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Chemical Structure| 885588-12-5 Chemical Structure| 885588-12-5

Structure of 885588-12-5

Chemical Structure| 885588-12-5

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Product Details of [ 885588-12-5 ]

CAS No. :885588-12-5
Formula : C6H3BrFNO2
M.W : 220.00
SMILES Code : OC(=O)C1=CC(Br)=NC=C1F
MDL No. :MFCD09261246
InChI Key :VRHKBNFQGHNLIJ-UHFFFAOYSA-N
Pubchem ID :46739277

Safety of [ 885588-12-5 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Computational Chemistry of [ 885588-12-5 ] Show Less

Physicochemical Properties

Num. heavy atoms 11
Num. arom. heavy atoms 6
Fraction Csp3 0.0
Num. rotatable bonds 1
Num. H-bond acceptors 4.0
Num. H-bond donors 1.0
Molar Refractivity 38.85
TPSA ?

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

50.19 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.17
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

1.5
Log Po/w (WLOGP)?

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

2.1
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.

0.09
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

1.86
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.34

Water Solubility

Log S (ESOL):?

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

-2.49
Solubility 0.717 mg/ml ; 0.00326 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.

-2.16
Solubility 1.52 mg/ml ; 0.00689 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

-2.54
Solubility 0.639 mg/ml ; 0.0029 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

No
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.

-6.58 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.

0.56

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)

1.85

Application In Synthesis of [ 885588-12-5 ]

* 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 [ 885588-12-5 ]

[ 885588-12-5 ] Synthesis Path-Downstream   1~2

  • 1
  • [ 67-56-1 ]
  • [ 885588-12-5 ]
  • [ 885588-14-7 ]
YieldReaction ConditionsOperation in experiment
81% With thionyl chloride; Methyl 2-bromo-5-fluoroisonicotinate:; To a solution of 2-bromo-5-fluoroisonicotinic acid (1.5 g, 6.82 mmol) in methanol (75 ml), thionyl dichloride (2.5 ml, 34.09 mmol) was added drop-wise. The reaction mixture was stirred overnight. The solvent was removed under high vacuum. The residual solid was distilled at 90 0C under vacuum to get 1.3g (81 %) of pure methyl 2-bromo-5- fluoroisonicotinate:
73% With thionyl chloride; at 0 - 20℃; for 16.0h; To a stirred solution of 2-bromo-5-fluoroisonicotinic acid (2.8 g, 12.78 mmol) in MeOH (30 ml), SOCI2 (7.54 g,63.9 mmol) was added at ooc and it was allowed to stir at rt for 16h. The reaction mixture was concentratedunder reduced pressure and the residue was dissolved in water (100 ml), basified to pH-8 using saturated NaHC03 solution, and extracted with EtOAc (2 x 100 ml). The combined organic layers were dried overanhydrous Na2S04, filtered and concentrated under reduced pressure to afford the title compound (2.2 g, 73%)as a pale yellow solid;LC-MS (method 8): Rt = 2.41 min; m/z = 234.07 (M+H+).
10.3 g With thionyl chloride; In methanol; at 0 - 20℃; for 24.5h; To a solution of 2-bromo-5-fluoro-pyridine-4-carboxylic acid (10.0 g, 45.5 mmol) in methanol (300 mL) cooled to 0C was added thionyl chloride (16.5 mL, 227.3 mmol) dropwise over 30 minutes. The reaction mixture was stirred at ambient temperature for 24 hours. Toluene (40 mL) was added to the reaction mixture. After evaporation of methanol, thionyl chloride was distilled out. The remaining toluene was evaporated on rotary evaporator affording the cmde product, which was dissolved in dichloromethane (30 mL) evaporated under reduced pressure affording methyl 2-bromo-5 -fluoropyridine-4-carboxylate (10.3 g). LCMS: MW (calcd): 232.9; MS (ES, m/z): 234, 236 (M+H).
  • 2
  • [ 885588-12-5 ]
  • [ 18107-18-1 ]
  • [ 885588-14-7 ]
YieldReaction ConditionsOperation in experiment
88.4% In methanol; benzene; for 1.5h;Cooling; a) methyl 2-bromo-5-fluoroisonicotinate To a cooled solution of 2-bromo-5-fluoroisonicotinic acid (3.0 g, 13.6 mmol) in benzene (20 ml) and methanol (10 ml) is dropwise over a period of 15 min added under stirring and cooling (trimethylsiliyl)diazomethane (2 M in ether, 14 ml, 28 mmol). The yellow solution is stirred for 1.5 h without cooling and evaporated to dryness. Purification of the residue (3.3 g) by chromatography on a 50 g Silicycle silica cartridge using a heptane/ethyl acetate 10-50% gradient affords methyl 2-bromo-5-fluoroisonicotinate (2.82 g, 88.4%) as a light yellow solid. mp.: 43-6 C. MS: m/z=233.9 (M+H+).
88.4% In methanol; benzene; for 1.75h;Cooling; To a cooled solution of 2-bromo-5-fluoroisonicotinic acid (3.0 g, 13.6 mmol) in benzene (20 ml) and methanol (10 ml) is dropwise over a period of 15 min added under stirring and cooling (trimethylsiliyl)diazomethane (2 M in ether, 14 ml, 28 mmol). The yellow solution is stirred for 1.5 h without cooling and evaporated to dryness. Purification of the residue (3.3 g) bychromatography on a 50 g Silicycle silica cartridge using a heptane / ethyl acetate 10-50% gradient affords methyl 2-bromo-5-fluoroisonicotinate (2.82 g, 88.4%) as a light yellow solid, mp.: 43 - 6C. MS: m/z= 233.9 (M+H+).
10.46 g In methanol; diethyl ether; toluene; at 0 - 20℃; for 2.5h; To a solution of 2-bromo-5-fluoro-pyridine-4-carboxylic acid (10.0 g, 45.5 mmol) in methanol (35 mL) and toluene (65 mL) cooled to 0C was added (trimethylsilyl)diazomethane (2.0 M solution in diethyl ether; 45.5 mL, 90.9 mmol) dropwise over 30 minutes. The reaction mixture was stirred at ambient temperature. After 2h, the reaction mixture was evaporated under reduced pressure affording the cmde product, which was dissolved in ethyl acetate (50 mL), washed with water (100 mL) and brine (50 mL) respectively, filtered through phase separator filter and evaporated under reduced pressureaffording methyl 2-bromo-5-fluoro-pyridine-4-carboxylate (10.46g). LCMS: MW (calcd): 232.9; MS (ES, m/z): 234, 236 (M+H).
In methanol; hexane; toluene; at 20℃; for 1.0h; 2-Bromo-5-fluoroisonicotinic acid(1.1 g) was mixed in toluene (15 mL) and methanol (5 mL).To this mixture was added 2M trimethylsilyldiazomethane / hexane solution at room temperature.The reaction mixture was stirred at room temperature for 1 hour.By concentrating the reaction mixture under reduced pressure,The title compound (1.17 g) was obtained as a crude product.

 

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