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Chemical Structure| 1250444-23-5 Chemical Structure| 1250444-23-5
Chemical Structure| 1250444-23-5

3-Bromo-2,6-difluorobenzonitrile

CAS No.: 1250444-23-5

4.5 *For Research Use Only !

Cat. No.: A116978 Purity: 97%

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Product Details of [ 1250444-23-5 ]

CAS No. :1250444-23-5
Formula : C7H2BrF2N
M.W : 218.00
SMILES Code : N#CC1=C(F)C=CC(Br)=C1F
MDL No. :MFCD16987589
InChI Key :IORVOBJVFPHSKR-UHFFFAOYSA-N
Pubchem ID :56604707

Safety of [ 1250444-23-5 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302
Precautionary Statements:P280-P305+P351+P338

Calculated chemistry of [ 1250444-23-5 ] Show Less

Physicochemical Properties

Num. heavy atoms 11
Num. arom. heavy atoms 6
Fraction Csp3 0.0
Num. rotatable bonds 0
Num. H-bond acceptors 3.0
Num. H-bond donors 0.0
Molar Refractivity 38.77
TPSA ?

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

23.79 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.84
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

2.53
Log Po/w (WLOGP)?

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

3.44
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.

3.05
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

3.32
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.84

Water Solubility

Log S (ESOL):?

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

-3.19
Solubility 0.141 mg/ml ; 0.000647 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.

-2.68
Solubility 0.459 mg/ml ; 0.00211 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

-3.9
Solubility 0.0274 mg/ml ; 0.000126 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

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.

-5.83 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

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<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)

1.9

Application In Synthesis of [ 1250444-23-5 ]

* 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.

  • Upstream synthesis route of [ 1250444-23-5 ]

[ 1250444-23-5 ] Synthesis Path-Upstream   1~2

  • 1
  • [ 1897-52-5 ]
  • [ 1250444-23-5 ]
YieldReaction ConditionsOperation in experiment
71% at 35℃; Inert atmosphere 2 L four-necked flask, 600mL60percent sulfuric acid was added, with stirring was added 2,6-difluorobenzonitrile 139.0g (1.0mol), in N2Under protection, control of the reaction temperature below 35°C, points added 250.5g of KBrO3 10 portions(1.5mol), TLC monitoring, the reaction 5-6 days, until starting material disappeared point, the reaction was stopped, the ice preparation 800mL20percent saline solution, the reaction mixture was poured into iced brine.After settlement products, quickly suction filtration to give a crude orange product with CCl4The crude product was dissolved, respectively, with 5percent NaHSO3Solution, saturated Na2CO3Solution was washed with water until the solution was neutral, dried over anhydrous sodium sulfate, the solution was filtered, 60 water bath rotary evaporation to give a pale yellow liquid was cooled to a standstill for some time as a pale yellow solid, distillation under reduced pressure, condensed steam heated, oil bath was raised to 90 deg.] C, taking the temperature of 58-62°C steam fraction, and cooled to obtain a white solid product, 71percent yield.
71% at 35℃; Inert atmosphere Take 2 L four bottles, add 600 mL of 60percent sulfuric acid, electric stirring by adding 2,6_ difluorobenzonitrile 139.0 g (1.0 mol). Under N2 protection, the control reaction temperature was below 35 ° C, and 250 μm g of KBr03 (1.5 mol) was added to 10 batches. TLC monitoring, reaction 5-6 days, until the raw material point disappears, stop the reaction, the preparation of 800 mL 20percent ice salt solution, the reaction solution Into the ice salt. After the product settling, the rapid filtration, the orange crude products, with CC14 dissolved crude products, respectively, with 5percent Of NaHS03 solution, saturated Na2C03 solution and water to the solution was neutral, dried over anhydrous sodium sulfate, the solution was filtered, the water bath 60 ° C steamed to obtain light yellow liquid, rest for some time to cool into a pale yellow solid, vacuum distillation, warm water condensing steam, oil The bath was heated to 90 ° C and the fraction at a steam temperature of 58-62 ° C was cooled to give a white solid product in 71percent yield
References: [1] Patent: CN104004016, 2016, B, . Location in patent: Paragraph 0043; 0044; 0045.
[2] Patent: CN104017021, 2016, B, . Location in patent: Paragraph 0030-0034.
[3] Patent: WO2013/39802, 2013, A1, . Location in patent: Page/Page column 37; 38.
[4] Patent: EP2755656, 2016, B1, . Location in patent: Paragraph 0118; 0119.
  • 2
  • [ 1897-52-5 ]
  • [ 1250444-23-5 ]
YieldReaction ConditionsOperation in experiment
70% at 0 - 20℃; for 24 h; A solution of 2,6- difluorobenzonitrile (5.0 g, 36 mmol) in concentrated sulfuric acid (25 mL) was treated with NBS (7.0 g, 29.5 mmol) at 0 °C and stirred at ambient temperature for 24 hours. Ice (about 100 g) was added to the reaction mixture. After melting, the mixture was extracted with MTBE (100 mL). The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 5: 1 to 1 :2 hexanes/ethyl acetate to give both 3- bromo-2,6-difluorobenzonitrile (5.5 g, 70percent yield) as solid and 3-bromo-2,6- difluorobenzamide (2.1 g, 25percent) as solid.
References: [1] Patent: WO2015/35223, 2015, A1, . Location in patent: Paragraph 0774.
 

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