126674-77-9|2-Amino-4,6-difluorobenzoic acid| Ambeed

Structure of 126674-77-9

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Quality Control of [ 126674-77-9 ] Purity: 98% SDS Specification

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Product Details of [ 126674-77-9 ]

CAS No. :	126674-77-9
Formula :	C₇H₅F₂NO₂
M.W :	173.12
SMILES Code :	O=C(O)C1=C(F)C=C(F)C=C1N
MDL No. :	MFCD03618449
InChI Key :	TWSZCEBPTKBNBR-UHFFFAOYSA-N
Pubchem ID :	14651972

Safety of [ 126674-77-9 ]

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

Computational Chemistry of [ 126674-77-9 ] Show Less

Physicochemical Properties

Num. heavy atoms	12
Num. arom. heavy atoms	6
Fraction Csp3	0.0
Num. rotatable bonds	1
Num. H-bond acceptors	4.0
Num. H-bond donors	2.0
Molar Refractivity	37.72
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	63.32 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.03
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	1.52
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.09
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.	0.75
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	1.36
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.35

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.17
Solubility	1.16 mg/ml ; 0.00668 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.	-2.46
Solubility	0.603 mg/ml ; 0.00348 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	-1.97
Solubility	1.87 mg/ml ; 0.0108 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.	-6.28 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	1.0 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)	1.24

Application In Synthesis of [ 126674-77-9 ]

* 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 [ 126674-77-9 ]

[ 126674-77-9 ] Synthesis Path-Downstream 1~35

1
[ 126674-77-9 ]
[ 67-56-1 ]
[ 379228-57-6 ]

References: [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 6465 - 6488.

2
[ 126674-93-9 ]
[ 126674-77-9 ]

Yield	Reaction Conditions	Operation in experiment
86%		Stage 3: 2-amino-4,6-difluorobenzoic acid First sodium hydroxide (6.70 g, 167 mmol) and then 30% hydrogen peroxide (6.7 ml) in water (60 ml) were added to a suspension of the product from stage 2 (4.58 g, 25 mmol) in water (125 ml) at 0 C. The mixture was stirred at room temperature for 20 h and then brought to pH 3 with formic acid (approx. 11 ml, severe foaming), during which the title compound precipitated out. The mixture was then filtered and product was dried over phosphorus pentoxide in a desiccator. Yield: 3.72 g (86%), white solid. Melting point: 198-202 C.

References: [1]Patent: US2008/293749,2008,A1 .Location in patent: Page/Page column 14.
[2]Journal of Medicinal Chemistry,2006,vol. 49,p. 6465 - 6488.
[3]Organic Process Research and Development,2010,vol. 14,p. 1078 - 1087.

3
[ 126674-77-9 ]
[ 379228-58-7 ]

References: [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 6465 - 6488.

4
[ 126674-77-9 ]
[ 379230-65-6 ]

References: [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 6465 - 6488.

5
[ 126674-77-9 ]
[ 379230-64-5 ]

References: [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 6465 - 6488.

6
[ 126674-77-9 ]
[ 379230-66-7 ]

References: [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 6465 - 6488.

7
[ 126674-77-9 ]
4-(6-chloro-2,3-methylenedioxyanilino)-5-morpholino-7-(2-pyrrolidin-1-ylethoxy)quinazoline [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 6465 - 6488.

8
3,5-difluoroaniline hydrochloride [ No CAS ]
[ 126674-77-9 ]

References: [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 6465 - 6488.

9
[ 190011-84-8 ]
[ 126674-77-9 ]

Yield	Reaction Conditions	Operation in experiment
		A portion (0.5 g) of the 2: 1 mixture of 2-amino-4,6-difluorobenzonitrile and 4-amino-2,6-difluorobenzonitrile described in Example 1 was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained 2-amino-4,6-difluorobenzonitrile (0.15 g). A mixture of the material so obtained, concentrated aqueous sulphuric acid (80%; 4 ml) and water (1 ml) was heated to30 1000C for 15 hours. The resultant solution was cooled to ambient temperature, diluted with water and basified by the addition of 1OM aqueous sodium hydroxide solution and washed with ethyl acetate (10 ml). The resultant aqueous solution was neutralised by the addition of dilute aqueous hydrochloric acid solution and extracted with ethyl acetate (20 ml). The EPO <DP n="54"/>organic layer was dried over magnesium sulphate and evaporated. There was thus obtained 2-amino-4,6-difluorobenzoic acid as a colourless solid (0.11 g; 97% HPLC purity using Method B, retention time 6.87 minutes); NMR Spectrum: (DMSOd6) 6.25 (m, IH), 6.4 (m, IH). A mixture of the material so obtained, 1,3,5-triazene (0.044 g), methanol (4 ml) and piperidine (0.038 ml) was heated to 7O0C for 24 hours. The resultant mixture was cooled to ambient temperature and evaporated. Diethyl ether (3 ml) and ethyl acetate (1 ml) were added and the resultant solid was isolated and washed with diethyl ether (1 ml). There was thus obtained 5,7-difluoro-3,4-dihydroquinazolin-4-one (0.048 g).

References: [1]Patent: WO2006/64217,2006,A2 .Location in patent: Page/Page column 52-53.

10
[ 290-87-9 ]
[ 126674-77-9 ]
[ 379228-58-7 ]

Yield	Reaction Conditions	Operation in experiment
	With piperidine; In methanol; at 70℃; for 24h;Product distribution / selectivity;	A portion (0.5 g) of the 2: 1 mixture of 2-amino-4,6-difluorobenzonitrile and 4-amino-2,6-difluorobenzonitrile described in Example 1 was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained 2-amino-4,6-difluorobenzonitrile (0.15 g). A mixture of the material so obtained, concentrated aqueous sulphuric acid (80%; 4 ml) and water (1 ml) was heated to30 1000C for 15 hours. The resultant solution was cooled to ambient temperature, diluted with water and basified by the addition of 1OM aqueous sodium hydroxide solution and washed with ethyl acetate (10 ml). The resultant aqueous solution was neutralised by the addition of dilute aqueous hydrochloric acid solution and extracted with ethyl acetate (20 ml). The EPO <DP n="54"/>organic layer was dried over magnesium sulphate and evaporated. There was thus obtained <strong>[126674-77-9]2-amino-4,6-difluorobenzoic acid</strong> as a colourless solid (0.11 g; 97% HPLC purity using Method B, retention time 6.87 minutes); NMR Spectrum: (DMSOd6) 6.25 (m, IH), 6.4 (m, IH). A mixture of the material so obtained, 1,3,5-triazene (0.044 g), methanol (4 ml) and piperidine (0.038 ml) was heated to 7O0C for 24 hours. The resultant mixture was cooled to ambient temperature and evaporated. Diethyl ether (3 ml) and ethyl acetate (1 ml) were added and the resultant solid was isolated and washed with diethyl ether (1 ml). There was thus obtained 5,7-difluoro-3,4-dihydroquinazolin-4-one (0.048 g).

References: [1]Patent: WO2006/64217,2006,A2 .Location in patent: Page/Page column 52-53.

11
[ 126674-77-9 ]
[ 62351-47-7 ]
[ 59-31-4 ]

Yield	Reaction Conditions	Operation in experiment
		Example 131 (5R)-12-(3,5-difluorophenyl)-5-ethyl-9,11-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3',4':6,7]indolizino [1,2-b]quinoline-3,15-dione <strong>[126674-77-9]2-amino-4,6-difluorobenzoic acid</strong> is treated according to a procedure similar to Stages 93a to 93c using 3,5-difluorophenylmagnesium bromide of Stage 93b, and the resulting amino-ketone is treated according to a procedure similar to Stage 86b. Stages 83f to 83h of the operating method of Example 83 above are applied to the quinolone obtained.
		EXAMPLE 131 (5R)-12-(3,5-difluorophenyl)-5-ethyl-9,11-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3',4':6,7]indolizino [1,2-b]quinoline-3,15-dione <strong>[126674-77-9]2-amino-4,6-difluorobenzoic acid</strong> is treated according to a procedure similar to Stages 93a to 93c using 3,5-difluorophenylmagnesium bromide of Stage 93b, and the resulting amino-ketone is treated according to a procedure similar to Stage 86b. Stages 83f to 83h of the operating method of Example 83 above are applied to the quinolone obtained.