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Chemical Structure| 887268-22-6 Chemical Structure| 887268-22-6

Structure of 887268-22-6

Chemical Structure| 887268-22-6

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Product Details of [ 887268-22-6 ]

CAS No. :887268-22-6
Formula : C8H8BrFO
M.W : 219.05
SMILES Code : COCC1=CC=C(F)C(Br)=C1
English Name :2-Bromo-1-fluoro-4-(methoxymethyl)benzene
MDL No. :MFCD04116324
InChI Key :QBVRUQXKXJMOGC-UHFFFAOYSA-N
Pubchem ID :2769416

Safety of [ 887268-22-6 ]

Computational Chemistry of [ 887268-22-6 ] Show Less

Physicochemical Properties

Num. heavy atoms 11
Num. arom. heavy atoms 6
Fraction Csp3 0.25
Num. rotatable bonds 2
Num. H-bond acceptors 2.0
Num. H-bond donors 0.0
Molar Refractivity 44.96
TPSA ?

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

9.23 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.45
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

2.36
Log Po/w (WLOGP)?

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

3.0
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.

3.03
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

3.24
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.82

Water Solubility

Log S (ESOL):?

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

-2.96
Solubility 0.242 mg/ml ; 0.00111 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.

-2.19
Solubility 1.4 mg/ml ; 0.0064 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

-4.07
Solubility 0.0187 mg/ml ; 0.0000855 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

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.

-5.96 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

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<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)

1.65

Application In Synthesis of [ 887268-22-6 ]

* 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.

  • Downstream synthetic route of [ 887268-22-6 ]

[ 887268-22-6 ] Synthesis Path-Downstream   1~9

  • 1
  • [ 77771-03-0 ]
  • [ 74-88-4 ]
  • [ 887268-22-6 ]
YieldReaction ConditionsOperation in experiment
84% Stage #1: 3-bromo-4-fluoro-benzyl alcohol With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Stage #2: methyl iodide In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 1h; 228.1 Step 1. Preparation of 2-bromo-1-fluoro-4-(methoxymethyl)benzene To a solution of (3-bromo-4-fluorophenyl)methanol (5.00 g, 24.4 mmol) in N,N-anhydrous N,N-dimethylformamide (50 mL) was added a 60% suspension of sodium hydride in mineral oil (1.37 g, 34.2 mmol) in portions at 0° C., and the mixture was stirred at 0° C. for 30 minutes. To it was then added iodomethane (4.15 g, 29.3 mmol) at 0° C. The mixture was allowed to warm to ambient temperature and stirred for 1 h. The reaction was quenched by addition of water (200 mL) and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with 2 to 5% of ethyl acetate in petroleum ether, afforded the title compound as a colorless oil (4.50 g, 84% yield): 1H NMR (400 MHz, CDCl3) δ7.57 (dd, J=6.4, 2.0 Hz, 1H), 7.28-7.23 (m, 1H), 7.11 (t, J=8.0 Hz, 1H), 4.42 (s, 2H), 3.41 (s, 3H).
With sodium hydride In tetrahydrofuran at 0℃; for 3h; 33.2 Step 2: Cool a solution of the product of Step 1 (1.20 g, 5.9 mmol) in THF (50 ml) in ice and add NaH (60% in oil, 0.33 g, 8.2 mmol), then CH3I (1.00 ml, 7.1 mmol). Stir 3 h and partition between ether and water. Dry (MgSO4) and concentrate to obtain the crude methyl ether as a yellow oil.
With sodium hydride In tetrahydrofuran for 3h; 22.2 Cool a solution of the product of Step 1 (1.20 g, 5.9 mmol) in THF (50 ml) in ice and add NaH (60% in oil, 0.33 g, 8.2 mmol), then CH3l (1.00 ml, 7.1 mmol). Stir 3 h and partition between ether and water. Dry (MgSO4) and concentrate to obtain the crude methyl ether as a yellow oil.
  • 2
  • [ 67-56-1 ]
  • [ 866862-23-9 ]
  • [ 887268-22-6 ]
YieldReaction ConditionsOperation in experiment
51% With 2,6-dimethylpyridine at 20℃; for 88h;
With 2,6-dimethylpyridine at 20℃; for 88h; 15 A solution of 3-bromo-4-fluorobenzyl methanesulfonate (Intermediate 14, 330 mg; 1.17 mmol) and 2,6-lutidine (176 μl 1.52 mmol) in methanol (4 ml.) was stirred for 16 hours at RT. Additional aliquots of 2,6-lutidine (176 μl 1.52 mmol each) were added once a day for a total of three days, during which stirring was continued at RT. The mixture was taken up in Et2O, washed with water, HCI (0.1 N in water) and brine. The organic phase was dried over MgSO4, filtered and concentrated with moderate vacuum and without heating affording the title compound as a pale yellow liquid. 1H NMR (300MHz, DMSO-d6) δ [ppm] 7.66 (1 H, d, J= 7.3 Hz), 7.38 (2H, m), 4.41 (2H, s), 3.30 (3H, s).
  • 4
  • [ 887268-22-6 ]
  • [ 2230144-43-9 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1.1: n-butyllithium / diethyl ether; tetrahydrofuran / 0.5 h / -78 °C 1.2: 1 h / -78 - 20 °C 2.1: caesium carbonate / dichloromethane / 12 h / 20 °C 3.1: dichloromethane; diethyl ether / 1 h / -50 - 20 °C 4.1: hydrogenchloride / methanol / 2 h / 20 °C 5.1: caesium carbonate / dimethyl sulfoxide / 12 h / 20 °C 6.1: hydrogenchloride / ethyl acetate / 1 h / 20 °C
  • 5
  • [ 887268-22-6 ]
  • [ 2230147-88-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: n-butyllithium / diethyl ether; tetrahydrofuran / 0.5 h / -78 °C 1.2: 1 h / -78 - 20 °C 2.1: caesium carbonate / dichloromethane / 12 h / 20 °C 3.1: dichloromethane; diethyl ether / 1 h / -50 - 20 °C 4.1: hydrogenchloride / methanol / 2 h / 20 °C
  • 6
  • [ 887268-22-6 ]
  • [ 2230147-85-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: n-butyllithium / diethyl ether; tetrahydrofuran / 0.5 h / -78 °C 1.2: 1 h / -78 - 20 °C 2.1: caesium carbonate / dichloromethane / 12 h / 20 °C
  • 7
  • [ 887268-22-6 ]
  • [ 2230147-86-9 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: n-butyllithium / diethyl ether; tetrahydrofuran / 0.5 h / -78 °C 1.2: 1 h / -78 - 20 °C 2.1: caesium carbonate / dichloromethane / 12 h / 20 °C 3.1: dichloromethane; diethyl ether / 1 h / -50 - 20 °C
  • 8
  • [ 887268-22-6 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: n-butyllithium / diethyl ether; tetrahydrofuran / 0.5 h / -78 °C 1.2: 1 h / -78 - 20 °C 2.1: caesium carbonate / dichloromethane / 12 h / 20 °C 3.1: dichloromethane; diethyl ether / 1 h / -50 - 20 °C 4.1: hydrogenchloride / methanol / 2 h / 20 °C 5.1: caesium carbonate / dimethyl sulfoxide / 12 h / 20 °C
  • 9
  • [ 887268-22-6 ]
  • [ 68-12-2 ]
  • [ 1896344-14-1 ]
YieldReaction ConditionsOperation in experiment
66% Stage #1: 2-bromo-1-fluoro-4-(methoxymethyl)benzene With n-butyllithium In tetrahydrofuran; diethyl ether at -78℃; for 0.5h; Stage #2: N,N-dimethyl-formamide In tetrahydrofuran; diethyl ether at -78 - 20℃; for 1h; 228.2 Step 2. Preparation of 2-fluoro-5-(methoxymethyl)benzaldehyde To a solution of 2-bromo-1-fluoro-4-(methoxymethyl)benzene (4.50 g, 20.54 mmol) in anhydrous tetrahydrofuran (50 mL) was added a 2.5 M solution of n-butyllithium in diethyl ether (9.86 mL, 3.94 mmol) -78° C. The reaction mixture was stirred for 30 minutes -78° C., and then anhydrous N,N-dimethylformamide (3.00 g, 41.09 mmol) was added to it. The reaction mixture was allowed to warm to ambient temperature and stirred for 1 h, and then quenched with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with 2 to 10% of ethyl acetate in petroleum ether, afforded the title compound as a colorless oil (2.30 g, 66% yield): 1H NMR (400 MHz, CDCl3) δ10.30 (s, 1H), 7.76 (dd, J=6.4, 2.0 Hz, 1H), 7.59-7.50 (m, 1H), 7.10 (dd, J=10.0, 8.4 Hz, 1H), 4.39 (s, 2H), 3.33 (s, 3H); MS (ES+) m/z 169.1 (M+1)
 

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