3 h and the excess reagent was removed in vacuo. The mixture was extracted with EA and purified by flash chromatography on silica gel column (PE/EA = 10/1, v/v) to give 2,5-difluoro-4- 5 g, 83% yield) as colorless oil.

References: [1]Patent: WO2012/7868,2012,A2 .Location in patent: Page/Page column 86.
[2]Patent: WO2015/103317,2015,A1 .Location in patent: Page/Page column 284.

14
[ 103877-80-1 ]
[ 3984-14-3 ]
[ 1443432-56-1 ]