878207-28-4|Methyl 2-bromo-4,5-difluorobenzoate| Ambeed

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Quality Control of [ 878207-28-4 ] Purity: 98% SDS Specification

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Product Details of [ 878207-28-4 ]

CAS No. :	878207-28-4
Formula :	C₈H₅BrF₂O₂
M.W :	251.02
SMILES Code :	O=C(OC)C1=CC(F)=C(F)C=C1Br
MDL No. :	MFCD08458104
Boiling Point :	No data available
InChI Key :	ZCGAVEFBZYWYJW-UHFFFAOYSA-N
Pubchem ID :	26985845

Safety of [ 878207-28-4 ]

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

Computational Chemistry of [ 878207-28-4 ] 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	4.0
Num. H-bond donors	0.0
Molar Refractivity	45.34
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.	2.28
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	2.67
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	3.35
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.	3.5
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	3.23
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	3.01

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.29
Solubility	0.129 mg/ml ; 0.000515 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.	-2.87
Solubility	0.335 mg/ml ; 0.00134 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	-3.89
Solubility	0.0323 mg/ml ; 0.000129 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.	-5.94 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.	0.55

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	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<0.0
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)	1.75

Application In Synthesis of [ 878207-28-4 ]

* 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 [ 878207-28-4 ]

[ 878207-28-4 ] Synthesis Path-Downstream 1~35

1
[ 878207-28-4 ]
[ 64695-84-7 ]

References: [1]Synthetic Communications,1992,vol. 22,p. 3067 - 3074.

2
[ 145286-17-5 ]
[ 878207-28-4 ]

References: [1]Synthetic Communications,1992,vol. 22,p. 3067 - 3074.

3
[ 942-06-3 ]
[ 878207-28-4 ]

References: [1]Synthetic Communications,1992,vol. 22,p. 3067 - 3074.

4
[ 18959-30-3 ]
[ 878207-28-4 ]

References: [1]Synthetic Communications,1992,vol. 22,p. 3067 - 3074.

5
[ 145286-16-4 ]
[ 878207-28-4 ]

References: [1]Synthetic Communications,1992,vol. 22,p. 3067 - 3074.

7
[ 67-56-1 ]
[ 64695-84-7 ]
[ 878207-28-4 ]

Yield	Reaction Conditions	Operation in experiment
92%	With thionyl chloride; In methanol; for 2.0h;Reflux;	Example 12 N-(2-cvano- 1 -(5-fluoro- 1 -hydroxy- 1.3 -dihydrobenzo c] [ 1.2"\|oxaborol-6-yloxy)propan-2-v l)-4-(trifluoromethoxy)benzamide The solution of 2-bromo-4,5-difluorobenzoic acid (1.00 g, 4.24 mmol) and SOCl2 (2 mL) in MeOH (12 mL) is refluxed for 2 h and cooled to rt. The reaction mixture is evaporated and the residue is purified by column chromatography on silica gel to give the desired product. (0.97 g, 92 % yield).
80.3%	With sulfuric acid; for 4.0h;Reflux;	General procedure: To a solution of 2-bromo-4-fluorobenzoic acid (2.17 g, 10.00 mmol) in methanol (10 mL) was added sulfuric acid (1.63 mL, 30 mmol) , the reaction mixture was refluxed for 4 h.The solvent was removed in vacuo.The mixture was diluted with diethyl ether, and washed water (50 mL * 3) and brine (50 mL * 3), dried over MgSO4. The solvent was removed under reduced pressure.The residue was purified by flash column chromatography with petroleum ether-ethyl acetate (80/1) as eluant to afford colorless liquid. Yield: 88.3%.This compound was prepared according to the general procedure reported by Baker.13 The spectral data were consistent with that reported in the literature.Yield: 80.3%. ESI-MS (m/z): 252.0 [M+1]+.
	With hydrogenchloride; In water; for 72.0h;Reflux;	A solution of 2-bromo-4,5-difluorobenzoic acid (5g, 21.10mmol) in methanol was treated with 1 mL of 10M hydrochloric acid and heated to reflux for 72 hours. The reaction mixture was evaporated under vacuum, dissolved in ether and washed with <n="73"/>water before drying (magnesium sulfate) and evaporation to a give the intermediate methyl 2-bromo-4,5-difluorobenzoate (5g) as a colourless oil.

	With sulfuric acid; at 0 - 80℃;	To a solution of 2-bromo-4,5-difluoro-benzoic acid (5 g, 21.10 mmol) in methanol (100 ml_) was added concentrated sulfuric acid (0.21 ml_, 2.11 mmol) at 0 C. The reaction mixture was then heated at 80 C for 4 hours. After cooling to room temperature, the mixture was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, then brine, dried over sodium sulfate, filtered, and concentrated to afford the crude product 2-bromo- 4,5-difluoro-benzoic acid methyl ester (1.48 g, 28%) as a clear oil, which was used in the next step without further purification.
		To a solution of R-13 (500 mg, 2.11 mmol) in CH2CI2 (10 mL) is added oxalyl chloride (0.54 mL, 6.33 mmol) dropwise followed by DMF (0.1 mL). The reaction mixture is stirred at room temperature for 0.5 hour and then cooled to 0 C and methanol (1.7 mL, 42.2 mmol) is added. The reaction is warmed to room temperature and stirred for 22 hours and concentrated in vacuo. The residue is dissolved in CH2CI2 and washed with water and brine. The organics are dried with a hydrophobic frit and concentrated in vacuo. The residue is purified by flash chromatography (SiC>2, 50% CH2CI2 in cyclohexane) to give R-14 (501.9 mg).

References: [1]Antimicrobial Agents and Chemotherapy,2016,vol. 60,p. 3980 - 3987.
[2]Patent: WO2014/149793,2014,A1 .Location in patent: Page/Page column 65.
[3]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 7101 - 7111.
[4]Patent: WO2009/138438,2009,A1 .Location in patent: Page/Page column 71-72.
[5]Patent: WO2010/55005,2010,A1 .Location in patent: Page/Page column 70.
[6]Patent: WO2012/58254,2012,A1 .Location in patent: Page/Page column 46.

8
[ 878207-28-4 ]
[ 100-46-9 ]
[ 1196693-82-9 ]

Yield	Reaction Conditions	Operation in experiment
	With dipotassium hydrogenphosphate; In dimethyl sulfoxide; at 75℃; for 18.0h;	A solution of the intermediate <strong>[878207-28-4]methyl 2-bromo-4,5-difluorobenzoate</strong> (4.4g, 17.53mmol) and benzylamine (2.066g, 2.108mL, 19.28mmol) in N,N-dimethylsulfoxide was treated with dibasic potassium phosphate (12.21g, 70.1 mmol) and heated to 75C for 18 hours in an open tube. The reaction mixture was then diluted with of ethyl acetate (20OmL), washed with of water (4x15OmL) and saturated brine before drying (sodium sulfate) and evaporation to yield the title compound (5.3g). 1H NMR (CDCI3, 400 MHz):delta 3.86 (2H, s), 4.40, (2H, d), 4.69 (1 H, br s), 6.91 (1 H, d), 7.35 (5H, m), 7.63 (1 H, d)

References: [1]Patent: WO2009/138438,2009,A1 .Location in patent: Page/Page column 72.

9
[ 878207-28-4 ]
[ 375853-82-0 ]
C₁₈H₂₁F₂NO₄ [ No CAS ]

References: [1]Tetrahedron Letters,2009,vol. 50,p. 5228 - 5230.

10
[ 878207-28-4 ]
[ 476620-55-0 ]

Yield	Reaction Conditions	Operation in experiment
		A solution of <strong>[878207-28-4]2-bromo-4,5-difluoro-benzoic acid methyl ester</strong> (1.45 g, 5.78 mmol) in toluene (42 ml_) was cooled at -78 C under nitrogen. Diisobutylaluminum hydride (1 M in toluene) (7.51 ml_, 7.51 mmol) was added drop-wise over 20 minutes. The reaction mixture was stirred at -78 C for another hour, and then allowed to warm to room temperature overnight. The reaction mixture was then cooled to 0 C and quenched with ethyl acetate, followed by addition of saturated Rochelle's salt solution. The biphasic slurry was then allowed to warm to room temperature and stirred for 2 hours. The organic layer was collected, dried over sodium sulfate, filtered, and concentrated to afford crude (2-bromo-4,5-difluoro-phenyl)-methanol (1.55 g, 90%), which was used in the next step without further purification.

References: [1]Patent: WO2010/55005,2010,A1 .Location in patent: Page/Page column 70.

11
[ 89466-08-0 ]
[ 878207-28-4 ]
[ 1238197-06-2 ]

References: [1]Journal of Combinatorial Chemistry,2010,vol. 12,p. 664 - 669.

12
[ 64695-84-7 ]
[ 74-88-4 ]
[ 878207-28-4 ]

Yield	Reaction Conditions	Operation in experiment
99.6%	With caesium carbonate; In acetone; for 1.0h;Reflux;	J15. 6-(5-(benzyloxy)-1H-indol-1-yl)-5-fluorobenzo[c][1,2]oxaborol-1(3H)-ol Methyl 2-bromo-4,5-difluorobenzoate [0219] To a solution of 2-bromo-4,5-diflurorobenzoic acid (23.7g, 10mmol) in acetone (150 mL) were added Cs2C03 (48.8g, 15mmol) and CH3I (lOmL, 15mmol). The mixture was stirred and refluxed for 1 hour then cooled to room temperature. The suspension was diluted with 300 mL petroleum ether. The solid was removed by filtration and washed with petroleum ether. The filtrate was concentrated to give clear oil product. (Yield: 25g, 99.6%). 1HNMR (500 MHz, DMSO-d6) delta 8.00 (t, 1H), 7.92 (t, 1H) and 3.88 (s, 3H) ppm.

References: [1]Patent: WO2011/63293,2011,A1 .Location in patent: Page/Page column 64.

13
[ 1215-59-4 ]
[ 878207-28-4 ]
[ 1309069-02-0 ]