13671-00-6|Methyl 2,6-difluorobenzoate| Ambeed

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Quality Control of [ 13671-00-6 ] Purity: 98% SDS Specification

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Product Details of [ 13671-00-6 ]

CAS No. :	13671-00-6
Formula :	C₈H₆F₂O₂
M.W :	172.13
SMILES Code :	O=C(OC)C1=C(F)C=CC=C1F
MDL No. :	MFCD00051778
InChI Key :	QNPFLTKQLFSKBY-UHFFFAOYSA-N
Pubchem ID :	518798

Safety of [ 13671-00-6 ]

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

Computational Chemistry of [ 13671-00-6 ] Show Less

Physicochemical Properties

Num. heavy atoms	12
Num. arom. heavy atoms	6
Fraction Csp3	0.12
Num. rotatable bonds	2
Num. H-bond acceptors	4.0
Num. H-bond donors	0.0
Molar Refractivity	37.64
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	26.3 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.0
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	1.96
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.59
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	2.54
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.37

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.38
Solubility	0.718 mg/ml ; 0.00417 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.	-2.14
Solubility	1.25 mg/ml ; 0.00729 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	-3.03
Solubility	0.162 mg/ml ; 0.00094 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.	-5.96 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	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)	1.27

Application In Synthesis of [ 13671-00-6 ]

* 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 [ 13671-00-6 ]

[ 13671-00-6 ] Synthesis Path-Downstream 1~35

1
[ 67-56-1 ]
[ 18063-02-0 ]
[ 13671-00-6 ]

References: [1]Journal of Medicinal Chemistry,1968,vol. 11,p. 814 - 819.
[2]Journal of Physical Organic Chemistry,2012,vol. 25,p. 267 - 270.

2
[ 35367-38-5 ]
[ 124-41-4 ]
[ 13671-00-6 ]
[ 140-38-5 ]

References: [1]Collection of Czechoslovak Chemical Communications,1989,vol. 54,p. 1363 - 1369.

3
[ 67-56-1 ]
2,6-difluorophenyl trifluoromethanesulphonate [ No CAS ]
CO [ No CAS ]
[ 13671-00-6 ]
Terephthalic acid mono-(4-bromo-phenyl) ester [ No CAS ]

References: [1]Journal of the Chemical Society. Chemical communications,1987,p. 904 - 905.

4
[ 67-56-1 ]
1-(2,6-difluorophenyl)propan-1-one [ No CAS ]
[ 13671-00-6 ]

References: [1]Journal of Organic Chemistry,2002,vol. 67,p. 1703 - 1704.

5
[ 67-56-1 ]
[ 385-00-2 ]
[ 13671-00-6 ]
[ 501433-14-3 ]

References: [1]European Journal of Organic Chemistry,2002,p. 3351 - 3358.

6
[ 533-37-9 ]
[ 13671-00-6 ]
7-fluorobenzo[c]cyclopentano[i,j]quinolizin-6-one [ No CAS ]
7-fluoro-6-hydroxy-4,5-dihydro-10b-azonia-acephenanthrylene; chloride [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 962 - 972.

7
[ 372-18-9 ]
[ 13671-00-6 ]

References: [1]European Journal of Organic Chemistry,2002,p. 3351 - 3358.
[2]Journal of Medicinal Chemistry,1968,vol. 11,p. 814 - 819.

8
[ 28177-48-2 ]
[ 13671-00-6 ]

References: [1]Journal of the Chemical Society. Chemical communications,1987,p. 904 - 905.

9
[ 385-00-2 ]
[ 13671-00-6 ]

References: [1]Journal of Medicinal Chemistry,1968,vol. 11,p. 814 - 819.

10
[ 13671-00-6 ]
[ 108-95-2 ]
[ 816454-65-6 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 80℃; for 6h;	a) Methyl 2-JZUORO-6-PHENOXYBENZOATE Methyl 2,6-difluorobenzoate (2 g), phenol (1.09 g), caesium carbonate (3.79 g), and dimethylformamide (10 mL) were loaded in a 100 mL round bottom flask and the resulting suspension heated to 80C for 6 h. After cooling the reaction to room temperature, water (30 mL) was added and the mixture extracted with dichloromethane (2 x 30 mL). The combined organic extracts were washed with brine (30 mL), dried (magnesium sulphate), filtered and evaporated in vacuo. The residue was purified by column chromatography (Silica: DICHLOROMETHANE/HEXANE 5: 2) to give the titled compound as a clear oil (1.7 g)

References: [1]Patent: WO2004/113303,2004,A1 .Location in patent: Page 26-27.

11
[ 13671-00-6 ]
[ 125309-34-4 ]

Yield	Reaction Conditions	Operation in experiment
65%	With hydroxylamine hydrochloride;	(a) 2,6-Difluorobenzhydroxamic acid. The title compound (65%) was obtained from <strong>[13671-00-6]methyl 2,6-difluorobenzoate</strong> and hydroxylamine hydrochloride by similar reactions and treatments as in Example 1(b). NMR spectrum(DMSO-d6)deltappm: 7.14-7.25(2H,m), 7.50-7.60(1H,m), 9.40(1H,brs), 11.15(1H,brs).

References: [1]Organic Process Research and Development,2016,vol. 20,p. 233 - 241.
[2]Patent: US5965591,1999,A .

12
[ 13671-00-6 ]
[ 84832-01-9 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sulfuric acid; at 20℃; for 2h;	Step 3: methyl 2,6-difluoro-3-nitrobenzoateTo a solution of <strong>[13671-00-6]methyl 2,6-difluorobenzoate</strong> (68.8 g, 0.4 mol) in con. H2SO4 (300 mL) was added potassium nitroperoxous acid (48.5 g, 0.48 mol) for three times and the resulting reaction mixture was stirred at room temperature for 2 hrs. The mixture was droped into ice-water (500 mL) and filtered. The solid was washed with water and dried to afford the desired product (89 g, 100%).1H NMR (DMSC i): ? 8.49-8.43 (1H, m), 7.56-7.51 (1H, m), 3.95 (3H, s).
100%	With sulfuric acid; potassium nitrate; at 20℃; for 2h;	The 2, 6 - difluoro-benzoic acid methyl ester (68.8g, 0.4 muM) dissolved in concentrated sulfuric acid (300 ml) in, addition of potassium nitrate (48.5g, 0 . 48 muM), continuing stirring at room temperature 2 hours. The resulting reaction solution is poured into crushed ice in slow, filtering, the resulting solid with a large number of washing and drying can be obtained as shown in the title compound (89g, 100%)
98%	With sulfuric acid; nitric acid; at 0℃; for 1h;	To a solution of compound 1 (21.0 g, 122.0 mmol) in concentrated sulfuric acid (50 mL) was added fuming nitric acid (8 mL) dropwise at 0 C. After the reaction mixture was stirred at 0 C for 1 h, it was poured into ice-water. The precipitate was collected by filtration and rinsed with water to give 2 (26.0 g, 98%) as a white solid, mp 58-60 C. 1H NMR (CDCl3): delta 8.25-8.22 (m, 1H), 7.15-7.11 (m, 1H), 4.01 (s, 3H).

80.6%	With sulfuric acid; nitric acid; at 0℃; for 0.5h;	Fuming nitric acid (1 1 g, 174 mmol) was added to a solution of methyl 2,6- difluorobenzoate (25 g, 145 mmol) in concentrated sulfuric acid (50 ml_) at 0 C, and the reaction was stirred for 30 min at 0C. The reaction mixture was poured over ice-water. The precipitate was filtered to give the title compound 25.1 g (80.6 % yield) 1H NMR (400 MHz, CDCI3) delta ppm 8.13-8.20 (m, 1 H), 7.02-7.10 (m, 1 H), 3.93 (s, 3H).
64%	With sulfuric acid; nitric acid; at 20℃; for 1h;Cooling with ice;	Sulfuric acid (37 mL) was slowly added to nitric acid (20 mL) under ice-cooling, and added <strong>[13671-00-6]methyl 2,6-difluorobenzoate</strong> (25.7 g,149 mmol), The reaction was gradually warmed to room temperature and stirring was continued for 1 hour. The reaction system was poured into ice-water and filtered to obtain a white solid compound P'(20.7 g, yield 64%).
64%	With sulfuric acid; nitric acid; at 20℃; for 1h;Cooling with ice;	Sulfuric acid (37 mL) was slowly added to nitric acid (20 mL) under ice-cooling, and <strong>[13671-00-6]methyl 2,6-difluorobenzoate</strong> (25.7 g, 149 mmol) and the reaction was gradually allowed to warm to room temperature. Stirring was continued for 1 hour, The reaction system was poured into ice-water and filtered to give a white solid compound d (20.7g, yield 64%)
	With sulfuric acid; nitric acid; In water; at 0 - 20℃; for 0.583333h;	To fuming nitric acid (3.87 mL, 86.6 mmol) at O 0C was slowly added concentrated sulfuric acid (7.27 mL, 136.4 mmol). After stirring for 5 min., <strong>[13671-00-6]methyl 2,6-difluorobenzoate</strong> (3.90 mL, 29.0 mmol) was added and the reaction mixture was allowed to warm to ambient temperature. After 30 min., the reaction mixture was poured into ice- water, and extracted thrice with dichloromethane. The combined organic portions were washed with saturated aqueous sodium bicarbonate, dried over MgSO4, filtered, and concentrated in vacuo to afford a colorless oil. MS(ES+) m/e 218 [M+eta]+. Upon standing, the oil solidified to a white solid, which was dissolved in ethanol (50.0 mL) and treated with ammonium hydroxide (1.0 mL, 29 % aqueous solution) at ambient temperature. After 4 h, additional ammonium hydroxide (0.8 mL, 29 % aqueous solution) was added and the reaction mixture was stirred overnight. The solution was concentrated and the residual solid was washed with isopropanol, filtered, washed with water, and dried in vacuo to afford the title compound (5.69 g, 92%) as a yellow solid. 1H NMR (400 MHz, DMSO-iie) delta ppm 8.33 (dd, J=9.5, 5.7 Hz, 1 H), 8.11 (br. s., 2 H), 6.62 (t, J=9.9 Hz, 1 H), 3.89 (s, 3 H). MS(ES+) m/e 215 [M+H]+.
	With sulfuric acid; nitric acid; at 0 - 20℃;	1a) Methyl 2-amino-6-fluoro-3-nitrobenzoate To fuming nitric acid (3.87 mL, 86.6 mmol) at 0 C. was slowly added concentrated sulfuric acid (7.27 mL, 136.4 mmol). After stirring for 5 min., <strong>[13671-00-6]methyl 2,6-difluorobenzoate</strong> (3.90 mL, 29.0 mmol) was added and the reaction mixture was allowed to warm to ambient temperature. After 30 min, the reaction mixture was poured into ice-water and extracted thrice with dichloromethane. The combined organic portions were washed with saturated aqueous sodium bicarbonate, dried over MgSO4, filtered, and concentrated in vacuo to afford a colorless oil. MS (ES+) m/e 218 [M+H]+. Upon standing, the oil solidified to a white solid, which was dissolved in ethanol (50.0 mL) and treated with ammonium hydroxide (1.0 mL, 29% aqueous solution) at ambient temperature. After 4 h, additional ammonium hydroxide (0.8 mL, 29% aqueous solution) was added and the reaction mixture was stirred overnight. The solution was concentrated and the residual solid was washed with isopropanol, filtered, washed with water, and dried in vacuo to afford the title compound (5.69 g, 92%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) delta ppm 8.33 (dd, J=9.5, 5.7 Hz, 1H) 8.11 (br. s., 2H) 6.62 (t, J=9.9 Hz, 1H) 3.89 (s, 3H). MS (ES+) m/e 215 [M+H]+.

References: [1]Patent: WO2013/71865,2013,A1 .Location in patent: Page/Page column 26.
[2]Patent: CN103102349,2017,B .Location in patent: Paragraph 0150-0153.
[3]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 1017 - 1021.
[4]Patent: WO2011/59610,2011,A1 .Location in patent: Page/Page column 102.
[5]Patent: CN104003979,2016,B .Location in patent: Paragraph 0385-0387.
[6]Patent: CN103923088,2016,B .Location in patent: Paragraph 0214; 0216-0218.
[7]Patent: WO2009/134850,2009,A1 .Location in patent: Page/Page column 16.
[8]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 2620 - 2623.
[9]Patent: US2010/305133,2010,A1 .Location in patent: Page/Page column 12.

13
[ 13671-00-6 ]
[ 346691-23-4 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 2620 - 2623.
[2]Patent: CN104003979,2016,B .
[3]Patent: US2010/305133,2010,A1 .

14
[ 13671-00-6 ]
[ 1370000-21-7 ]