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Chemical Structure| 1000994-95-5 Chemical Structure| 1000994-95-5

Structure of 1000994-95-5

Chemical Structure| 1000994-95-5

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Product Details of [ 1000994-95-5 ]

CAS No. :1000994-95-5
Formula : C8H7BrF2
M.W : 221.04
SMILES Code : CC(F)(F)C1=CC=C(Br)C=C1
MDL No. :MFCD11110333
InChI Key :QXIBKCFAFRHORF-UHFFFAOYSA-N
Pubchem ID :45158847

Safety of [ 1000994-95-5 ]

GHS Pictogram:
Signal Word:Danger
Hazard Statements:H227-H301-H315-H319
Precautionary Statements:P210-P280-P301+P310-P305+P351+P338
Class:6.1
UN#:2810
Packing Group:

Computational Chemistry of [ 1000994-95-5 ] Show Less

Physicochemical Properties

Num. heavy atoms 11
Num. arom. heavy atoms 6
Fraction Csp3 0.25
Num. rotatable bonds 1
Num. H-bond acceptors 2.0
Num. H-bond donors 0.0
Molar Refractivity 43.9
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.

2.38
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

3.69
Log Po/w (WLOGP)?

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

4.29
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.

4.25
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

3.54
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

3.63

Water Solubility

Log S (ESOL):?

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

-3.87
Solubility 0.0296 mg/ml ; 0.000134 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.

-3.38
Solubility 0.0921 mg/ml ; 0.000417 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

-4.25
Solubility 0.0124 mg/ml ; 0.0000561 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

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

Yes
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.

-5.03 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

0.0 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<2.0
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)

1.27

Application In Synthesis of [ 1000994-95-5 ]

* 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 [ 1000994-95-5 ]

[ 1000994-95-5 ] Synthesis Path-Upstream   1~2

  • 1
  • [ 99-90-1 ]
  • [ 1000994-95-5 ]
YieldReaction ConditionsOperation in experiment
77% With diethylamino-sulfur trifluoride In dichloromethane at 50℃; Inert atmosphere Example 63A1-Bromo-4-(1,1-difluoroethyl)benzene; Under argon, 3.0 g (15.07 mmol) of 1-(4-bromophenyl)ethanone were initially charged in 30 ml of dichloromethane, and 15.9 ml (120.57 mmol) of [ethyl(trifluoro-λ4-sulphanyl)amino]ethane (DAST) were added slowly. The reaction solution was then slowly warmed to 50° C. and stirred at this temperature overnight. After the reaction had ended, the reaction solution was slowly poured into ice-water. The organic phase was then separated off, and the aqueous phase was extracted three more times with dichloromethane. The combined organic phases were dried over magnesium sulphate. After filtration, the solvent was removed under reduced pressure. The crude product was purified chromatographically on silica gel (mobile phase petroleum ether/dichloromethane 4:1). This gave 2.56 g (11.58 mmol, 77percent of theory) of the title compound as a yellowish liquid.GC-MS (Method 1): Rt=2.84 min; m/z=220/222 (M)+.
76% With (bis-(2-methoxyethyl)amino)sulfur trufluoride In tetrahydrofuran; methanol for 96 h; Reflux Example 48A
1-Bromo-4-(1,1-difluoroethyl)benzene
A solution of 10.0 g (50.2 mmol) of 4-bromoacetophenone in tetrahydrofuran (20 ml) was admixed with 50.0 ml (151 mmol, 50percent in tetrahydrofuran) of bis(2-methoxyethyl)aminosulphur trifluoride (Deoxofluor) and 3 drops of methanol, and then stirred under reflux for 4 days.
The reaction mixture was cautiously added dropwise to a mixture of saturated aqueous sodium hydrogencarbonate solution and ice (1:1) and then extracted with diethyl ether.
The organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure.
The residue was purified by means of column chromatography (silica gel, petroleum ether/dichloromethane 3:1). Yield: 8.46 g (76percent of theory)
1H NMR (400 MHz, DMSO-d6): δ=7.70 (d, 2H), 7.52 (d, 2H), 1.96 (t, 3H).
76% With methanol; (bis-(2-methoxyethyl)amino)sulfur trufluoride In tetrahydrofuran for 96 h; Reflux Example 68A1-Bromo-4-(1,1-difluoroethyl)benzene A solution of 10.0 g (50.2 mmol) of 4-bromoacetophenone in tetrahydrofuran (20 ml) was admixed with 50.0 ml (151 mmol, 50percent in tetrahydrofuran) of bis(2-methoxyethyl)aminosulphur trifluoride (Deoxofluor) and 3 drops of methanol, and then stirred under reflux for four days. The reaction mixture was cautiously added dropwise to a mixture of saturated aqueous sodium hydrogencarbonate solution and ice (1:1) and then extracted with diethyl ether. The organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by means of column chromatography (silica gel, petroleum ether/dichloromethane 3:1). Yield: 8.46 g (76percent of theory)1H NMR (400 MHz, DMSO-d6): δ=7.70 (d, 2H), 7.52 (d, 2H), 1.96 (t, 3H).
59% at 85℃; for 15 h; Deoxo-Fluor (registered trademark) (22.2 g) was added to 1-(4-bromophenyl)ethanone (20.0 g) and the mixturewas stirred at 85°C for 15 hours. Under icecooling, ice water and an aqueous solution of potassium carbonate wereadded to the reaction solution, followed by extraction with chloroform. The solvent was evaporated under reducedpressure and the obtained residue was purified by silica gel column chromatography (hexane) to give the title compound(13.0 g, yield 59percent) as a yellow oil.1H NMR (600 MHz, CDCl3) δ ppm 1.91 (t, J=18.2 Hz, 3H), 7.50 (d, J=8.3 Hz, 2H), 7.86 (d, J=8.3 Hz, 2H).
25% With (bis-(2-methoxyethyl)amino)sulfur trufluoride In dichloromethane; toluene at 20 - 85℃; for 20 h; Ionic liquid; Sealed tube Step A: Preparation of l-bromo-4-(l,l-difluoroethyl)benzene. [00211] To a vial equipped with a magnetic stir bar were added a solution of l-(4- bromophenyl)ethanone (295 mg, 1.48 mmol) in anhydrous DCM (3.0 mL) followed by a 50percent solution of Deoxofluor® in toluene (1.6 mL, 4.45 mmol) at room temperature under N2 and the vial was sealed. The reaction mixture was stirred for approximately 15 h at room temperature, but little conversion had taken place. The mixture was concentrated, treated with additional Deoxofluor® solution (0.66 mL, 1.79 mmol),and warmed to and stirred at 85 °C under N2 for 5 h. The reaction mixture was cooled to 0 °C and carefully quenched by adding sat'd aq NaHC03 dropwise until gas evolution ceased. The bi-phasic mixture was extracted with DCM (2 x 5 mL), and the combined extracts were dried over Na2S04, filtered, and concentrated. The residue was purified by column chromatography (Si02, 0-^50 EtOAc in hexanes) to afford the title compound (83 mg, 25percent)as a clear liquid: 1H NMR (400 MHz, CDC13) δ 7.58 - 7.53 (m, 2H), 7.41 - 7.35 (m, 2H), 1.90 (t, J = 18.1 Hz, 3H); 19F NMR (376 MHz, CDC13) δ -87.86; IR (Thin Film) 1599, 1294, 1089 cm"1; EIMS mlz 220/221.
17.26 g With (bis-(2-methoxyethyl)amino)sulfur trufluoride In chloroform at 50℃; for 35 h; Inert atmosphere Under argon atmosphere, into a 500-ml reaction vessel made of tetrafluoroethylene-perfluoroalkyl vinyl ether copolymer (PFA) and equipped with a stirring apparatus were placed 25 g (126 mmol) of 4-bromoacetophenone, 111 g (500 mmol) of bis(2-methoxyethyl)aminosulfur trifluoride, and 250 ml of anhydrous chloroform, so that a homogeneous solution was prepared. And then, the solution was reacted at an internal temperature of about 50°C for 35 hours. Subsequently, the reaction solution was cooled to room temperature, and then the reaction solution was added to 1000 ml of a saturated aqueous solution of sodium hydrogen carbonate, which was cooled in ice. Subsequently, the mixture was subjected to extraction with 500 ml of chloroform. The solvent was distilled off under a reduced pressure, and then the reaction mixture was purified by silica gel column chromatography (hexane: 100 vol percent), to provide 17.26 g of Compound (4-1) in the form of a colorless liquid. [0134] The properties of Compound (4-1) were as follows. 1H-NMR (400MHz, CDCl3, 8 (ppm)); 1.90 (3H, t, J=18.1Hz), 7.54 (2H, d, J=2.3Hz), 7.57 (2H, d, J=2.4Hz) CI-MS; 222 (M+2)
17.26 g With (bis-(2-methoxyethyl)amino)sulfur trufluoride In chloroform at 50℃; for 35 h; Inert atmosphere Under argon atmosphere, into a 500-ml reaction vessel 30 made of tetrafluoroethylene-perfluoroalkyl vinyl ether copolymer (PFA) and equipped with a stirring apparatus were placed 25 g (126 mmol) of 4-bromoacetophenone, 111 g (500 mmol) of bis(2-methoxyethyl)aminosulthr trifluoride, and 250 ml of anhydrous chloroform, so that a homogeneous solution was prepared. And then, the solution was reacted at an internal temperature of about 50° C. for 35 hours. Subsequently, the reaction solution was cooled to room temperature, and then the reaction solution was added to 1000 ml of a saturated aqueous solution of sodium hydrogen carbonate, which was cooled in ice. Subsequently, the mixture was subjected to extraction with 500 ml of chloroform. The solvent was distilled off under a reduced pressure, and then the reaction mixture was purified by silica gel column chromatography (hexane: 100 vol percent), to provide 17.26 g of Compound (4-1) in the form of a colorless liquid.The properties of Compound (4-1) were as follows. ‘H-NMR (400 MHz, CDC13, ö (ppm)); 1.90 (3H, t, J=18. 1 Hz), 7.54 (2H, d, J=2.3 Hz), 7.57 (2H, d, J=2.4 Hz)CI-MS; 222 (M+2)4045

References: [1] Patent: US2012/172448, 2012, A1, . Location in patent: Page/Page column 34.
[2] Patent: US2010/305111, 2010, A1, . Location in patent: Page/Page column 26.
[3] Patent: US2011/21489, 2011, A1, . Location in patent: Page/Page column 34-35.
[4] Patent: EP2921489, 2015, A1, . Location in patent: Paragraph 0110; 0111.
[5] Patent: WO2015/160665, 2015, A1, . Location in patent: Paragraph 00211.
[6] Patent: EP2829542, 2015, A1, . Location in patent: Paragraph 0133; 0134.
[7] Patent: US9290516, 2016, B2, . Location in patent: Page/Page column 41.
  • 2
  • [ 139139-81-4 ]
  • [ 115134-88-8 ]
  • [ 1000994-95-5 ]
References: [1] Chemistry - An Asian Journal, 2016, vol. 11, # 12, p. 1789 - 1792.
 

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