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Chemical Structure| 89642-49-9 Chemical Structure| 89642-49-9

Structure of 89642-49-9

Chemical Structure| 89642-49-9

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Product Details of [ 89642-49-9 ]

CAS No. :89642-49-9
Formula : C7H3BrN2O2
M.W : 227.02
SMILES Code : N#CC1=CC=C(Br)C([N+]([O-])=O)=C1
English Name :4-Bromo-3-nitrobenzonitrile
MDL No. :MFCD00982006
InChI Key :FXRMUJPWDOLCLX-UHFFFAOYSA-N
Pubchem ID :3926861

Safety of [ 89642-49-9 ]

Computational Chemistry of [ 89642-49-9 ] Show Less

Physicochemical Properties

Num. heavy atoms 12
Num. arom. heavy atoms 6
Fraction Csp3 0.0
Num. rotatable bonds 1
Num. H-bond acceptors 3.0
Num. H-bond donors 0.0
Molar Refractivity 47.68
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

69.61 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

1.39
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

2.16
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

2.23
Log Po/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.

1.02
Log Po/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

0.33
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.43

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-2.91
Solubility 0.278 mg/ml ; 0.00122 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.

-3.25
Solubility 0.126 mg/ml ; 0.000557 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

-2.72
Solubility 0.429 mg/ml ; 0.00189 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.

-6.15 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<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)

1.97

Application In Synthesis of [ 89642-49-9 ]

* 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 [ 89642-49-9 ]

[ 89642-49-9 ] Synthesis Path-Downstream   1~10

  • 1
  • [ 110-89-4 ]
  • [ 89642-49-9 ]
  • [ 32117-03-6 ]
YieldReaction ConditionsOperation in experiment
With ethanol; sodium acetate
  • 2
  • [ 623-00-7 ]
  • [ 89642-49-9 ]
YieldReaction ConditionsOperation in experiment
56% With sulfuric acid; nitric acid at 0 - 20℃; for 3h; 1 4-Bromo-3-nitrobenzonitrile To a solution of 4-bromobenzonitrile (4.0 g, 22 mmol) in conc. H2SO4 (10 mL) was added dropwise at 0° C. nitric acid (6 mL). The reaction mixture was stirred at 0° C. for 30 min, and then at room temperature for 2.5 h. The resulting solution was poured into ice-water. The white precipitate was collected via filtration and washed with water until the washings were neutral. The solid was recrystallized from an ethanol/water mixture (1:1, 20 mL) twice to afford 4-bromo-3-nitrobenzonitrile as a white crystalline solid (2.8 g, 56%). 1H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 1H), 8.06 (d, J=8.4 Hz, 1H), 7.99 (d, J=8.4 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ 150.4, 137.4, 136.6, 129.6, 119.6, 117.0, 112.6; HPLC ret. time 1.96 min, 10-100% CH3CN, 5 min gradient; ESI-MS 227.1 Ink (MH+).
With nitric acid
With sulfuric acid; potassium nitrate Eingiessen in Wasser;
With nitric acid In sulfuric acid 1 4-Bromo-3-nitrobenzonitrile Example 1 4-Bromo-3-nitrobenzonitrile To a solution of 4-bromobenzonitrile (4.0 g, 22 mmol) in conc. H2SO4 (10 mL) was added dropwise at 0° C. nitric acid (6 mL). The reaction mixture was stirred at 0° C. for 30 min, and then at room temperature for 2.5 h. The resulting solution was poured into ice-water. The white precipitate was collected via filtration and washed with water until the washings were neutral. The solid was recrystallized from an ethanol/water mixture (1:1, 20 mL) twice to afford 4-bromo-3-nitrobenzonitrile as a white crystalline solid (2.8 g, 56%). 1H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 1H), 8.06 (d, J=8.4 Hz, 1H), 7.99 (d, J=8.4 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ 150.4, 137.4, 136.6, 129.6, 119.6, 117.0, 112.6; HPLC ret. time 1.96 min, 10-100% CH3CN, 5 min gradient; ESI-MS 227.1 m/z (MH+).

  • 3
  • [ 89642-49-9 ]
  • [ 72635-78-0 ]
YieldReaction ConditionsOperation in experiment
84% With iron; ammonium chloride In methanol; water at 60℃; 5.11. General Procedure A: nitroaryl reduction General procedure: The appropriate nitroaryl (1 eq), iron powder (4 eq), and ammoniumchloride (6 eq) were combined in 2:1 methanol/water (0.2 M) andstirred at 60 C for 18-24 h. Once cooled to r.t., the reaction mixture waspassed through a plug of Celite. The filtrate was extracted with DCM (3x)and the combined organic portions were washed with brine (1x), driedover sodium sulfate, filtered, and concentrated in vacuo to afford theproduct. The product was purified by column chromatography ifrequired.
With hydrogenchloride; tin(ll) chloride
With ethanol; tin(ll) chloride Reflux; 10 3-amino-4-bromobenzonitrile (SC9a). 4-Bromo-3 -nitrobenzonitrile (1g, 4.4 mmol) in EtOH (10 ml) was treated with SnCl2(4.17 g, 22 mmol) and heated under reflux for 90 min. The mixture was cooled down, diluted with EtOAc poured to crushed ice, basified with sat. NaHCCE and the thick precipitate was filtered off and washed with EtOAc. The filtrate was washed with brine, dried over MgSO4and evaporated. The crude product was used without further purification. White solid (0.74g, 85%).
With ethanol; tin(ll) chloride Reflux; 10 3-amino-4-bromobenzonitrile (SC9a). 4-Bromo-3 -nitrobenzonitrile (1g, 4.4 mmol) in EtOH (10 ml) was treated with SnCl2(4.17 g, 22 mmol) and heated under reflux for 90 min. The mixture was cooled down, diluted with EtOAc poured to crushed ice, basified with sat. NaHCCE and the thick precipitate was filtered off and washed with EtOAc. The filtrate was washed with brine, dried over MgSO4and evaporated. The crude product was used without further purification. White solid (0.74g, 85%).
> 99 %Spectr. With hydrogen In ethanol at 20℃;

  • 4
  • [ 89642-49-9 ]
  • [ 1066-54-2 ]
  • [ 914106-27-7 ]
YieldReaction ConditionsOperation in experiment
66% With triethylamine at 60℃; for 3h;
66% With copper(l) iodide; triethylamine at 60℃; for 3h; 3; 3.g General Procedure for Silyl Acetylenes (61 b,e,f). Cul (2 mol %) was added to a stirred mixture of an aryl halide 60, (trimethylsilyl)acetylene (min. 1.3 equiv), and PdCl2(PPh3)2 (2 mol %) in triethylamine. See . The mixture was heated at 60 °C until the reaction was complete (ca. 3 h). Salts were filtered off and washed with EtOAc. Combined filtrates were evaporated under reduced pressure, and the residue was purified by column chromatography eluding with hexane/EtOAc. The recovered material was recrystallized as necessary. 3-nitro-4-[2-(trimethylsilyl)ethynyl]benzonitrile (61 b) was prepared from aryl bromide 60b as an off-white solid (1.61 g, 66%): mp 81-82 °C (toluene/hexane); 1H NMR δ 8.69 (d, J = 1.6 Hz, 1H), 8.20 (dd, J = 8.0 and 1.6 Hz, 1H), 7.94 (d, J = 8.2 Hz, 1H), 0.27 (s, 9H); HPLC (Method B) tR 8.39 min (100 area % at 254 nm). Anal. (C12H12N2O2Si) C, H, N. A second general method is depicted in Scheme 2 immediately hereinabove and comprises the cycloaddition of cyanophenylacetylenes 51 and benzaldehyde chlorooximes 52 in the presence of bis(tributyltin) oxide, see Moriya, O., et al., J. Chem. Soc., Perkin Trans., 1, 413-417 (1994); Moriya, O., et al., J. Chem. Soc., Chem. Commun., 17-18 (1991), or triethylamine, see Thomsen, l., et al., Acta Chem. Scand. (B), 319-313 (1988), in nonpolar solvents to give isoxazole dinitriles 53a-h,k-s and bromonitrile 53i. The latter was treated with copper(I) cyanide to give dinitrile 53j. See Friedman. L., et al., J. Org. Chem., 26, 2522-2524 (1961). This method also afforded alternate routes to dinitriles 50a,b,g, k prepared by the first method as provided in Scheme 1. The phenylacetylene synthons 51a-g were prepared as shown in Scheme 3 below. Starting materials 60a,e,g were commercially available. Nitration of 60a gave 60b. See Borsche, W., L., et al., Chem. Ber., 49, 2222-2243 (1916). The latter was reduced to aniline 56, see Blanksma, J. J., et al., Recl. Trav. Chim. Pays-Bas, 66, 365-373 (1947), which underwent diazotization followed by treatment with copper(l) chloride to give chlorobenzene 60c. Triflate 60d was prepared by treatment of 4-bromo-3-hydroxybenzonitrile with triflic anhydride. The preparation of aryl iodide 60f began with the known transformation of aldehyde 57 to iodo derivative 58. See Lulinski, P., et al., Bull. Chem. Soc. Jpn., 73(4), 951-956 (2000). Treatment of 58 with hydroxylamine hydrochloride gave aldoxime 59, which was dehydrated to give nitrile 60f using acetic anhydride. The aryl halides or triflates 60a-g were treated with (trimethylsilyl)acetylene, see Roesch. K. R., et al., J. Org. Chem., 66, 412-420 (2001), or with 2-methyl-3-butyn-2-ol, see Bleicher, L. S., et al., J. Org. Chem., 63, 1109-1118 (1998), to give intermediates 61a-f or 62a-f, respectively, of which 61a,d and 62a have been reported previously. See Dirk. S. M., et al., Tetrahedron, 59(3), 287-293 (2003); Bleicher, L. S., et al., J. Org. Chem., 63, 1109-1118 (1998). The acetylenes 51 (of which 51a,e were known previously), see Blackburn, B. K., et al., J. Med. Chem., 40(5), 717-729 (1997); Dulog, L., et al., Liebigs Ann. Chem., 9, 1663-1671 (1995), were obtained by the treatment of intermediates 61 or 62 with cesium carbonate in acetonitrile or sodium hydride in toluene, respectively. See Bleicher, L. S., et al., J. Org. Chem., 63, 1109-1118 (1998). The use of cesium carbonate in acetonitrile was introduced for the deprotection of intermediates 61 after the treatment of compound 61b with potassium carbonate in methanol, see Blackburn, B. K., et al., J. Med. Chem., 40(5), 717-729 (1997), failed to give product 51b. The pathway using 2-methyl-3-butyn-2-ol provided more economical preparations of all phenylacetylenes 51 except nitro analog 51b. ; Reagents and conditions: (a) fuming HNO3, H2SO4; (b) Fe, AcOH, EtOH; (c) NaNO2, aq. HCl, then CuCl; (d) NalO4, l2, AcOH, AC2O, H2SO4; (e) NH2OH HCl, Py, EtOH (f) Ac2O; (g) TMSA, Pd2Cl2(PPh3)2, Cul, Et3N; (h) TMSA, PPh3, Pd(PPh3)4, Cul, piperidine; (j) 2-methyl-3-butyn-2-ol, Pd2Cl2(PPh3)2, Cul, Et3N; (k) 2-methyl-3-butyn-2-ol, 10% Pd/C, PPh3, Cul, aq. K2CO3/DME; (I) Cs2CO3, aq. CH3CN or MeOH; (m) NaH, toluene.
  • 5
  • [ 89642-49-9 ]
  • [ 914105-97-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 66 percent / Et3N / CuI; PdCl2(PPh3)2 / 3 h / 60 °C 2: 95 percent / aq. Cs2CO3 / acetonitrile / 0.75 h / 0 °C
  • 6
  • [ 89642-49-9 ]
  • [ 914106-07-3 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 66 percent / Et3N / CuI; PdCl2(PPh3)2 / 3 h / 60 °C 2: 95 percent / aq. Cs2CO3 / acetonitrile / 0.75 h / 0 °C 3: 67 percent / bis(tributyltin) oxide / CH2Cl2
  • 7
  • [ 89642-49-9 ]
  • [ 914106-13-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 66 percent / Et3N / CuI; PdCl2(PPh3)2 / 3 h / 60 °C 2: 95 percent / aq. Cs2CO3 / acetonitrile / 0.75 h / 0 °C 3: 83 percent / bis(tributyltin) oxide / benzene
  • 8
  • [ 89642-49-9 ]
  • [ 914104-45-3 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: 66 percent / Et3N / CuI; PdCl2(PPh3)2 / 3 h / 60 °C 2.1: 95 percent / aq. Cs2CO3 / acetonitrile / 0.75 h / 0 °C 3.1: 67 percent / bis(tributyltin) oxide / CH2Cl2 4.1: HCl / ethanol; dioxane / 0 - 20 °C 4.2: 32 percent / NH3 / ethanol
  • 9
  • [ 89642-49-9 ]
  • [ 914104-64-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: 66 percent / Et3N / CuI; PdCl2(PPh3)2 / 3 h / 60 °C 2.1: 95 percent / aq. Cs2CO3 / acetonitrile / 0.75 h / 0 °C 3.1: 83 percent / bis(tributyltin) oxide / benzene 4.1: HCl / ethanol; dioxane / 0 - 20 °C 4.2: 21 percent / NH3 / ethanol
  • 10
  • [ 89642-49-9 ]
  • [ 109-76-2 ]
  • [ 848589-41-3 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 4-bromo-3-nitrobenzonitrile; Trimethylenediamine Stage #2: With hydrogenchloride In ethanol 2 [0126] N i-(4-cyano-2-nitro-phenyl)-propane-l ,3-diamine monohydrochloride. mp >230°C;FTIR (KBr) cm"1: 3364.13, 2929.80, 2222.94, 1625.89, 1561.22, 1524.98, 1410.25, 1364.46, 1261.01, 1176.10, 921.75, 819.69; 1H NMR (D2O, 4.79) δ: 8.58 (IH, d, J=I.54Hz, 3-Ar-H), 7.73 (IH, dd, J=1.70, 9.13Hz, 5-Ar-H), 7.12 (IH, d, J=9.15Hz, 6-Ar-H), 3.58 (2H, t, J=6.91Hz, 3- CH2), 3.13 (2H, t, J=8.01Hz, 1-CH2), 2.08 (2H, m, 2-CH2); 13C NMR (DMSO-d6) δ: 146.68, 137.58, 131.90, 131.01, 118.22, 115.90, 96.29, 36.06, 29.78, 25.77; HRMS(CI) calculated for C10H12N4O2: (M+l) 221.1039, found 221.1040.
 

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