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Chemical Structure| 216076-11-8

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Product Details of [ 216076-11-8 ]

CAS No. :216076-11-8
Formula : C13H10ClNO
M.W : 231.68
SMILES Code : ClC1=CC=CC=C1C(CC2=CC=NC=C2)=O
MDL No. :MFCD04114383
InChI Key :BMSUUDSMTHMTQQ-UHFFFAOYSA-N
Pubchem ID :11379248

Safety of [ 216076-11-8 ]

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

Computational Chemistry of [ 216076-11-8 ] Show Less

Physicochemical Properties

Num. heavy atoms 16
Num. arom. heavy atoms 12
Fraction Csp3 0.08
Num. rotatable bonds 3
Num. H-bond acceptors 2.0
Num. H-bond donors 0.0
Molar Refractivity 63.93
TPSA ?

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

29.96 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.07
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

2.61
Log Po/w (WLOGP)?

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

3.16
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.

2.21
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

3.84
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.78

Water Solubility

Log S (ESOL):?

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

-3.28
Solubility 0.122 mg/ml ; 0.000528 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.

-2.89
Solubility 0.299 mg/ml ; 0.00129 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

-5.52
Solubility 0.000703 mg/ml ; 0.00000303 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

Yes
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.

-5.86 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.

0.55

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)

1.69

Application In Synthesis of [ 216076-11-8 ]

* 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 [ 216076-11-8 ]

[ 216076-11-8 ] Synthesis Path-Upstream   1~3

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  • [ 108-89-4 ]
  • [ 216076-11-8 ]
YieldReaction ConditionsOperation in experiment
71% With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane; water REFERENCE EXAMPLE 16
1-(2-Chlorophenyl)-2-(4-pyridyl)ethanone
To a stirred solution of diisopropylamine (15.4 mL) in dry tetrahydrofuran (100 mL) cooled at -50° C., was added a solution of 1.6 M n-butyllithium in hexane (69 mL) dropwise.
After addition, the resulting mixture was stirred for 10 min at the same temperature, followed by the addition of a solution of γ-picoline (20 g) in dry tetrahydrofuran (10 mL) at -30° C.
After an additional 1 h stirring, a solution of N-(2-chlorobenzoyl)propyleneimine (20 g) in dry tetrahydrofuran (10 mL) was added dropwise to the resulting mixture at -10° C.
After addition the mixture was stirred for another 2 h at ambient temperature.
Water (100 mL) was added to the mixture and extracted with ethyl acetate.
The extract was washed with water, dried, and concentrated under reduced pressure.
The residue was purified using silica-gel column chromatography (hexane-ethyl acetate, 1:1) to give the title compound (16.4 g, yield 71percent).
oil. 1H-NMR (CDCl3) δ: 4.28 (2H, s), 7.20 (2H, d, J=6.2 Hz,), 7.28-7.39 (1H, m), 7.41-7.48 (3H, m), 8.56 (2H, d, J=6.2 Hz).
71% With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane; water Reference Example A 16
1-(2-chlorophenyl)-2-(4-pyridyl)ethanone
A solution of diisopropylamine (15 mL) in anhydrous tetrahydrofuran (100 mL) was cooled at -50OEC and 1.6 M n-butyllithium/hexane solution (69 mL) was added dropwise with stirring.
After completion of dropwise addition, the mixture was stirred for 10 min and a solution of γ-picoline (20 g) in anhydrous tetrahydrofuran (10 mL) was added dropwise at -30OEC.
The mixture was stirred for 1 h and a solution of N-(2-chlorobenzoyl)propyleneimine (20 g) in anhydrous tetrahydrofuran (10 mL) was added dropwise at -10OEC.
After completion of dropwise addition, the mixture was stirred for at room temperature for 2 h.
To the reaction mixture was added water (100 mL) and the mixture was extracted with ethyl acetate.
The extract was washed with water, and after drying, the solvent was evaporated.
The residue was purified by silica gel column chromatography (hexane-ethyl acetate=1:1) to give the title compound (16 g, yield 71percent).
oil.
1H-NMR (CDCl3) δ: 4.28 (2H, s), 7.20 (2H, d, J= 6.2 Hz), 7.28-7.39 (1H, m), 7.41-7.48 (3H, m), 8.56 (2H, d, J= 6.2 Hz).
71% With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane; water Reference Example A 16
1-(2-chlorophenyl)-2-(4-pyridyl)ethanone
A solution of diisopropylamine (15 mL) in anhydrous tetrahydrofuran (100 mL) was cooled at -50°C and 1.6 M n-butyllithium/hexane solution (69 mL) was added dropwise with stirring.
After completion of dropwise addition, the mixture was stirred for 10 min and a solution of γ-picoline (20 g) in anhydrous tetrahydrofuran (10 mL) was added dropwise at -30°C.
The mixture was stirred for 1 h and a solution of N-(2-chlorobenzoyl)propyleneimine (20 g) in anhydrous tetrahydrofuran (10 mL) was added dropwise at -10°C.
After completion of dropwise addition, the mixture was stirred for at room temperature for 2 h.
To the reaction mixture was added water (100 mL) and the mixture was extracted with ethyl acetate.
The extract was washed with water, and after drying, the solvent was evaporated.
The residue was purified by silica gel column chromatography (hexane-ethyl acetate=1:1) to give the title compound (16 g, yield 71percent).
oil
1H-NMR (CDCl3) δ: 4.28 (2H, s), 7.20 (2H, d, J= 6.2 Hz), 7.28-7.39 (1H, m), 7.41-7.48 (3H, m), 8.56 (2H, d, J= 6.2 Hz).
71% With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane; water Reference Example 16
1-(2-chlorophenyl)-2-(4-pyridyl)ethanone
A solution of diisopropylamine (15 mL) in anhydrous tetrahydrofuran (100 mL) was cooled at -50°C and 1.6 M n-butyllithium/hexane solution (69 mL) was added dropwise with stirring.
After completion of dropwise addition, the mixture was stirred for 10 min and a solution of γ-picoline (20 g) in anhydrous tetrahydrofuran (10 mL) was added dropwise at -30°C.
The mixture was stirred for 1 h and a solution of N-(2-chlorobenzoyl)propyleneimine (20 g) in anhydrous tetrahydrofuran (10 mL) was added dropwise at -10°C.
After completion of dropwise addition, the mixture was stirred for at room temperature for 2 h.
To the reaction mixture was added water (100 mL) and the mixture was extracted with ethyl acetate.
The extract was washed with water, and after drying, the solvent was evaporated.
The residue was purified by silica gel column chromatography (hexane-ethyl acetate=1:1) to give the title compound (16 g, yield 71percent).
oil.
1H-NMR (CDCl3) δ: 4.28 (2H, s), 7.20 (2H, d, J= 6.2 Hz), 7.28-7.39 (1H, m), 7.41-7.48 (3H, m), 8.56 (2H, d, J= 6.2 Hz).

References: [1] Chemical and Pharmaceutical Bulletin, 2005, vol. 53, # 4, p. 410 - 418.
[2] Patent: US6436966, 2002, B1, .
[3] Patent: EP1354603, 2003, A1, .
[4] Patent: EP1402900, 2004, A1, .
[5] Patent: EP1205478, 2002, A1, .
[6] Chemical and Pharmaceutical Bulletin, 2008, vol. 56, # 8, p. 1126 - 1137.
  • 2
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YieldReaction ConditionsOperation in experiment
47%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran; cyclohexane at -78 - 0℃; for 0.5 h;
Stage #2: at -78 - 20℃;
To lithium diisopropyl amide (6.5 mL, 1.6 M in cyclohexane, 10.4 mmol) in THF (20.0 mL) at -78 °C was added a solution of 4-picoline (1.07g mL, 11.5 mmol) in THF (10.0 mL) dropwise. The dry ice bath was removed. The reaction mixture was stirred at 0 "C for 30 minutes, and cooled back to -78 °C. A solution of 2-chloro-N-methoxy-N- methylbenzamide (21) (2.39 g, 12 mmol) in THF (10.0 mL) was added dropwise. The reaction mixture was warmed to room temperature and stirred overnight. White solid was filtered off and dissolved in ethyl acetate. The organic phase was washed with water, brine, dried over dried magnesium sulfate and concentrated under vacuum to give l-(2-chlorophenyl)-2-(pyridin-4-yl)ethanone (22) (1.09 g, 4.7 mmol, 47percent) as white solid.
47%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran; cyclohexane at -78 - 20℃;
Stage #2: at -78 - 20℃;
l-(2-Chlorophenyl)-2-(pyridin-4-yl)ethanone (22): To lithium diisopropyl amide (6.5 mL, 1.6 M in cyclohexane, 10.4 mmol) in THF (20.0 mL) at -78 0C was added a solution of 4-picoline (1.07g mL, 1 1.5 mmol) in THF (10.0 mL) dropwise. The dry ice bath was removed. The reaction mixture was stirred at 0 0C for 30 minutes, and cooled back to -78 0C. A solution of 2-chloro-N-methoxy-N-methylbenzamide (21) (2.39 g, 12 mmol) in THF (10.0 mL) was added dropwise. The reaction mixture was warmed to room temperature and stirred overnight. White solid was filtered off and dissolved in ethyl acetate. The organic phase was washed with water, brine, dried over dried magnesium sulfate and concentrated under vacuum to give l-(2-chlorophenyl)-2- (pyridin-4-yl)ethanone (22) (1.09 g, 4.7 mmol, 47percent) as white solid.
References: [1] Patent: WO2009/91759, 2009, A1, . Location in patent: Page/Page column 49.
[2] Patent: WO2009/91760, 2009, A1, . Location in patent: Page/Page column 41.
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  • [ 216076-11-8 ]
References: [1] Chemical and Pharmaceutical Bulletin, 2005, vol. 53, # 4, p. 410 - 418.
 

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