630125-49-4|1-Bromo-3-nitro-5-(trifluoromethyl)benzene| Ambeed

Structure of 630125-49-4

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Quality Control of [ 630125-49-4 ] Purity: 95% SDS Specification

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Product Details of [ 630125-49-4 ]

CAS No. :	630125-49-4
Formula :	C₇H₃BrF₃NO₂
M.W :	270.00
SMILES Code :	FC(C1=CC([N+]([O-])=O)=CC(Br)=C1)(F)F
MDL No. :	MFCD03788719
InChI Key :	YHTVYRKVFAFVLP-UHFFFAOYSA-N
Pubchem ID :	7015411

Safety of [ 630125-49-4 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H227-H302-H315-H319-H332-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 630125-49-4 ] Show Less

Physicochemical Properties

Num. heavy atoms	14
Num. arom. heavy atoms	6
Fraction Csp3	0.14
Num. rotatable bonds	2
Num. H-bond acceptors	5.0
Num. H-bond donors	0.0
Molar Refractivity	47.97
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	45.82 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.67
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	3.33
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	4.53
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.	2.68
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	1.43
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.73

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.8
Solubility	0.0431 mg/ml ; 0.00016 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.	-3.97
Solubility	0.029 mg/ml ; 0.000107 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	-3.52
Solubility	0.0821 mg/ml ; 0.000304 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.	-5.58 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)	2.12

Application In Synthesis of [ 630125-49-4 ]

* 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 [ 630125-49-4 ]

[ 630125-49-4 ] Synthesis Path-Downstream 1~35

1
[ 630125-49-4 ]
[ 822-36-6 ]
[ 916975-92-3 ]

Yield	Reaction Conditions	Operation in experiment
78.2%	With isoquinolin-8-ol; copper(l) iodide; potassium carbonate; triethylamine; In N,N-dimethyl-formamide; at 100 - 140℃; for 5h;	13.5 g of <strong>[630125-49-4]3-bromo-5-nitro-trifluorotoluene</strong> (13.5 g, 0.05 mol), 5.0 g of 4-methyl-1H-imidazole (5.0 g, 0.06 mol), 1.42 g of cuprous iodide (1.42 g, 7.5 mmol), 2.2 g of 8-hydroxyisoquinoline (2.2 g, 7.5 mmol), 7.6 g of potassium carbonate (0.055 mol) and 50 mL of N,N-dimethylformamide were added to a 250 mL three-necked bottle, heated to 100 C., stirred to dissolve. Added with 0.75 g of triethylamine (0.75 g, 7.5 mmol), continued to heat to 140 C., reacted for 5 hours, to complete the reaction detected by TLC. Cooled down to 50-60 C., filtered, and the filter cake was washed with ethyl acetate, the filter liquor was washed with saline water and water, concentrated, then recrystallized by ethyl acetate and n-hexane (1:1), to get 10.6 g of yellow solid 3-(4-methyl-1H-imidazol-1-yl)-5-nitro-trifluorotoluene, with a yield of 78.2%, melting point 118-120 C., MS-ESI (m/z): 272(M+H), 1H NMR (400 MHz, CDCl3) delta 8.45(s, 2H), 7.95(s, 1H), 7.93(s, 1H), 7.16(s, 1H), 2.33(s, 3H).
53.3%		Example 13 4-Methyl-1 -(3-nitro-5-tiotaf luoromethyl-phenyl)-1 H-imidazole (IX) (by aromatic substitution)4-Methylimidazole (10.5 g, 125.5 mmol) and potassium carbonate (12.0 g, 119.6 mmol) is suspended in Lambda/,Lambda/-dimethylformamide (80 mL) and stirred at 1000C for 1 hour. A solution of 1-fluoro-3-nitro-5-trifluoromethyl-benzene (12.5 g, 59.8 mmol) in EPO <DP n="26"/>ty/V-dimethylformamide (20 mL) is added over 10 minutes. The mixture is stirred at 1080C internal temperature for 3 hours. HPLC analysis shows complete consumption of the fluoride starting material. The mixture is cooled down to about 200C and water (200 mL) is added over 1 hour. The resulting suspension is filtered to give 17.5 g of wet solid (HPLC: 88.8 area% desired isomer, 8.9 area% undesired isomer/byproduct). A suspension of this material in water (100 mL) is stirred for 1 hour at room temperature. The solid is filtered, washed with water (100 mL) and dried at 50C under reduced pressure to give the crude product. HPLC analysis shows more than 90 area% of the desired product. Re-crystallization: A solution of above crude product (9.5 g) in ethyl acetate (50 mL) is treated for 2 hours at 700C with activated carbon (1 g) and filter aid (1 g) and, thereafter, is filtered, and the filtrate is evaporated to dryness to give 11.1 g of a residue. This material is dissolved in ethyl acetate (3.25 g) and heptane (50 mL) under reflux. The solution is seeded at 65C with 4-methyl-1-(3-nitro-5-trifluoromethyl-phenyl)-1H-imidazole and allowed to cool down to room temperature over night and afterwards stirred at 00C for 3 hours. The solid formed is filtered, washed with heptane (20 mL) and dried at 500C under reduced pressure to give 4-methyl-1-(3-nitro-5-trifluoromethyl-phenyl)-1 /-/-imidazole as a solid. Yield overall: 53.3% (HPLC purity: 98.2 area%), Melting point: 117-118C
21.1%	With copper(l) iodide; potassium carbonate; ethylenediamine; In N,N-dimethyl-formamide; at 110℃; for 23h;Product distribution / selectivity;	Example 10 4-Methyl-1-(3-nitro-5-trifluoromethyl-phenyl)-1H-imidazole (IX) (by catalyzed coupling)To a stirred suspension of <strong>[630125-49-4]1-bromo-3-nitro-5-trifluoromethyl-benzene</strong> (4.05 g, 15 mmol), 4-methyl-1 W-imidazole (2.01 g, 24 mmol, 98%) and potassium carbonate (3.73 g, 27 mmol) in Lambda/,Lambda/-dimethylformamide (10 mL) are added ethylenediamine (0.141 mL, 2.1 mmol) and copper(l) iodide (0.204 g, 1.05 mmol). The vigorously stirred mixture is heated to 110 0C for 23 hours. After that, most of the 1-bromo-3-nitro-5-trifluoromethyl- benzene is converted, and the suspension is allowed to cool down to room temperature. The mixture is diluted with terf-butyl methyl ether (30 mL) and 5% aqueous NaCI solution (30 mL) and isopropyl acetate (15 mL) are added. The aqueous layer is separated and extracted with a mixture of tert-buty methyl ether (10 mL) and isopropyl acetate (5 mL). The organic layers are combined and filtered. The filtrate is washed with water (10 mL), treated for 5 minutes with ethylenediamine (0.303 mL), washed with water (10 mL), 5% aqueous sodium EPO <DP n="24"/>metabisulfite solution (10 mL) and water (10 ml.) before it is treated with activated carbon (1.2 g) at room temperature for 1 hour. The suspension is filtered using filter aid, and the filtrate is evaporated to dryness under reduced pressure to give a clear, red-brown oil which solidifies upon standing at room temperature. The obtained solid is purified by column chromatography on silica gel eluting with a 4:5 mixture of ethyl acetate and hexane (in the presence of 0.5 volume% of triethylamine) to afford mainly 4-methyl-1-(3-nitro- 5-trifluoromethyl-phenyl)-1 /-/-imidazole as a pale yellow solid. Yield: 21.1% (HPLC purity: 96.7 area%) Melting point: 118-119C.

References: [1]Patent: US2016/311777,2016,A1 .Location in patent: Paragraph 0029.
[2]Patent: WO2006/135640,2006,A2 .Location in patent: Page/Page column 24-25.
[3]Patent: WO2006/135640,2006,A2 .Location in patent: Page/Page column 22-23.

2
[ 98-46-4 ]
[ 630125-49-4 ]

Yield	Reaction Conditions	Operation in experiment
89.6%		Example 14 1-Bromo-3-nitro-5-trifluoromethyl-benzene (Xl)To a solution of 1-nitro-3-trifluoromethyl-benzene (41.1 mL, 300 mmol, 97%, purchased from Aldrich) in dichloromethane (240 mL) is added 98% sulfuric acid (45.7 mL, 840 mmol) over 10 minutes. The vigorously stirred resulting biphasic mixture is warmed to 35C and 1 ,3-dibromo-5,5-dimethyl-imidazolidine-2,4-dione (53.1 g in total, 180 mmol) is added in six equal portions over five hours. The mixture is stirred at 35C for additional19 hours. Thereafter, more than 97% of the starting material is converted according to HPLC analysis. The reaction mixture is allowed to cool to room temperature and added over20 minutes to a stirred 2 M aqueous NaOH solution (210 mL) of 0-5C while cooling with an ice-water bath. The internal temperature rises temporarily to about 35C. The two layers are separated. The aqueous layer is extracted with hexane (3 x 200 mL). The combined organic layers are washed with water (200 mL), 5% aqueous sodium metabisulfite solution (2 x EPO <DP n="27"/>200 ml_), 8% aqueous NaHCO3 solution (200 ml_) and 10% aqueous NaCI solution (200 mL) and, thereafter, the solvents are evaporated at reduced pressure and 45C. The obtained liquid is distilled at 0.71 mbar and a bath temperature of 70-800C to give 1-bromo-3-nitro-5- trifluoromethyl-benzene as a pale yellow liquid. Yield: 89.6% (1H-NMR purity: about 95%). 1H-NMR (400 MHz, CDCI3): 8.11 ppm (m, 1 H), 8.45 ppm (m, 1 H), 8.58-8.59 ppm (m, 1 H). Boiling point: approximately 68 0C at 0.71 mbar.
24.7 g	With sulfuric acid; bromine; at 60 - 70℃; for 14h;Cooling with ice;	Under 100 mL concentrated sulfuric acid ice-water bath, added 19.1 g (0.1 mol) of nitrobenzotrifluoride, added dropwise liquid bromine (15.8 g, 0.1 mol) by batch at room temperature, controlled the reaction temperature at 60-70 C. to react for 14 hours, to complete the reaction detected by TLC. Leaved it standstill for layering, washed the organic phases with 5% sodium hydroxide and saturated salt water, concentrated, to get 24.7 g of orange red oily matter 3-bromo-5-nitro-trifluorotoluene, with a yield of 91.8%, boiling point 74-76 C. (70 Pa); EI-MS (m/z): 269(M+H); 1H NMR (400 MHz, CDCl3) delta 8.59-8.60(m, 1H), 8.46(m, 1H), 8.12(m, 1H).

References: [1]Patent: WO2006/135640,2006,A2 .Location in patent: Page/Page column 25-26.
[2]RSC Advances,2015,vol. 5,p. 1522 - 1528.
[3]Patent: US2016/311777,2016,A1 .Location in patent: Paragraph 0028.

3
[ 630125-49-4 ]
[ 375853-82-0 ]
[ 1365803-06-0 ]

Yield	Reaction Conditions	Operation in experiment
82.8%	With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate; at 120℃; for 5h;	Mix l-bromo-3-nitro-5-(trifluoromethyl)benzene (200 mg, 0.65 mmol), tert-butyl 4-(4,4,5,5-tetramemyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-l(2H)-carboxylate (175 mg, 0.65 mmol), tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.03 mmol) in dioxane and saturated sodium bicarbonate solution (3:1, 10 mL), stir the mixture at 120C for 1.5 hrs. Cool to room temperature; concentrate under reduced pressure to give the crude product. Purify by flash chromatography (silica gel, EtOAc:PE=20:l) to afford the product as a yellow solid (310 mg, 82.8%). MS: (M+23): 395.2
82.8%	With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate; In 1,4-dioxane; at 120℃; for 1.5h;	Mix <strong>[630125-49-4]1-bromo-3-nitro-5-(trifluoromethyl)benzene</strong> (200 mg, 0.65 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (175 mg, 0.65 mmol), tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.03 mmol) in dioxane and saturated sodium bicarbonate solution (3:1, 10 mL), stir the mixture at 120 C. for 1.5 hrs. Cool to room temperature; concentrate under reduced pressure to give the crude product. Purify by flash chromatography (silica gel, EtOAc:PE=20:1) to afford the product as a yellow solid (310 mg, 82.8%). MS: (M+23): 395.2.
47%	With potassium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In N,N-dimethyl-formamide; at 80℃;	fert-Butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine- 1 (2H)-carboxylate (200 mg, 0.646 mmol), l-bromo-3-nitro-5-(trifluoromethyl)benzene (261 mg, 0.969 mmol), Pd(dppf 2Ci2 dichloromethane adduct (52 mg, 0.064 mmol) and potassium carbonate (268 mg, 1.94 mmol) were suspended in anhydrous N,N-dimethylformamide (5 mL). The mixture was stirred at 80 C overnight and then was cooled to room temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate, was filtered and was concentrated. The residue was purified by column chromatography (eluted with ethyl acetate:Hexanes = 1 : 10) to give tert-butyl 4-[3- nitro-5-(trifluoromethyl)phenyl]-3,6-dihydropyridine-l(2H)-carboxylate (1 14 mg, 47% yield) as a yellow sticky oil. XH NMR (400 MHz, CDC13): delta 8.37 (s, 1H), 8.33 (s, 1H), 7.89 (s, 1H), 6.27 (s, 1H), 4.09 (s, 2H), 3.65 (t, 2H), 2.55 (s, 2H), 1.46 (s, 9H).

891 mg

With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate; In 1,4-dioxane; at 120℃; for 6h;

To a solution of <strong>[630125-49-4]1-bromo-3-nitro-5-(trifluoromethyl)benzene</strong> (1.0 g, 3.70 mmol) in 1,4-dioxane (35 mL) were added tert-butyl 4-(4,4,5 ,5 -tetramethyl- 1,3 ,2-dioxaborolan-2-yl)-5 ,6-dihydropyridine-1(2H)-carboxylate (1.1 g, 3.70 mmol),tetrakis(triphenylphosphine)palladium(0) (213 mg, 0.18 mmol) and saturated aqueous sodium bicarbonate solution (15 mL) and the mixture was heated at 120 C for 6 h. The mixture was cooled to RT and diluted with ethyl acetate. The organic layer was washed with water followed by brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel column chromatography to yield 891 mg of thedesired compound. ?H NMR (400 MHz, DMSO-d6) oe 1.52 (s, 9H), 2.60 (br s, 2H), 3.71 (t, J= 5.6 Hz, 2H), 4.18 (br s, 2H), 6.32 (br s, 1H), 7.94 (s, 1H), 8.39 (s, 1H), 8.42 (s, 1H).

References: [1]Patent: WO2014/418,2014,A1 .Location in patent: Page/Page column 63.
[2]Patent: US2015/197511,2015,A1 .Location in patent: Paragraph 0307; 0308.
[3]Patent: WO2012/37132,2012,A1 .Location in patent: Page/Page column 50; 51.
[4]Journal of Medicinal Chemistry,2019,vol. 62,p. 306 - 316.
[5]Patent: WO2018/215668,2018,A1 .Location in patent: Page/Page column 81; 82.

4
[ 630125-49-4 ]
[ 861881-13-2 ]

References: [1]Patent: WO2012/37132,2012,A1 .
[2]Patent: WO2014/418,2014,A1 .
[3]Patent: US2015/197511,2015,A1 .

5
[ 630125-49-4 ]
[ 1365803-07-1 ]

References: [1]Patent: WO2012/37132,2012,A1 .
[2]Patent: WO2014/418,2014,A1 .
[3]Patent: US2015/197511,2015,A1 .

6
[ 630125-49-4 ]
[ 1365803-08-2 ]

References: [1]Patent: WO2012/37132,2012,A1 .

7
[ 630125-49-4 ]
[ 1044271-86-4 ]