Methyl 2-bromo-4-nitrobenzoate

Cat.NO.:A139667 Purity:97%

Product Details of [ 100959-22-6 ]

CAS No. :	100959-22-6
Formula :	C₈H₆BrNO₄
M.W :	260.04
SMILES Code :	O=C(OC)C1=CC=C([N+]([O-])=O)C=C1Br
MDL No. :	MFCD07779271
Boiling Point :	No data available
InChI Key :	XYMZAFDNPJLOTP-UHFFFAOYSA-N
Pubchem ID :	15833211

Safety of [ 100959-22-6 ]

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

Computational Chemistry of [ 100959-22-6 ] Show Less

Physicochemical Properties

Num. heavy atoms	14
Num. arom. heavy atoms	6
Fraction Csp3	0.12
Num. rotatable bonds	3
Num. H-bond acceptors	4.0
Num. H-bond donors	0.0
Molar Refractivity	54.24
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	72.12 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.83
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	2.7
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.14
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.	1.58
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	0.25
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.7

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.27
Solubility	0.139 mg/ml ; 0.000534 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.	-3.87
Solubility	0.0353 mg/ml ; 0.000136 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	-2.71
Solubility	0.507 mg/ml ; 0.00195 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	Yes
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	Yes
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.	-5.97 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	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<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)	1.97

Application In Synthesis of [ 100959-22-6 ]

* 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 [ 100959-22-6 ]

[ 100959-22-6 ] Synthesis Path-Downstream 1~4

1
[ 100959-22-6 ]
[ 98545-64-3 ]

Yield	Reaction Conditions	Operation in experiment
94.2%	With tin(II) chloride dihdyrate; In ethyl acetate; for 4h;Reflux;	To a solution of compound 20 (4.5g, 17.0mmol) in EtOAc (100mL) was added SnCl2·2H2O (38.3g, 0.17mol). The mixture was heated to reflux and stirred for 4h. The mixture was poured into saturated NaHCO3 (500mL) and EtOAc (370mL). The organic layer was washed with brine (300mL), and dried over anhydrous MgSO4. The residue after rotary evaporation was purified by column chromatography over silica gel to give compound 21 as a solid (3.68g, 94.2% yield). 1H NMR (400MHz, CDCl3): delta 7.75 (d, J=8.5 Hz, 1H), 6.92 (d, J=2.2Hz, 1H), 6.57 (dd, J=8.5, 2.2Hz, 1H), 4.04 (brs, 2H) and 3.86 (s, 3H) ppm; mp: 96-98C.
		To a suspension of 2-bromo-4-nitro-benzoic acid methyl ester [100959-22-6] (350 mg, 1.35 mmol) in MeOH (60 mL) were subsequently added tin powder (1.6 g, 13.5 mmol) and 3N aqueous HCI (27.8 mL, 83 mmol). The mixture was stirred overnight at RT. The liquid phase was decanted from the excess tin and neutralized by adding a saturated aqueous NaHC03 solution. An equal amount of water by volume was added and the water phase was extracted with EtOAc (3x). The combined organics were dried (Phase Separator) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluent: EtOAc/c-hexane 1 :4) to give the title compound as yellow solid. MS (LC/MS): 230 [M+H]+; tR (HPLC conditions b): 2.89 min.

References: [1]Organic Letters,2013,vol. 15,p. 3234 – 3237.
[2]Chinese Chemical Letters,2011,vol. 22,p. 1411 – 1414.
[3]European Journal of Medicinal Chemistry,2014,vol. 81,p. 59 – 75.
[4]Organic Process Research and Development,2019,vol. 23,p. 1686 – 1694.
[5]Academia Republicii Populare Romine, Baza de Cercetari Stiintifice, Timisoara, Studii si Cercetari, Stiinte Chimice,1956,vol. 4,p. 175,178.
[6]Patent: WO2012/93101,2012,A1 .Location in patent: Page/Page column 236-237.

2
[ 100959-22-6 ]
[ 7439-89-6 ]
[ 98545-64-3 ]

Yield	Reaction Conditions	Operation in experiment
95%	With ammonium chloride; In aqueous 2-propanol;	Example 54C methyl-2-bromo-4-aminobenzoate A solution of methyl 2-bromo-4-nitrobenzoate (970 mg, 3.73 mmol), iron powder 1.25 g (22.4 mmol) and ammonium chloride (239 mg, 4.48 mmol) in aqueous 2-propanol (20%, 15 mL) was heated to reflux for 30 minutes, cooled, filtered, and concentrated under reduced pressure. The residue was partitioned between diethyl ether (20 mL) and water (5 mL). The organic layer was washed with brine (1*5 mL), dried (MgSO4), filtered, and concentrated to provide the titled compound (813 mg, 95%).

References: [1]Patent: US2002/35137,2002,A1 .

3
[ 100959-22-6 ]
[ 32338-02-6 ]
[ 98545-64-3 ]

Yield	Reaction Conditions	Operation in experiment
96.0%		Next, the nitro group of methyl 2-bromo-4-nitrobenzoate (6.38 g, 24.6 mmol) was chemoselectively reduced with 5 nCl2.2H2O (27.8 g, 123.2 mmol) in a manner similar to that described for compound 6 to deliver methyl 4-amino-2-bromobenzoate in 96.0% (5.41 g) yield as a yellow solid. 1H-NMR (CDCl3, 400 MHz) delta 7.74 (1H, d, J=8.8 Hz, Ar), 6.90 (1H, d, J=1.6 Hz, Ar), 6.55 (1H, dd, J=8.8 Hz, 1.6 Hz, Ar), 4.06 (2H, s, NH2), 3.83 (3H, s, OCH3); 13C-NMR (CDCl3, 100 MHz) delta 165.9, 150.4, 133.6, 124.1, 119.7, 119.6, 112.7, 51.8; MS (ESI) m/z Calcd for C8H8BrNO2 (M+): 229.0, Found: 230.1 (M+H+).

References: [1]Patent: US2014/256817,2014,A1 .Location in patent: Page/Page column.

4
[ 454482-11-2 ]
[ 100959-22-6 ]
C₁₄H₁₆N₂O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With (1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 90℃; for 2h;Inert atmosphere;	To a solution ofmethyl 2-bromo-4-nitrobenzoate (CAS: 100959-22-6) (2.00 g, 7.69 mmol) in 1,4-dioxane (20 mL) were added H.O (10 mL), Cs2CO; (5.00 g, 15.38 mmol), <strong>[454482-11-2]1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine</strong> (CAS: 454482-11-2) (2.60 g, 11.54 mmol) and Pd(dppfhCl. (562 mg, 0.77 mmol). The reaction was stirred under Ar at 90 C for 2h. The cooled reaction mixture wasdiluted with water (200 mL) and extracted with EtOAc (200 mL X 3). The combined organic extracts were washed with water (200 mL X 3), dried over anhydrous NaoSOsx,filtered and concentrated. The residue was purified by silica gel chromatography (eluent: DCM/MeOHfrom 40/1 to 30/1, v/v) to give intermediate 160 (2.1 g, 99% yield) as a brownoil.

References: [1]Patent: WO2019/120209,2019,A1 .Location in patent: Page/Page column 191.

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