[ CAS No. 95668-21-6 ]

Name: 95668-21-6|1-Bromo-2-nitro-4-(trifluoromethoxy)benzene|98%
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Quality Control of [ 95668-21-6 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 95668-21-6 ]

CAS No. :	95668-21-6	MDL No. :	MFCD13194446
Formula :	C₇H₃BrF₃NO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	LHWANFWEBHKYCZ-UHFFFAOYSA-N
M.W :	286.00	Pubchem ID :	18350449
Synonyms :

Calculated chemistry of [ 95668-21-6 ]

Physicochemical Properties

Num. heavy atoms :	15
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	3
Num. H-bond acceptors :	6.0
Num. H-bond donors :	0.0
Molar Refractivity :	49.65
TPSA :	55.05 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.28 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.92
Log Po/w (XLOGP3) :	3.89
Log Po/w (WLOGP) :	4.52
Log Po/w (MLOGP) :	2.64
Log Po/w (SILICOS-IT) :	1.01
Consensus Log Po/w :	2.8

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-4.16
Solubility :	0.0197 mg/ml ; 0.0000689 mol/l
Class :	Moderately soluble
Log S (Ali) :	-4.74
Solubility :	0.00516 mg/ml ; 0.000018 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-3.25
Solubility :	0.16 mg/ml ; 0.00056 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.27

Safety of [ 95668-21-6 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 95668-21-6 ]

* 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.

Upstream synthesis route of [ 95668-21-6 ]
Downstream synthetic route of [ 95668-21-6 ]

[ 95668-21-6 ] Synthesis Path-Upstream 1~2

1
[ 2267-23-4 ]
[ 95668-21-6 ]

Yield	Reaction Conditions	Operation in experiment
78%	With tert.-butylnitrite; copper(ll) bromide In acetonitrile at 20℃; for 1 h;	INTERMEDIATE 244-Bromo-3-nitrophenyl trifiuoromethyl ether To a solution of 2-nitro-4-[(trifluoromethyl)oxy]aniline (2.0 g, 9.0 mmol) in acetonitrlle (50 mL) was added tert-butylnitrite (7.4 g, 72 mmol). The solution was stirred 2 min and then Copper(II) bromide (40 g, 180 mmol) was added. The solution stirred for 1 h at rt. The reaction was partitioned between EtOAc (500 mL) and 1N HCl (aq) (100 mL). The layers were separated, and the organics were washed with 1N HCl (aq) (3.x.50 mL), dried over MgSO₄, filtered, and the volatiies were evaporated under reduced pressure, and the residue was purified by flash column chromatography (0 to 20percent EtOAc:hexanes) to give 2.0 g (78percent) of the title compound. ¹H NMR (400 MHz, CDCl₃): δ 7.78 (d, J=8.79 Hz, 1H), 7.76 (s, 1H), 7.32 (s, 1H, J=8.79 Hz).
78%	With tert.-butylnitrite; copper(ll) bromide In acetonitrile at 20℃; for 1 h;	Intermediate 24: 4-Bromo-3-πitrQphenyi..trjflMQ.romet.h.y.J..etherTo a solution of 2-nitro-4-[(tπ^uoromoethyi)oxy]arsHine (2.0 g, 9.0 mrno.) ^"m acetoπitrile (50 mL) was added te/.pound.butyinitrite (7.4 g, 72 mmol). The solution was stirred 2 min and then Copper(ll) bromide (40 g, 180 mmol) was added. The solution stirred for 1 h at rt The reaction was partitioned between EtOAc (500 rπL) and 1 N HCi (aq) (100 mL). The iayers were separated, and the organics were washed mth 1N HCi (aq) (3 x 50 ml), dried over .VlgS04, filtered, and the volatiles were evaporated under reduced pressure, and the residue was purified by flash column chromatography (0 to 20percent <n="117"/>EiOAc:hexanes) to give 2,0 g (78percent) of the title compound. ¹H NMR (400 MHz, CDCI₃): δ 7.78 (d_s J- 8.79 Hz, 1H), 7,76 (s, IH), 7,32 (s, 1 H, J- 8.79 Hz).

Reference： [1] Patent: US2008/300247, 2008, A1, . Location in patent: Page/Page column 50
[2] Patent: WO2007/143456, 2007, A2, . Location in patent: Page/Page column 115-116

2
[ 64628-73-5 ]
[ 7787-70-4 ]
[ 95668-21-6 ]

Reference： [1] Patent: US6323155, 2001, B1,

[ 95668-21-6 ] Synthesis Path-Downstream 1~40

1
[ 2267-23-4 ]
[ 95668-21-6 ]

Yield	Reaction Conditions	Operation in experiment
78%	With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 20℃; for 1h;	INTERMEDIATE 244-Bromo-3-nitrophenyl trifiuoromethyl ether To a solution of <strong>[2267-23-4]2-nitro-4-[(trifluoromethyl)oxy]aniline</strong> (2.0 g, 9.0 mmol) in acetonitrlle (50 mL) was added tert-butylnitrite (7.4 g, 72 mmol). The solution was stirred 2 min and then Copper(II) bromide (40 g, 180 mmol) was added. The solution stirred for 1 h at rt. The reaction was partitioned between EtOAc (500 mL) and 1N HCl (aq) (100 mL). The layers were separated, and the organics were washed with 1N HCl (aq) (3×50 mL), dried over MgSO4, filtered, and the volatiies were evaporated under reduced pressure, and the residue was purified by flash column chromatography (0 to 20% EtOAc:hexanes) to give 2.0 g (78%) of the title compound. 1H NMR (400 MHz, CDCl3): delta 7.78 (d, J=8.79 Hz, 1H), 7.76 (s, 1H), 7.32 (s, 1H, J=8.79 Hz).
78%	With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 20℃; for 1h;	Intermediate 24: 4-Bromo-3-?itrQphenyi..trjflMQ.romet.h.y.J..etherTo a solution of 2-nitro-4-[(t?^uorom°thyi)oxy]arsHine (2.0 g, 9.0 mrno.) "m aceto?itrile (50 mL) was added te/£butyinitrite (7.4 g, 72 mmol). The solution was stirred 2 min and then Copper(ll) bromide (40 g, 180 mmol) was added. The solution stirred for 1 h at rt The reaction was partitioned between EtOAc (500 r?L) and 1 N HCi (aq) (100 mL). The iayers were separated, and the organics were washed mth 1N HCi (aq) (3 x 50 ml), dried over .VlgS04, filtered, and the volatiles were evaporated under reduced pressure, and the residue was purified by flash column chromatography (0 to 20% <n="117"/>EiOAc:hexanes) to give 2,0 g (78%) of the title compound. 1H NMR (400 MHz, CDCI3): delta 7.78 (ds J- 8.79 Hz, 1H), 7,76 (s, IH), 7,32 (s, 1 H, J- 8.79 Hz).

Reference： [1]Patent: US2008/300247,2008,A1 .Location in patent: Page/Page column 50
[2]Patent: WO2007/143456,2007,A2 .Location in patent: Page/Page column 115-116

2
[ 95668-21-6 ]
[ 929039-97-4 ]
[ 959999-81-6 ]

Yield	Reaction Conditions	Operation in experiment
97%	With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 60℃; for 16h;	intermediate 25: Methyl 3-0(1 /?)-1-(2-chloro-3-hydroxyphenyi)ethylloxy>-5-{5-Step A - Methyl 3-[(1 lambda)-1-(2-chlorophenyl)ethyi]oxy}-5-({2-nilro-4- [{trif.uoromethyi)oxy]phenyl}ami?o)-2-thiophe?ecarboxy.ate4-8romo-3-nitr°phe?yi t?fluoromethy. ether (2,0 g, 7.0 mmoi) and methyl 5- arnino-3-[(1 lambda}-1-{2-chlorophenyl)ethy.]oxy}-2-thiophenecart)oxyiate (2.2 g, 7.0 mmo.) were dissolved in 1,4-dioxane (SO ml) with stirring in a flask equipped with a stir bar, reflux condenser, and thermometer. The solution was degassed for 15 min by bubbling N2 through the stirring solution. 959- D5methy[-4,5-bs{dlphenylphosphi?o)xa?thene (0.18 g, 0.31 rnmol), cesium carbonate (11 g, 35 mmol), and tris(dibenzyiideneacetone) dipalladiurn(O) (0.13 g, 0.14 mmol} were added. The reaction was heated to 602C and stirred for 16 h. The reaction was cooled to rt and filtered through Ceite. The solid was washed with 20% MeOH in DCM. The volatiles were evaporated under reduced pressure and the residue was purified by flash column chromatography (0 Io 50% EtGAcDCM) to give 3.5 g (97%) of the Me compound as a solid. MS (ESI): 516 [M+HJ+-.

Reference： [1]Patent: WO2007/143456,2007,A2 .Location in patent: Page/Page column 116

3
[ 64628-73-5 ]
[ 7787-70-4 ]
4-bromo-2-chloro-1-trifluoromethoxybenzene [ No CAS ]
[ 95668-21-6 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogen bromide; sodium nitrite; In sulfuric acid; water; acetic acid;	Reference Example 24 A solution of <strong>[64628-73-5]3-chloro4-trifluoromethoxyaniline</strong> (5.1 g) in acetic acid (31 ml) was stirred and treated with sodium nitrite (2.16 g) in concentrated sulphuric acid (14 ml) at below 18 C. After an additional 1 hour at 10 C., the solution was added to a mixture of copper (I) bromide (7.7 g) and hydrobromic acid (24.5 ml) in water at 40-50 C. The reaction was completed by heating at 50 C. for 2 hours, water was added and the mixture filtered. The filtrate was extracted with ether, washed with sodium bicarbonate, dried (magnesium sulphate) and evaporated to give 3-chloro-4-trifluoromethoxy-bromobenzene (6.05 g) as a brown oil, NMR (CDCl3) 7.10(m,1H), 7.35(m,1H), 7.55(d,1H). By proceeding in a similar manner 2-nitro-4-trifluoromethoxy-bromobenzene was prepared, NMR (CDCl3) 7.35(m,1H), 7.75(m,1H), 7.8(d,1H).

Reference： [1]Patent: US6323155,2001,B1

4
[ 95668-21-6 ]
2-nitro-4-(trifluoromethoxy)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In toluene;	Reference Example 37 A solution of <strong>[95668-21-6]2-nitro-4-trifluoromethoxy-bromobenzene</strong> (2.0 g) in N,N-dimetbylformamide (2 ml) was treated with copper (I) cyanide (0.62 g) and the mixture heated at 150 C. for 1 hour. Toluene (10 ml) was added and the mixture was maintained at reflux for 1 hour. The mixture was filtered and the filtrate evaporated to give a dark oil which was purified by chromatography eluding with ethyl acetate/hexane (1:9) to give 2-nitro-4-trifluoromethoxybenzonitrile (1.1 g) as a yellow liquid, NMR (CDCl3) 7.65(m,1H), 8.0(d,1H), 8.15(m,1H).

Reference： [1]Patent: US6323155,2001,B1

5
[ 95668-21-6 ]
[ 1335114-86-7 ]

Reference： [1]Tetrahedron Letters,2011,vol. 52,p. 5211 - 5213

6
[ 95668-21-6 ]
[ 93267-04-0 ]
[ 1335114-85-6 ]

Yield	Reaction Conditions	Operation in experiment
63%		Degassed anhydrous DMF (42 mL) was added to zinc (13.72 g, 209.8 mmol) under a flow of argon. Chlorotrimethylsilane (5.30 mL, 42.0 mmol) was added and the mixture stirred vigorously for 30 min. Stirring was stopped and the zinc was allowed to settle. The supernatant was decanted under a flow of argon and the zinc washed with degassed DMF (2 × 20 mL). A solution of Boc-3-iodoalanine methyl ester (29.9 g, 90.9 mmol) in degassed DMF (75 mL) was added to the zinc. Upon addition an exotherm was observed. The cloudy gray solution was stirred for 30 min at room temperature and then the zinc was allowed to settle. This was repeated for a second batch of zincate. The two batches of zincate were combined by decanting the supernatant into a clean flask under a flow of argon. A solution of bromide 8 (40.0 g, 140 mmol) in degassed DMF (120 mL), palladium acetate (1.57 g, 6.99 mmol), and X-Phos (6.67 g, 14.0 mmol) were added sequentially. The reaction was heated at 40 C. After 16 h the reaction mixture was poured into water (400 mL) and ethyl acetate (250 mL) was added. The mixture was filtered through a pad of celite, washing the filter cake with ethyl acetate (2 × 50 mL). The layers were separated, the aqueous extracted with ethyl acetate (100 mL) and the organics combined. The organics were then washed with brine (5 × 400 mL), dried (MgSO4), and concentrated in vacuo. The resulting residue was purified by dry flash chromatography (2% ethyl acetate in heptane to 20%) to give compound 9 as a brown solid (35.95 g, 63%).1H NMR (400 MHz, CDCl3): 7.84 (s, 1H), 7.47-7.36 (m, 2H), 5.22-5.14 (m, 1H), 4.72-4.63 (m, 1H), 3.74 (s, 3H), 3.57 (dd, 1H), 3.25-3.15 (m, 1H), 1.33 (s, 9H).

Reference： [1]Tetrahedron Letters,2011,vol. 52,p. 5211 - 5213

7
[ 95668-21-6 ]
[ 93267-04-0 ]
C₁₅H₁₇F₃N₂O₅ [ No CAS ]

Reference： [1]Tetrahedron Letters,2011,vol. 52,p. 5211 - 5213

8
[ 14597-58-1 ]
[ 95668-21-6 ]
[ 1314091-71-8 ]

Reference： [1]ACS Medicinal Chemistry Letters,2011,vol. 2,p. 708 - 713

9
[ 95668-21-6 ]
3-(((1R)-1-(2-chloro-3-(4-piperidinyloxy)phenyl)ethyl)oxy)-5-(5-((trifluoromethyl)oxy)-1H-benzimidazol-1-yl)-2-thiophenecarboxamide [ No CAS ]

Reference： [1]Patent: WO2007/143456,2007,A2

10
[ 95668-21-6 ]
C₂₇H₂₅ClF₃N₃O₅S [ No CAS ]

Reference： [1]Patent: WO2007/143456,2007,A2

11
[ 95668-21-6 ]
methyl 3-[((1R)-1-(2-chloro-3-[(1-methyl-4-piperidinyl)oxy]phenyl}ethyl)oxy]-5-{5-[(trifluoromethyl)oxy]-1H-benzimidazol-1-yl}-2-thiophenecarboxylate [ No CAS ]

Reference： [1]Patent: WO2007/143456,2007,A2

12
[ 95668-21-6 ]
3-[((1R)-1-{2-chloro-3-[(1-methyl-4-piperidinyl)oxy]phenyl}ethyl)oxy]-5-{5-[(trifluoromethyl)oxy]-1H-benzimidazol-1-yl}-2-thiophenecarboxamide [ No CAS ]

Reference： [1]Patent: WO2007/143456,2007,A2

13
[ 95668-21-6 ]
1,1-dimethylethyl 4-((2-chloro-3-((1R)-1-((2-((methoxy)carbonyl)-5-(5-((trifluoromethyl)oxy)-1H-benzimidazol-1-yl)-3-thienyl)oxy)ethyl)phenyl)oxy)-1-piperidinecarboxylate [ No CAS ]

Reference： [1]Patent: WO2007/143456,2007,A2

14
[ 95668-21-6 ]
[ 959999-82-7 ]

Reference： [1]Patent: WO2007/143456,2007,A2

15
[ 95668-21-6 ]
C₂₂H₁₆ClF₃N₂O₄S [ No CAS ]

Reference： [1]Patent: WO2007/143456,2007,A2

16
[ 95668-21-6 ]
[ 959909-78-5 ]

Reference： [1]Patent: WO2007/143456,2007,A2

17
[ 95668-21-6 ]
[ 959999-80-5 ]

Reference： [1]Patent: WO2007/143456,2007,A2

18
[ 95668-21-6 ]
[ 959999-83-8 ]

Reference： [1]Patent: WO2007/143456,2007,A2

19
[ 288-88-0 ]
[ 95668-21-6 ]
1-(2-nitro-4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole [ No CAS ]