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Structure of 327-51-5

Chemical Structure| 327-51-5

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Product Details of [ 327-51-5 ]

CAS No. :327-51-5
Formula : C6H2Br2F2
M.W : 271.88
SMILES Code : C1=C(Br)C(=CC(=C1F)Br)F
MDL No. :MFCD00000346
InChI Key :GLVMLJCMUBZVTJ-UHFFFAOYSA-N
Pubchem ID :67596

Safety of [ 327-51-5 ]

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

Computational Chemistry of [ 327-51-5 ] Show Less

Physicochemical Properties

Num. heavy atoms 10
Num. arom. heavy atoms 6
Fraction Csp3 0.0
Num. rotatable bonds 0
Num. H-bond acceptors 2.0
Num. H-bond donors 0.0
Molar Refractivity 41.76
TPSA ?

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

0.0 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.37
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

3.5
Log Po/w (WLOGP)?

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

4.33
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.

4.63
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

4.05
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

3.78

Water Solubility

Log S (ESOL):?

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

-4.17
Solubility 0.0182 mg/ml ; 0.0000669 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Moderately soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-3.18
Solubility 0.178 mg/ml ; 0.000656 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

-4.66
Solubility 0.00595 mg/ml ; 0.0000219 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Moderately soluble

Pharmacokinetics

GI absorption?

Gatrointestinal absorption: according to the white of the BOILED-Egg

Low
BBB permeant?

BBB permeation: according to the yolk of the BOILED-Egg

No
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

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.

-5.47 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

1.0
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

1.0
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)

1.68

Application In Synthesis of [ 327-51-5 ]

* 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 [ 327-51-5 ]

[ 327-51-5 ] Synthesis Path-Downstream   1~4

  • 1
  • [ 109-72-8 ]
  • [ 327-51-5 ]
  • [ 357405-75-5 ]
YieldReaction ConditionsOperation in experiment
In diethyl ether; a 4-Bromo-2,5-difluorobenzaldehyde n-Butyllithium (1.95M in hexanes, 10.2 ml)) was added dropwise to a stirred solution of 1,4-dibromo-2,5-difluorobenzene (5 g, 18.4 mmol) in diethyl ether (60 ml) at -70° C. After 1 h, the solution was warmed to 0° C. over 1 h, diluted with water, the layers separated and the ether layer dried over sodium sulphate and evaporated. Purification by column chromatography (Biotage), eluding with 5percent ethyl acetate/hexane, gave a yellow oil (1.82 g). 1H NMR 300 MHz (CDCl3) 10.28 (1H, s), 7.61 (1H, dd), 7.48 (1H, dd).
  • 2
  • [ 327-51-5 ]
  • [ 357405-75-5 ]
YieldReaction ConditionsOperation in experiment
74% With ammonium chloride; In tetrahydrofuran; N,N-dimethyl-formamide; Method 6 4-Bromo-2,5-difluorobenzaldehyde To 1,4-dibromo-2,5-difluorobenzene (10.28 g, 37.81 mmol) in tetrahydrofuran (80 mL) at -40° C. was isopropylmagnesium chloride lithium chloride complex (29.1 mL, 37.81 mmol) added dropwise. After 1 h at -40° C. was N,N-dimethylformamide (58 mL, 756 mmol) added and the mixture was stirred for 30 minutes at -40° C. NH4Cl (2M, aq, 100 mL) was added and the mixture was extracted with ethyl acetate. The organic phase was dried with MgSO4 and concentrated to give 4-bromo-2,5-difluorobenzaldehyde (6.20 g, 74percent) as a solid. 1H NMR (500 MHz, CHLOROFORM-d) delta ppm 10.28 (d, 1H) 7.61 (dd, 1H) 7.48 (dd, 1 H).
  • 3
  • [ 327-51-5 ]
  • [ 68-12-2 ]
  • [ 357405-75-5 ]
YieldReaction ConditionsOperation in experiment
86% Example 31 Preparation of 4-bromo-2,5-difluorobenzaldehyde [0289] 2,5-dibromo-1,4-difluorobenzene (10.0 g, 36.77 mmol) in diethyl ether (150 mL) at -78 C. was added n-butyl lithium (2.5 M in Hexanes, 14.86 mL, 37.15 mmol) dropwise under nitrogen. The reaction mixture was stirred at -78 C. for 30 min. Dry DMF (3.13 mL, 40.46 mmol) in diethyl ether (10 mL) was added dropwise and reaction was slowly warmed to room temperature over 2 h. The reaction was quenched with aqueous saturated ammonium chloride solution (25 mL) and extracted with diethyl ether. The organic phase was washed with saturated brine solution, dried (Na2SO4), filtered, and concentrated under reduced pressure (Note: Product is highly volatile). The crude product was purified by flash chromatography (SiO2, eluting with 2-20% ethyl acetate in hexanes) to provide the title compound as a pale yellow solid (7.0 g, 86%): 1H NMR (400 MHz, CDCl3): delta 7.50 (dd, J=5.08, 8.92 Hz, 1H), 7.62 (dd, J=5.80, 7.68 Hz, 1H), 10.30 (d, J=2.76 Hz, 1H).
66.7% To a stirred solution of XXXII-1 (12 g, 44.1 mmol) in THF (150 mL) was added dropwise of XXXII-1A (44.1 mmol, 34 mL, 1.3 M) at -40 C. After stirred 1 h at -40 C., DMF (64 g, 882 mmol) was added and the mixture was stirred overnight. NH4Cl (aq., 2M) was added and the mixture was extracted with EtOAc. The organic phase was dried with Na2SO4. The solvent was removed in vacuo and the residue was purified by column chromatography (PE/EA=10/1) to afford XXXII-2 (6.5 g, yield: 66.7%).
55.8% To a solution of l,4-dibromo-2,5-difluorobenzene (15 g, 55 mmol) in toluene (600 mL) cooled to -78 C was added butyllithium (22 mL, 55 mmol) and the reaction was kept at -78 C for 30 minutes. N,N-dimethylformamide (4.4 g, 61 mmol) was added and the reaction was stirred for 2 hours while warming to ambient temperature. To the reaction was added water (200 mL) and EtOAc (400 mL) and the organic layers were separated. The organic layer was washed with brine (200 mL), dried over MgS04, filtered and concentrated in vacuo. The crude material was chromatographed eluting with 5% EtOAc/Hexane to yield 4-bromo-2,5-difluorobenzaldehyde (6.7 g, 55.8%).
37% n-Butyl lithium (3.6 ml,7.7 mmol) was added drop wise to a solution of 1,4- dibromo-2,5-difluoro-benzene (2g, 7.35mmol) in dry ether at -78C under nitrogen atmosphere and the resulting mixture was stirred at -78C for 30 minutes. This was followed by the addition of DMF (0.85ml, 11.03mmol) in dry THF. The resultant was stirred at room temperature for 1 hour. The reaction was monitored by TLC (5% ethyl acetate in hexane). The reaction mixture was partitioned between ethyl acetate and saturated ammonium chloride. The organic layer was concentrated and purified by column chromatography on silica gel (2% ethyl acetate in hexane) to afford 600mg of the product (37% yield).1H NM (CDC13, 300 MHZ): delta 10.27-10.26 (d, 1H), 7.61-7.57 (t, 1H), 7.49- 7.44 (q, 1H)
To a Et2O solution (200 mL) containing 1,4-dibromo-2,5-difluorobenzene (19.72 g, 72.5 mmol) cooled to -78 degrees C. was added 30.5 mL of a 2.5 M hexanes solution of n-BuLi (76.2 mmol). The resulting green solution was stirred for 20 min at -78 degrees C. when DMF (7.95 g, 10.8 mmol) was added. The reaction was stirred for 30 min and then quenched with H2O. The organics were taken up in EtOAc and washed with sat. NaHSO4 followed by drying over MgSO4. The solvent was removed in vacuo and the residual oil purified on the Biotage (2-5% EtOAc/hexanes) yielding 11.4 g (51.7 mmol) of 4-bromo-2,5-difluorobenzaldehyde. 1H NMR (400 MHz, CDCl3) delta 10.2 (s, 1H), 7.57 (m, 1H), 7.45 (m, 1H) ppm.

  • 4
  • [ 327-51-5 ]
  • [ 392338-15-7 ]
  • tert-butyl (R)-(1-(4-bromo-2,5-difluorophenyl)pyrrolidin-3-yl)(methyl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
46% With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 80℃; for 4h;Inert atmosphere; (1019) (1020) intermediate 31-1 (1021) [00354] Into a 100-mL round-bottom flask that purged and maintained under an inert atmosphere of nitrogen was added 4-bromo-2-chloro-l-iodobenzene (1.20 g, 3.78 mmol), benzyl piperazine-l -carboxylate (0.924 g, 4, 19 mmol), NaOtBu (1.10 g, 1 1.4 mmol), XantPhos (0.695 g, 1.20 mmol), Pd2(dba)3 (0.393 g, 0.430 mmol), and toluene (10 mL). The reaction mixture was stirred for 4 h at 60 C and then concentrated in vacuo to provide a crude product that was purified by FCC eluting with ethyl acetate/petroleum ether (1 : 10) to afford benzyl 4-(4-bromo-2- chlorophenyl)piperazine-l -carboxylate as a colorless oil (713 mg, 46%). LCMS (ESI, m/z) 409, 41 1 [ M 1 [ j .
 

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