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Chemical Structure| 4659-45-4 Chemical Structure| 4659-45-4

Structure of 4659-45-4

Chemical Structure| 4659-45-4

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Product Details of [ 4659-45-4 ]

CAS No. :4659-45-4
Formula : C7H3Cl3O
M.W : 209.46
SMILES Code : O=C(Cl)C1=C(Cl)C=CC=C1Cl
MDL No. :MFCD00000662
InChI Key :JBLIDPPHFGWTKU-UHFFFAOYSA-N
Pubchem ID :78392

Safety of [ 4659-45-4 ]

GHS Pictogram:
Signal Word:Danger
Hazard Statements:H314
Precautionary Statements:P264-P280-P301+P330+P331-P303+P361+P353-P304+P340+P310-P305+P351+P338+P310-P363-P405-P501
Class:8
UN#:3265
Packing Group:

Computational Chemistry of [ 4659-45-4 ] 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 1.0
Num. H-bond donors 0.0
Molar Refractivity 46.65
TPSA ?

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

17.07 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.03
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

3.21
Log Po/w (WLOGP)?

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

3.37
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.

3.2
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

3.62
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

3.09

Water Solubility

Log S (ESOL):?

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

-3.5
Solubility 0.0665 mg/ml ; 0.000317 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.

-3.24
Solubility 0.12 mg/ml ; 0.000575 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

-4.2
Solubility 0.0132 mg/ml ; 0.0000631 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.

-5.3 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)

1.33

Application In Synthesis of [ 4659-45-4 ]

* 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 [ 4659-45-4 ]

[ 4659-45-4 ] Synthesis Path-Downstream   1~8

  • 1
  • [ 40963-14-2 ]
  • [ 4659-45-4 ]
  • N-(1-Carbamoyl-1,2-dimethyl-propyl)-2,6-dichloro-benzamide [ No CAS ]
  • 2
  • [ 2406-90-8 ]
  • [ 4659-45-4 ]
  • [ 862822-09-1 ]
  • 3
  • [ 1793-07-3 ]
  • [ 95753-55-2 ]
  • [ 4659-45-4 ]
  • [ 74-88-4 ]
  • [ 401901-92-6 ]
YieldReaction ConditionsOperation in experiment
Fmoc-Phe(4-nitro)-OH (2.5g), 2,6-dichlorobenzoyl chloride (0.745mL) and pyridine (1.5mL) in a solution of NMP (25mL) were added to Wang resin (0.76mmol/g, 2.3g) and stirred at room temperature for 16 hours. After removing the excess solvent, the resin was washed with DMF three times, dichloromethane three times and NMP twice. In order to conduct capping of an unreacted hydroxyl group on the resin, the resin was treated with acetic anhydride (20mL), pyridine (20mL) and NMP (20mL) for 2 hours. After removing the excess solvent, the resin was washed with DMF three times and dichloromethane three times, and dried under reduced pressure.Process 2 Removal of Fmoc group A DMF solution of 20% piperidine (25mL) was added to the resin obtained in Process 1 and reacted for 15 minutes. After removing the solvent, the resin was washed with DMF and dichloromethane three times each, and dried under reduced pressure.Process 3 Acylation reaction 2,6-dichlorobenzoyl chloride (1.1mL), 2,6-lutidine (1.6mL) and NMP (26mL) were added to 2.0g of the resin obtained in Process 2 and reacted for 6 hours. After removing the excess solvent, the resin was washed with DMF and dichloromethane three times each, and dried under reduced pressure.Process 4 Reduction of nitro group NMP (30mL) · EtOH (1.5mL) solution of SnCl2· 2H2O (15.0g) was added to 1.5g of the resin obtained in Process 3 and reacted for 16 hours. After removing the reaction solvent, the resin was washed with DMF and dichloromethane three times each.Process 5 Construction of quinazoline-2,4-dione ring 2g of the resin obtained in Process 4 was reacted in NMP solution (32mL) of methyl 2-isocyanatebenzoate (1.92g) for 16 hours. After removing the reaction solvent, the resin was washed with DMF and dichloromethane three times each. DMF solution of 20% piperidine was added to the resin for 1 hour. After removing the reaction solvent, the resin was washed with DMF and dichloromethane three times each and dried under reduced pressure.Process 6 Alkylation Methyl iodide (0.75mmol), 18-crown-6 (30mg), NMP (1mL) and K2CO3 (35mg) were added to 20mg of the resin obtained in Process 5 and reacted for 3 days. After removing the reaction solvent, the resin was washed with DMF, water, DMF and dichloromethane three times each and dried under reduced pressure.Process 7 Cleavage from resin The resin obtained in Process 6 was treated with trifluoroacetic acid containing 5% of water for 1 hour. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified with high-pressure liquid chromatography (water/acetonitrile) to obtain 8mg of the intended compound. MS(ESI MH+) : 512 CHNO : C25H19Cl2N3O5
  • 4
  • [ 851785-21-2 ]
  • [ 4659-45-4 ]
  • C18H17Cl2NO5S [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine; In dichloromethane; at 0 - 20℃; for 12.0h; EXAMPLE 16 [0322] This example describes the synthesis of which was prepared according to the procedure below. [0323] To a solution of 0.2 mmol of compound 8.4 (Example 8c or 8e) in 1 mmol of Et3N and 5 mL of dry CH2C12 was added 0.22 mmol of 2,6- dichlorobenzoyl chloride at 0C, the resulting mixture was stirred at room temperature for 12 hours. The solvent was removed and the residue was dried in vacuo. Subsequently, the residue was treated with 0. 8 mmol of LiOH-H20 in 2 mL of THF and 0.5 mL of H20. After stirring at room temperature for 30 minutes, the reaction mixture was added 1.0 mL of 1. ON aq. HC1. The organic solvent was removed, and the residue was diluted with 10 mL of brine. The mixture was extracted with EtOAc and the extract was dried with anhydrous Na2SO4. The solvent was removed and the residue was dried in vacuo to give the desired compound in 65% yield. 1H NMR (400 MHz, CD30D) 6 7.92 (s, 1 H), 7. 82 (d, J=6. 85 Hz, 1 H), 7.71 (d, J=6. 85 Hz, 1 H), 7.56 (t, J=7. 83 Hz, 1 H), 7.34 (m, 3 H), 5. 08 (dd, J=9. 78, 4.89 Hz, 1 H), 3.45 (dd, J=14. 67,4. 89 Hz, 1 H), 3.14 (dd, J=14. 67,9. 78 Hz, 1 H), 3.08 (s, 3 H) ppm; ESI-MS (m/z) : (M+H+) 416.00.
  • 5
  • [ 159783-22-9 ]
  • [ 4659-45-4 ]
  • [ 1365992-55-7 ]
  • [ 1365992-56-8 ]
YieldReaction ConditionsOperation in experiment
With pyridine; at 3 - 20℃; for 3.16667h;Inert atmosphere; 2,6-Dichlorobenzoyl chloride (13.7 mL,95.6 mmol) was added dropwise, over 10 minutes, to a solution of <strong>[159783-22-9]3,5-difluoropyridin-4-ylamine</strong> (10.37 g,79.7 mmol) in pyridine (160 mL) at a temperature of between 3 and 5 C, under argon. The reaction mixture was allowed to warm to room temperature over 1 hour and then stirred at room temperature for 2 hours. The volatiles were removed under reduced pressure and the resultant residue was treated with HC1 (IN, 120 mL). The resultant suspension was stirred at room temperature for 45 minutes and the precipitate was collected by filtration, washing with water. A mixture of 2,6-dichloro-N-(3,5-difluoropyridin-4-yl)-benzamide and of 2,6- dichloro-N-(2,6-dichlorobenzoyl)-N-(3,5-difluoropyridin-4-yl)-benzamide (22.0 g) was obtained.A suspension of this mixture (22.0 g) in IN NaOH (200 mL) and MeOH (200 mL) was heated at 65 C for 7 hours then slowly cooled to room temperature. The pH of the mixture was adjusted to 4-5 by dropwise addition of 12N HC1, controlling the exotherm by the use of an ice-bath. The residue was left standing at room temperature for 18 hours and then the resultant solid was collected by filtration, washing with water, to afford the title compound as an off-white solid (14.65 g, 61% yield over two steps). LCMS (Method D): RT = 2.93 min, m/z: 303 [M+H+].
  • 6
  • [ 271-73-8 ]
  • [ 4659-45-4 ]
  • (2,6-dichlorophenyl)(1H-pyrazolo[3,4-b]pyridin-1-yl)methanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
With dmap; triethylamine; In tetrahydrofuran; at 90℃; for 4h; To a solution of <strong>[271-73-8]1H-<strong>[271-73-8]pyrazolo[3,4-b]pyridine</strong></strong> (500 mg, 4.20 mmol) in THF (8 mL) was added 2,6-dichlorobenzoyl chloride (879 mg, 4.20 mmol), TEA (1.755 mL, 12.59 mmol) and DMAP (256 mg, 2.099 mmol). The reaction was stirred at 90° C. for 4 hours. LCMS show no starting material and the desired product formed. The reaction mixture was concentrated and purified by silica gel column chromatography (SiO2, EtOAc/PE=0percent to 50percent) to give (2,6-dichlorophenyl)(1H-pyrazolo[3,4-b]pyridin-1-yl)methanone. MS: 292 (M+1)
  • 7
  • [ 17413-10-4 ]
  • [ 4659-45-4 ]
  • [ 1055212-30-0 ]
YieldReaction ConditionsOperation in experiment
92% With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 3h;Cooling with ice; Comparative Example 2 2,6-dichloro-N-[(2,3-dihydro-1,4-benzodioxin-6-yl)methyl]benzamide To a mixture of 2,3-dihydro-1,4-benzodioxin-6-yl)methylamine (50 mg, 0.30 mmol) and dichloromethane (1 mL) were added N,N-diisopropylethylamine (0.11 mL, 0.61 mmol) and 2,6-dichlorobenzoyl chloride (0.043 mL, 0.30 mmol) under ice cooling and the resultant was stirred at room temperature for 3 hours. The reaction mixture was purified by column chromatography on silica gel (heptane:ethyl acetate=2:1) to give the title compound (94 mg, 92% yield), 1H-NMR Spectrum (CDCl3) delta (ppm): 4.24 (s, 4 H), 4.57 (d, J=5.47 Hz, 2 H), 5.94 (br. s, 1 H), 6.81-6.92 (m, 3 H), 7.21 -7.33 (m, 3 H).
  • 8
  • methylaluminium sesquichloride [ No CAS ]
  • [ 4659-45-4 ]
  • [ 2040-05-3 ]
YieldReaction ConditionsOperation in experiment
With aluminium trichloride; at 40℃; Hereinafter there are listed examples of ketones obtainalbe or obtained by the process of the invention: hexanone-3 decanone-4 ... o-chloropropiophenone m-chloroacetophenone 3-chloro-5-methylpropiophenone 2,6-dichloroacetophenone m-bromopropiophenone p-bromoacetophenone p-bromopropiophenone ...
 

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