153775-33-8|2,4-Difluoro-5-nitrobenzoic acid| Ambeed

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Quality Control of [ 153775-33-8 ] Purity: 97% SDS Specification

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Product Details of [ 153775-33-8 ]

CAS No. :	153775-33-8
Formula :	C₇H₃F₂NO₄
M.W :	203.10
SMILES Code :	OC(=O)C1=C(F)C=C(F)C(=C1)[N+]([O-])=O
MDL No. :	MFCD04115713
InChI Key :	MDFSGDMPHMKKGB-UHFFFAOYSA-N
Pubchem ID :	2782822

Safety of [ 153775-33-8 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H332-H335
Precautionary Statements:	P261-P280-P305+P351+P338

Computational Chemistry of [ 153775-33-8 ] Show Less

Physicochemical Properties

Num. heavy atoms	14
Num. arom. heavy atoms	6
Fraction Csp3	0.0
Num. rotatable bonds	2
Num. H-bond acceptors	6.0
Num. H-bond donors	1.0
Molar Refractivity	42.14
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	83.12 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	0.61
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	1.48
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.41
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.	1.38
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	-0.02
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.17

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.22
Solubility	1.23 mg/ml ; 0.00607 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.	-2.83
Solubility	0.299 mg/ml ; 0.00147 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	-1.72
Solubility	3.91 mg/ml ; 0.0192 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	No
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.	-6.49 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	0.0
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	2.0 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)	1.89

Application In Synthesis of [ 153775-33-8 ]

* 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 [ 153775-33-8 ]

[ 153775-33-8 ] Synthesis Path-Downstream 1~35

1
[ 153775-33-8 ]
[ 35010-29-8 ]

References: [1]Journal of Agricultural and Food Chemistry,1996,vol. 44,p. 3643 - 3652.

2
[ 1583-58-0 ]
[ 153775-33-8 ]

Yield	Reaction Conditions	Operation in experiment
98%	With sulfuric acid; nitric acid; at 0 - 20℃; for 16.5h;	Step A To a suspension of 2,4-difluorobenzoic acid (9.985 g, 63.2 mmol) in concentrated sulfuric acid (30 mL) at 0 C. was added fuming nitric acid (30 mL) over 30 min. The mixture was allowed to warm to RT and stirred for an additional 16 h. The homogeneous mixture was poured onto ice and extracted with ethyl acetate. The organic extract was washed with water, dried and concentrated in vacuo to afford 2,4-difluoro-5-nitrobenzoic acid (12.56 gm, 98%) as pale yellow solid.
98%	With sulfuric acid; nitric acid; In water; at 20 - 50℃; for 3.5h;	Nitric Acid (120 mL) was added slowly to a cold solution of sulfuric acid (200 mL) 2,4- difluorobenzoic acid (65 g, 0 41 mol, 1 equiv) was added portionwise over 1 5 h and the reaction allowed to warm to RT The reaction mixture was heated to 50 0C for 2h and then poured slowly onto ice The product was extracted into ethyl acetate, dried over Na2SO4, filtered and concentrated to give intermediate 17 (82 g, 98% yield) as a yellow solid 1H NMR (400 MHz, DMSO-cfe) delta ppm 8 56 (t, J=I 87 Hz, 1 H), 7 82 (t, J=10 71 Hz, 1 H)
98%	With sulfuric acid; nitric acid; at 0 - 20℃; for 16.5h;	A) To a suspension of 2,4-difluorobenzoic acid (9. 985 g, 63.2 mmol) in concentrated sulfuric acid (30 [ML)] at [0 C] was added fuming nitric acid (30 [ML)] over 30 min. The mixture was allowed to warm to RT and stirred for additional 16 h. The homogeneous mixture was poured over ice and extracted with ethyl acetate. The organic extract was washed with water, dried and concentrated in vacuo to afford 2,4- difluoro-5-nitrobenzoic acid (12.56 gm, 98%) as pale yellow solid.

98%	With sulfuric acid; nitric acid; at 20 - 50℃; for 3.5h;	The synthesis of intermediate 22; <n="23"/>Intermediate 16; 2,4-difluoro-5-nitrobenzoic acid; F O; Nitric Acid (120 ml.) was added slowly to a cold solution of sulfuric acid (200 mL). 2,4-difluorobenzoic acid (65 g, 0.41 mol, 1 equiv) was added portio?wise over 1.5 h and the reaction allowed to warm to RT. The reaction mixture-was heated to 50 0C for 2h and then poured slowly onto ice. The product was extracted into ethyl acetate, dried over Na2SO4, filtered and concentrated to give intermediate 16 (82 g, 98% yield) as a yellow solid.1H NMR (400 MHz, DMSO-CZ6) delta ppm 8.56 (t, J=I, .87 Hz, 1 H), 7.82 (t, ./=10.71 Hz, 1 H).
98%	With sulfuric acid; nitric acid; at 20 - 50℃; for 3.5h;	Intermediate 1; 2,4-difluoro-5-nitrobe?zoic acid; Nitric Acid (120 mL) was added slowly to a cold solution of sulfuric acid (200 mL). 2,4- difluorobenzoic acid (65 g, 0.41 mol, 1 equiv) was added portionwise over 1.5 h and the reaction allowed to warm to RT. The reaction mixture was heated to 50 0C for 2h and then poured slowly onto ice. The product was extracted into ethyl acetate, dried overNa2SO4, filtered and concentrated to give intermediate 1 (82 g, 98% yield) as a yellow solid.1H NMR (400 MHz, DMSO-dbeta) delta ppm 8.56 (t, J=7.87 Hz, 1 H), 7.82 (t, J=10.71 Hz, 1 H).
61%	With nitric acid; In sulfuric acid;	2,4-Difluoro-5-nitrobenzoic acid 2,4-Difluorobenzoic acid (5 g, 0.031 M) was dissolved in concentrated sulfuric acid (30 ml), and cooled to 0. The mixture was stirred, and fuming nitric acid (d 1.567 g/ml, 1.91 ml, 0.047 M) added dropwise, keeping the temperature below 5. After stirring for 3 hours, the mix was poured onto ice, and organics extracted into dichloromethane (2*75 ml). The combined organic layers were washed with water, dried (MgSO4), and evaporated to give 2,4-difluoro-5-nitrobenzoic acid (3.9 g, 61%). Nmr (DMSO-d6): delta7.18 (t, 1H); 8.88 (t, 1H); 9.93 (br, 1H).
	With sulfuric acid; nitric acid; In water; at 0 - 5℃; for 14h;	Step 1 -Preparation of 2,4-difluoro-5-nitrobenzoic Acid To a cold mixture of 2,4-difluoro benzoic acid (3.0 g, 18.98 mmol) and conc. H2SO4 (10 mL), fuming HNO3 (3 mL) was added at 0 C. The reaction mixture was stirred at 0-5 C. for 14 h and quenched in ice cold water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 3.0 g of the desired product. 1HNMR (DMSO-d6): delta 7.83-7.90 (m, 1H), 8.57-8.62 (m, 1H).

References: [1]Patent: US2004/77696,2004,A1 .Location in patent: Page/Page column 9.
[2]Patent: WO2009/75960,2009,A1 .Location in patent: Page/Page column 21.
[3]Patent: WO2004/13145,2004,A1 .Location in patent: Page 41.
[4]Patent: WO2009/58919,2009,A1 .Location in patent: Page/Page column 21-22.
[5]Patent: WO2009/58923,2009,A1 .Location in patent: Page/Page column 11.
[6]Journal of Medicinal Chemistry,2003,vol. 46,p. 1905 - 1917.
[7]Patent: US5478820,1995,A .
[8]Journal of Agricultural and Food Chemistry,1996,vol. 44,p. 3643 - 3652.
[9]Patent: US2012/108583,2012,A1 .Location in patent: Page/Page column 22.

3
[ 153775-33-8 ]
[ 221560-09-4 ]

References: [1]Journal of Medicinal Chemistry,2003,vol. 46,p. 1905 - 1917.
[2]Journal of Medicinal Chemistry,2006,vol. 49,p. 3766 - 3769.

4
[ 153775-33-8 ]
[ 639858-45-0 ]

Yield	Reaction Conditions	Operation in experiment
98%	With hydrogen;palladium 10% on activated carbon; In ethanol; for 2h;	EXAMPLE 3; A solution of <strong>[153775-33-8]2,4-difluoro-5-nitrobenzoic acid</strong> (purchased from Combi-Blocks Inc) (6.09 g, 30 mmol) in ethanol (80 mL) was hydrogenated with Pd/C (0.7 g, 10%) under hydrogen atmosphere for 2 hrs. The mixture was filtered and the filtrate was concentrated to afford a solid (50.10 g, 98% yield).
97%	With hydrogen;palladium 10% on activated carbon; In ethanol; under 1551.49 Torr; for 2h;	Step B To a solution of <strong>[153775-33-8]2,4-difluoro-5-nitrobenzoic acid</strong> (0.998 g, 4.91 mmol) in ethanol (50 mL) was added 10% palladium on charcoal (107 mg) and the mixture was hydrogenated at 30 psi. After 2 h, the mixture was degassed, filtered and the filtrate was concentrated in vacuo to afford 2,4-difluoro-5-aminobenzoic acid (0.83 g, 97%) as tan solid. LC/MS (ESI); (M-H)-=172.
97%	With hydrogen;palladium 10% on activated carbon; In ethanol; under 1551.49 Torr; for 2h;	B) To a solution of the above compound A (0.998 g, 4.91 mmol) in ethanol (50 [ML)] was added 10% palladium on charcoal (107 mg) and the mixture was subjected to hydrogenation at 30 psi. After 2 h, the mixture was degassed, filtered and the filtrate was concentrated in vacuo to afford 2,4-difluoro-5-aminobenzoic acid (0.83 g, 97%) as tan solid. [LC/MS] (ESI); [(M-H)-=] 172.

References: [1]Patent: US2006/9454,2006,A1 .Location in patent: Page/Page column 13.
[2]Patent: US2004/77696,2004,A1 .Location in patent: Page/Page column 9.
[3]Patent: WO2004/13145,2004,A1 .Location in patent: Page 41.
[4]Journal of Medicinal Chemistry,2005,vol. 48,p. 3991 - 4008.

5
[ 153775-33-8 ]
[ 639858-44-9 ]

References: [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 3766 - 3769.

6
[ 153775-33-8 ]
2,4-difluoro-N-methyl-5-nitro-benzamide [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 3766 - 3769.

7
[ 153775-33-8 ]
[ 639858-69-8 ]

References: [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 3766 - 3769.

8
[ 153775-33-8 ]
[ 639858-71-2 ]

References: [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 3766 - 3769.

9
[ 153775-33-8 ]
2,4-Difluoro-N-methyl-5-[2-(Pyridin-2-ylamino)-thiazole-5-ylmethyl]-amino}-benzamide [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 3766 - 3769.

10
[ 153775-33-8 ]
N-Cyclopropyl-2,4-difluoro-5-[2-(pyridin-2-ylamino)-thiazol-5-ylmethyl]-amino}-benzamide [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 3766 - 3769.

11
[ 153775-33-8 ]
[ 658085-51-9 ]