123843-65-2|2,6-Difluoro-4-methoxybenzoic acid| Ambeed

CAS No. :	123843-65-2
Formula :	C₈H₆F₂O₃
M.W :	188.13
SMILES Code :	O=C(O)C1=C(F)C=C(OC)C=C1F
MDL No. :	MFCD02949623
InChI Key :	LGHVYSAINQRZJQ-UHFFFAOYSA-N
Pubchem ID :	2778228

Safety of [ 123843-65-2 ]

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

Computational Chemistry of [ 123843-65-2 ] Show Less

Physicochemical Properties

Num. heavy atoms	13
Num. arom. heavy atoms	6
Fraction Csp3	0.12
Num. rotatable bonds	2
Num. H-bond acceptors	5.0
Num. H-bond donors	1.0
Molar Refractivity	39.81
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	46.53 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.43
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	1.62
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.51
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.	2.17
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	2.08
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.96

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.24
Solubility	1.09 mg/ml ; 0.0058 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.	-2.21
Solubility	1.16 mg/ml ; 0.00617 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	-2.46
Solubility	0.654 mg/ml ; 0.00348 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.	-6.3 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)	1.38

Application In Synthesis of [ 123843-65-2 ]

* 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 [ 123843-65-2 ]

[ 123843-65-2 ] Synthesis Path-Downstream 1~56

1
[ 93343-10-3 ]
[ 123843-65-2 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; n-butyllithium; In tetrahydrofuran; hexane;	2) To THF (200 ml) was dissolved 3,5-difluoroanisol (134 g) and then 1.64 M of n-butyllithium/hexane (568 ml) was added and stirred for 1 hour. The mixture formed was added to a solution of dryice (9.4 g) dissolved in THF (100 ml), and was stirred at room temperature for 2 hours. After the reaction, the mixture was added with diluted hydrochloric acid (700 ml) and extracted with ethyl acetate (700 ml). The organic layer separated was washed with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to give 2,6-difluoro-4-methoxybenzoic acid (102 g).

References: [1]Molecular Crystals and Liquid Crystals (1969-1991),1989,vol. 172,p. 165 - 190.
[2]Patent: US6149990,2000,A .

2
[ 123843-65-2 ]
[ 125369-56-4 ]

Yield	Reaction Conditions	Operation in experiment
	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 50℃; for 3h;	To a mixture of <strong>[123843-65-2]2,6-difluoro-4-methoxybenzoic acid</strong> (2.0 g, 10.6 mmol) in dichloromethane (30 mL) were added oxalyl chloride (1.49 g, 1 1.7 mmol) and A,N-dimethylformamide (1 drop). The reaction mixture was heated at 50 C for 3 h, cooled to room temperature and concentrated under reduced pressure to provide the title compound as an oil (2.0 g).
	With thionyl chloride; In N,N-dimethyl-formamide; for 3h;Reflux;	3 hours under reflux to a stirred solution of <strong>[123843-65-2]2,6-difluoro-4-methoxybenzoic acid</strong> in thionyl chloride (7ml) (0.25g, 1.34mmol), was added a drop of DMF, then the reaction mixture heated. After cooling to room temperature, the excess reagent was removed under reduced pressure to give the crude residue. Sections of this crude residue and 4- (6-methyl-imidazo [1,2-a] pyridin-2-yl) aniline (0.30 g, 1.34 mmol) and amide coupling using in dry pyridine (15 ml) the amide prepared as described in, work-up and flash chromatography (2: 1 EtOAc / hexanes, then EtOAc, then MeOH) later, the title compound (0.24g, 45%) as a pale yellow solid Obtained

References: [1]Molecular Crystals and Liquid Crystals (1969-1991),1989,vol. 172,p. 165 - 190.
[2]Tetrahedron Letters,2004,vol. 45,p. 95 - 98.
[3]Patent: WO2011/51958,2011,A1 .Location in patent: Page/Page column 36.
[4]Journal of Medicinal Chemistry,2013,vol. 56,p. 7084 - 7099.
[5]Patent: JP5667058,2015,B2 .Location in patent: Paragraph 0753.

3
[ 64-17-5 ]
[ 123843-65-2 ]
(2,6-difluoro-4-methoxyphenyl)carbamic acid ethyl ester [ No CAS ]

References: [1]Tetrahedron Letters,2004,vol. 45,p. 95 - 98.

4
[ 124-38-9 ]
[ 93343-10-3 ]
[ 123843-65-2 ]

Yield	Reaction Conditions	Operation in experiment
77%		To a solution of 1, 3-difluoro-5-methoxybenzene (40.0 g, 277.7 mmol) in THF (250 mL) was added n-BuLi (120 mL, 361.1 mmol) dropwise at -78 with N 2 protected. After addition, the resulting mixture was stirred for 1 h at -78 . Then dry ice (61 g, 1.39 mol) was added and the reaction mixture was allowed to room temperature and stirred for 10 min. Then the reaction mixture was added 1 N HCl at 0 and extracted with EA/THF (200 mL x3) . The combined organic layers were dried over anhydrous Na 2SO 4, filtered and concentrated to give crude product. The crude product was triturated in PE/EA=25: 1 and filtered to give product (40 g, 77%yield) as off-white solid. 1H NMR (400 MHz, DMSO-d 6) : delta 13.42 (brs, 1H) , 8.85 (s, 1H) , 8.80 (s, 1H) , 3.80 (s, 3H) .v
5.00 g		Under a nitrogen atmosphere, a 1.6 M solution of n-butyllithium in hexane (31.2 mL) was added to a solution of 1,3-difluoro-5-methoxybenzene (5.54 g) in THF (120 mL) at -78 C., and the mixture was stirred at -78 C. for 30 min. Sublimated dry ice (8.46 g) was added to the reaction solution through a silica gel tube at -78 C., and the mixture was stirred at room temperature for 5 min. To the reaction solution was added 1N hydrochloric acid at 0 C., and the mixture was extracted with ethyl acetate/THF. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained solid was washed with hexane and diisopropyl ether to give the title compound (5.00 g) as a white solid. (1338) 1H NMR (400 MHz, DMSO-d6) delta 3.83 (3H, s), 6.82 (2H, d, J=11.0 Hz), 13.43 (1H, brs).

References: [1]Heterocycles,2006,vol. 67,p. 489 - 494.
[2]Tetrahedron Letters,2004,vol. 45,p. 95 - 98.
[3]Patent: WO2020/57511,2020,A1 .Location in patent: Page/Page column 176-177.
[4]Patent: US2016/115128,2016,A1 .Location in patent: Paragraph 1337; 1338.

5
[ 123843-65-2 ]
[ 125369-57-5 ]

Yield	Reaction Conditions	Operation in experiment
72%		To a solution of 2, 6-difluoro-4-methoxybenzoic acid (45.0 g, 240 mmol) in CH 2Cl 2 (120mL) was added DMF (0.1 mL) and oxalyl chloride (50 mL, 840 mmol) dropwise. The reaction mixture was stirred for 30 min and then concentrated to give a residue. The residue was dissolved in DCM (120 mL) and then was added into a mixture of NH 4OH/THF (200mL/200mL) slowly. After addition the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated, re-dissolved in water and extracted with DCM (300 mLx3) . The combined organic phases were washed with brine, dried over anhydrous Na 2SO 4 and filtered. The filtrate was concentrated. The residue was triturated in PE/EA (20: 1, 500 mL) and filtered to give the product (32 g, 72%yield) as a yellow solid. MS (ESI) m/z: 188.2 (M+H) +.

References: [1]Patent: WO2020/57511,2020,A1 .Location in patent: Page/Page column 176-177.
[2]Heterocycles,2006,vol. 67,p. 489 - 494.
[3]Molecular Crystals and Liquid Crystals (1969-1991),1989,vol. 172,p. 165 - 190.

6
[ 123843-65-2 ]
[ 601517-02-6 ]