2-Bromo-4-fluorobenzoic acid

Cat.NO.:A205155 Purity:97%

Product Details of [ 1006-41-3 ]

CAS No. :	1006-41-3
Formula :	C₇H₄BrFO₂
M.W :	219.01
SMILES Code :	O=C(O)C1=CC=C(F)C=C1Br
MDL No. :	MFCD00055370
InChI Key :	RRKPMLZRLKTDQV-UHFFFAOYSA-N
Pubchem ID :	1268169

Safety of [ 1006-41-3 ]

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

Computational Chemistry of [ 1006-41-3 ] Show Less

Physicochemical Properties

Num. heavy atoms	11
Num. arom. heavy atoms	6
Fraction Csp3	0.0
Num. rotatable bonds	1
Num. H-bond acceptors	3.0
Num. H-bond donors	1.0
Molar Refractivity	41.06
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	2.27
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.71
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	2.32
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.31

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.97
Solubility	0.237 mg/ml ; 0.00108 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.	-2.69
Solubility	0.447 mg/ml ; 0.00204 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	-2.91
Solubility	0.269 mg/ml ; 0.00123 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.	-6.02 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	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 [ 1006-41-3 ]

* 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 [ 1006-41-3 ]

[ 1006-41-3 ] Synthesis Path-Downstream 1~2

1
[ 1006-41-3 ]
2-bromo-4-fluoro-6-nitrobenzoic acid [ No CAS ]
[ 1036389-83-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; potassium nitrate; at 0 – 20℃; for 3.16667h;	Potassium nitrate (11.54 g, 114 mmol) was added portionwise to a solution of 2-bromo-4-fluorobenzoic acid (25 g, 114 mmol) in sulfuric Acid (228 mL) <n=”138″/>at 0 0C over 10 min. The reaction mixture was stirred for 3 h at ambient temperature. The reaction mixture was poured onto ice. The resulting precipitate was washed with water and dried in vacuo to yield a mixture of 21A and 2-Br-4-F-6-nitrobenzoic acid (9: 1) as a white solid (19.5 g). 7 g of this solid was purified by prep HPLC (0.1% TFA, H2OMeOH, 35% to 60%) to yield 21A (5.6 g, 21.21 mmol) as a white solid. MS (ESI) m/z 262.1/264.1 (M-H)”. 1H NMR (400 MHz, CD3OD) delta ppm 7.91 (d, J=10.44 Hz, 1 H) 8.61 (d, J=8.25 Hz, 1 H).;

References: [1]Patent: WO2008/79759,2008,A1 .Location in patent: Page/Page column 136-137.
[2]ACS Medicinal Chemistry Letters,2016,vol. 7,p. 1077 – 1081.

2
[ 1006-41-3 ]
[ 1036389-83-9 ]

Yield	Reaction Conditions	Operation in experiment
86%	With sulfuric acid; nitric acid; In water; at 20℃; for 1h;Cooling with ice;	Fuming nitric acid (4 ml, 45.60 mmol) was added dropwise to a mixed solution of 2-bromo-4-fluorobenzoic acid (10 g, 45.66 mmol) and concentrated sulfuric acid (34 ml) under ice-cooling.The reaction system was dripped into ice water and stirred rapidly for 1 hour. The solid was collected by filtration, washed with ice water and dried to give 10.40 g of a white solid (10.4 g), which was washed with water and evaporated to dryness to give a white solid Solid, yield 86%.
73%	With sulfuric acid; nitric acid; at 0 – 20℃; for 3h;	Fuming 113 nitric acid (8 mL) was added dropwise to a mixture of 114 2-bromo-4-fluorobenzoic acid (20 g, 91.2 mmol) in 115 concentrated sulfuric acid (68 mL) at 0 C. After stirring at room temperature for 3 h, the mixture was poured into ice water and stirred rapidly for 1 hour. The solid was collected by filtration, washed with water and dried to give 116 compound 16A (17.59 g, 73% yield) as a white solid: 1H NMR (400 MHz, CDCl3) delta 8.81 (d, J=8 Hz, 1H), 7.73 (d, J=10 Hz, 1H).
52%	With sulfuric acid; potassium nitrate; at 0 – 20℃; for 3h;	To a solution of 183 (25 g, 114 mmol) in sulfuric acid (228 mL) is added potassium nitrate (11.5 g, 114 mmol) at 0 C over 10 minutes. After stirring at room temperature for 3 hours, the mixture is poured onto ice and the solid is collected by filtration, washed with water, dned,and purified by prep-HPLC (water/MeOH with 0.1% TFA, 35% to 60%) to give 184 as a white solid (5.6 g, 52% yield). (MS: [M+Hf 265.2)

	With sulfuric acid; potassium nitrate; at 0 – 20℃; for 3.16667h;	Intermediate 7: 6-amino-5-fluoroisoindolin-l-one; <n=”94″/>Intermediate 7A:; [00206] Potassium nitrate (11.54 g, 114 mmol) was added portionwise to a solution of 2-bromo-4-fluorobenzoic acid (25 g, 114 mmol) in sulfuric acid (228 mL) at 0 0C over 10 min. The reaction mixture was stirred for 3 h at ambient temperature. The reaction mixture was poured onto ice. The resulting precipitate was washed with water and dried in vacuo to yield a mixture of Intermediate 7 A and 2-Br-4-F-6- nitrobenzoic acid (9: 1) as a white solid (19.5 g). 7 g of this solid was purified by prep HPLC (0.1% TFA, H2OMeOH, 35% to 60%) to yield Intermediate 7A (5.6 g, 21.21 mmol) as a white solid. MS (ESI) m/z 262.1/264.1 (M-H)”.
	With sulfuric acid; potassium nitrate; at 0 – 20℃; for 3h;	To a cooled solution of 2-bromo-4-fluorobenzoic acid (5.00 g, 22.83 mmol) in sulfuric acid (42.5 mL) at 0 C. was added potassium nitrate portionwise (2.31 g, 22.83 mmol) over 5 minutes with the resulting solution stirred at ambient temperature for 3 h. After this time the reaction mixture was poured onto ice and the resultant precipitate was filtered, washing with water and dried in vacuo for 60 h to afford a mixture of regioisomers favouring the title compound (4:1; 5.03 g, 70% yield) as an off-white solid. 1H NMR (250 MHz, DMSO-d6) delta [ppm] 8.51 (d, J=8.0 Hz, 1H), 8.17 (d, J=10.9 Hz, 1H). LCMS (Analytical Method A): Rt=0.91 min; MS (ESIPos) m/z=261.8/263.8 (M-H)-, Br isotope pattern.

References: [1]Patent: CN106146474,2016,A .Location in patent: Paragraph 0097 – 0098.
[2]Patent: US2018/291002,2018,A1 .Location in patent: Paragraph 0444; 0445.
[3]Patent: WO2017/176812,2017,A1 .Location in patent: Paragraph 0451.
[4]Patent: WO2008/79836,2008,A2 .Location in patent: Page/Page column 86-87.
[5]Patent: US2019/177279,2019,A1 .Location in patent: Paragraph 0861-0864.

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