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Structure of 13726-21-1

Chemical Structure| 13726-21-1

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Product Details of [ 13726-21-1 ]

CAS No. :13726-21-1
Formula : C9H8ClNO
M.W : 181.62
SMILES Code : COC1=C(Cl)C=CC(CC#N)=C1
MDL No. :MFCD09907926
InChI Key :XOSGKJSNVLAMGY-UHFFFAOYSA-N
Pubchem ID :20460956

Safety of [ 13726-21-1 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P280-P301+P312-P302+P352-P305+P351+P338

Computational Chemistry of [ 13726-21-1 ] Show Less

Physicochemical Properties

Num. heavy atoms 12
Num. arom. heavy atoms 6
Fraction Csp3 0.22
Num. rotatable bonds 2
Num. H-bond acceptors 2.0
Num. H-bond donors 0.0
Molar Refractivity 47.47
TPSA ?

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

33.02 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.99
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

1.81
Log Po/w (WLOGP)?

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

2.41
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.

2.01
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

2.77
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.2

Water Solubility

Log S (ESOL):?

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

-2.34
Solubility 0.822 mg/ml ; 0.00453 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.

-2.12
Solubility 1.37 mg/ml ; 0.00754 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

-3.63
Solubility 0.0425 mg/ml ; 0.000234 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

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.

-6.12 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)

1.43

Application In Synthesis of [ 13726-21-1 ]

* 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 [ 13726-21-1 ]

[ 13726-21-1 ] Synthesis Path-Downstream   1~4

  • 1
  • [ 13726-16-4 ]
  • [ 13726-21-1 ]
  • 2
  • [ 143-33-9 ]
  • [ 103347-14-4 ]
  • [ 13726-21-1 ]
YieldReaction ConditionsOperation in experiment
48% In ethanol; at 60℃; To a solution of <strong>[103347-14-4]4-bromomethyl-1-chloro-2-methoxy-benzene</strong> (68.5 g, 0.290 mol) in C2H5OH (90%, 500 mL) was added NaCN (28.5 g, 0.580 mol). The mixture was stirred at 60 C. overnight. Ethanol was evaporated and the residue was dissolved in H2O. The mixture was extracted with ethyl acetate (300 mL×3). The combined organic layers were washed with brine, dried over Na2SO4 and purified by column chromatography on silica gel (petroleum ether/ethyl acetate 30:1) to give 2-(4-chloro-3-methoxyphenyl)acetonitrile (25 g, 48%). 1H NMR (400 MHz, CDCl3) delta 7.36 (d, J=8 Hz, 1H), 6.88-6.84 (m, 2H), 3.92 (s, 3H), 3.74 (s, 2H). 13C NMR (100 MHz, CDCl3) delta 155.4, 130.8, 129.7, 122.4, 120.7, 117.5, 111.5, 56.2, 23.5.
In ethanol; water; at 20℃; The 28 g (0.166 mmol) of 38b from the previous step, NaCN (28 g; 0.58 mmol; 3.5 equiv.) and 500 mL of 90% aqueous EtOH were stirred at room temperature overnight. The crude residue was partitioned between EtOAc/H2O (359 mL of each), washed with brine, dried, filtered and evaporated. The crude product was purified by SiO2 chromatography eluting with a EtOAc/hexane gradient (100% hexane to 90% hexane) to afford 21 g of 38c.
In N,N-dimethyl-formamide; at 20℃; for 2h; (ii) (4-Chloro-3-methoxyphenyl)acetic acidThe product from step (i), DMF (200 ml) and sodium cyanide (20 g) were charged to a flask and stirred for 2 h at RT. The residue was partitioned between ether and water; the organics were separated, washed with water, dried (MgSO4) and evaporated under reduced pressure. Potassium hydroxide (40 g in water) was added and the mixture heated at reflux for 24 h. The reaction mixture was cooled to RT and extracted with ether. The aq layer was acidified to pH 1 with concentrated HCl and extracted with ethyl acetate. The organic layer was washed with water, dried (MgSO4) and evaporated under reduced pressure. The residue was triturated with isohexane/ether, and then filtered to give the subtitle compound (12.2 g).
In N,N-dimethyl-formamide; at 20℃; for 2h; The product from step (i) DMF (200 ml) and sodium cyanide (20 g) were charged to a flask and stirred for 2 h at RT. The residue was partitioned between ether and water; the organics were separated, washed with water, dried (MgSO4) and evaporated under reduced pressure. Potassium hydroxide (40 g in water) was added and the mixture heated at reflux for 24 h. The reaction mixture was cooled to RT and extracted with ether. The aqueous layer was acidified to pH 1 with concentrated HCl and extracted with ethyl acetate. The organic layer was washed with water, dried (MgSO4) and evaporated under reduced pressure. The residue was triturated with isohexane/ether, and then filtered to give the subtitle compound (12.2 g).
In ethanol; water; at 20℃; The 28 g (0.166 mmol) of 9b from the previous step, NaCN (28 g; 0.58 mmol; 3.5 equiv.) and 500 mL of 90% aqueous EtOH were stirred at room temperature overnight. The crude residue was partitioned between EtOAc/H2O (359 mL of each), washed with brine, dried, filtered and evaporated. Silica gel chromatography and elution with a gradient (100% hexane-90:10 hexane:EtOAc) yielded 21 g of 9c.
In ethanol; water; at 20℃; The 28 g (0.166 mmol) of 9b from the previous step, NaCN (28 g; 0.58 mmol; 3.5 equiv.) and 500 mL of 90% aqueous EtOH were stirred at room temperature overnight. The crude residue was partitioned between EtOAc/H2O (359 mL of each), washed with brine, dried, filtered and evaporated. Silica gel chromatography and elution with a gradient (100% hexane?90:10 hexane:EtOAc) yielded 21 g of 9c.

  • 3
  • [ 773837-37-9 ]
  • [ 103347-14-4 ]
  • [ 13726-21-1 ]
YieldReaction ConditionsOperation in experiment
75% In ethanol; water; for 2h;Reflux; To a solution of <strong>[103347-14-4]5-(bromomethyl)-3-chloroanisole</strong> (12) (412 g, 1.75 mol) in EtOH (2 L) and H20 (0.5 L) was added NaCN (129 g, 2.63 mol) and the reaction mixture was heated to reflux for 2 h with mechanical stirring. The reaction mixture was cooled and diluted with water (3.5 L). The mixture was extracted with diethyl ether (2 L x 2) and the combined organic layers were washed with aq. 5% HC1 (2.5 L), satd NaHC03 (2.5 L) and brine (2.5 L), dried over anhydrous MgS04, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Hex/EtOAc = 5: 1) to afford 2-(4-chloro-3-methoxyphenyl)acetonitrile (13) (240 g, 75%) as yellow solid. 1H NMR (400MHz, CDC13): delta 7.35-7.36 (d, 1H), 6.86 (s, 1H), 6.84-6.86 (d, 1H), 3.92 (s, 3H), 3.74 (s, 2H).
75% In ethanol; water; for 2h;Reflux; To a solution of <strong>[103347-14-4]5-(bromomethyl)-3-chloroanisole</strong> (12) (412 g, 1.75 mol) in EtOH (2 L) and H2O (0.5 L) was added NaCN (129 g, 2.63 mol) and the reaction mixture was heated to reflux for 2 h with mechanical stirring. The reaction mixture was cooled and diluted with water (3.5 L). The mixture was extracted with diethyl ether (2 L x 2) and the combined organic layers were washed with aq. 5% HCl (2.5 L), satd NaHCO3 (2.5 L) and brine (2.5 L), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Hex/EtOAc = 5:1) to afford 2-(4-chloro-3-methoxyphenyl)acetonitrile (13) (240 g, 75%) as yellow solid. 1H NMR (400MHz, CDCl3): delta 7.35-7.36 (d, IH), 6.86 (s, IH), 6.84-6.86 (d, IH), 3.92 (s, 3H), 3.74 (s, 2H).
48% In ethanol; at 60℃; To a solution of <strong>[103347-14-4]4-bromomethyl-1-chloro-2-methoxy-benzene</strong> (68.5 g, 0.290 mol) in C2H5OH (90%, 500 mL) was added NaCN (28.5 g, 0.580 mol). The mixture was stirred at 60 C. overnight. Ethanol was evaporated and the residue was dissolved in H2O. The mixture was extracted with ethyl acetate (300 mL*3). The combined organic layers were washed with brine, dried over Na2SO4 and purified by column chromatography on silica gel (petroleum ether/ethyl acetate 30:1) to give 2-(4-chloro-3-methoxyphenyl)acetonitrile (25 g, 48%). 1H NMR (400 MHz, CDCl3) delta 7.36 (d, J=8 Hz, 1H), 6.88-6.84 (m, 2H), 3.92 (s, 3H), 3.74 (s, 2H). 13C NMR (100 MHz, CDCl3) delta 155.4, 130.8, 129.7, 122.4, 120.7, 117.5, 111.5, 56.2, 23.5.
  • 4
  • [ 103347-14-4 ]
  • [ 13726-21-1 ]
YieldReaction ConditionsOperation in experiment
48% With NaCN; In C2H5OH; water; 2-(4-Chloro-3-methoxyphenyl)acetonitrile To a solution of <strong>[103347-14-4]4-bromomethyl-1-chloro-2-methoxy-benzene</strong> (68.5 g, 0.290 mol) in C2H5OH (90%, 500 mL) was added NaCN (28.5 g, 0.580 mol). The mixture was stirred at 60 C. overnight. Ethanol was evaporated and the residue was dissolved in H2O. The mixture was extracted with ethyl acetate (300 mL*3). The combined organic layers were washed with brine, dried over Na2SO4 and purified by column chromatography on silica gel (petroleum ether/ethyl acetate 30:1) to give 2-(4-chloro-3-methoxyphenyl)acetonitrile (25 g, 48%). 1H NMR (400 MHz, CDCl3) delta 7.36 (d, J=8 Hz, 1H), 6.88-6.84 (m, 2H), 3.92 (s, 3H), 3.74 (s, 2H). 13C NMR (100 MHz, CDCl3) delta 155.4, 130.8, 129.7, 122.4, 120.7, 117.5, 111.5, 56.2, 23.5.
 

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