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Chemical Structure| 4964-76-5

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Product Citations

Product Citations

Lee, Myoungmi Melanie ;

Abstract: Heteroarenes bearing nitrogen centers such as pyridines and quinolines are ubiquitous in pharmaceuticals, agrochemicals, and other small molecules of medicinal interest. Among them, quinoline derivatives belong to a significant class of bioactive molecules in the field of drugs and pharmaceuticals and they also display significant activity against numerous viruses and bacterium. Previous studies on enantioselective synthesis of α-heterocyclic amine derivatives include diastereoselective addition of organometallics to enantiopure pyridyl imines derived from Ellman auxiliary, and enantioselective reduction of a pyridyl ketone, conversion to a leaving group, and azide displacement followed by the reduction to obtain the amine. In addition, numerous other methods have been developed to prepare alkylated N-heteroarenes. However, protocols for enantioselective synthesis are rather limited and these stereospecific transformations require stoichiometric amounts of optically pure reagents and do not create new stereogenic centers. Considering the aforementioned limitations, the Ge group investigated addition of a chiral Cu‒alkyl species, generated by insertion of alkenes into a chiral Cu‒H complex to quinoline N-oxides to produce chiral 2-alkylated quinolines. This strategy that utilizes quinoline N-oxide as an electrophile inspired us to expand the methodology to afford enantioenriched chiral 2-aminoalkyl quinolines from quinoline N-oxide and 2-azadienes via a copper-catalyzed process. However, there are possible challenges to this reaction including a reductive dimerization of 2-azadiene, v reduction of quinoline N-oxides to quinolines, and potential catalyst deactivation. If these challenges can be overcome, this strategy could represent a practical protocol to prepare chiral aminoalkylated quinolines from readily available quinoline N-oxides and alkenes.

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Product Details of [ 4964-76-5 ]

CAS No. :4964-76-5
Formula : C10H9NO
M.W : 159.19
SMILES Code : COC1=CC=C2C=CC=NC2=C1
MDL No. :MFCD00870291
InChI Key :IVHJSNNMKJWPFW-UHFFFAOYSA-N
Pubchem ID :78666

Safety of [ 4964-76-5 ]

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

Computational Chemistry of [ 4964-76-5 ] Show Less

Physicochemical Properties

Num. heavy atoms 12
Num. arom. heavy atoms 10
Fraction Csp3 0.1
Num. rotatable bonds 1
Num. H-bond acceptors 2.0
Num. H-bond donors 0.0
Molar Refractivity 48.24
TPSA ?

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

22.12 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.08
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

2.37
Log Po/w (WLOGP)?

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

2.24
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.

1.49
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

2.46
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.13

Water Solubility

Log S (ESOL):?

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

-2.87
Solubility 0.214 mg/ml ; 0.00135 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.

-2.48
Solubility 0.533 mg/ml ; 0.00335 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

-3.82
Solubility 0.0243 mg/ml ; 0.000153 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.

-5.59 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)

1.21

Application In Synthesis of [ 4964-76-5 ]

* 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.

  • Upstream synthesis route of [ 4964-76-5 ]
  • Downstream synthetic route of [ 4964-76-5 ]

[ 4964-76-5 ] Synthesis Path-Upstream   1~2

  • 1
  • [ 4964-76-5 ]
  • [ 36023-06-0 ]
YieldReaction ConditionsOperation in experiment
93.1% With N-Bromosuccinimide In dichloromethane at 20℃; for 12 h; Inert atmosphere 4.2 g of RL-0107 was placed in a 100 mL three-necked flask, and N-bromosuccinimide (NBS) was added thereto. Further, 60 mL of dichloromethane was added, and argon gasReplacement was done. The reaction was further carried out at room temperature for 12 hours. After completion of the reaction, sodium thiosulfate (Na2S 2 O 3) was added and extracted with a water / ethyl acetate system. The organic layer was collected, dried over anhydrous magnesium sulfateAfter drying, the solvent was removed and purified by column chromatography to obtain 5.9 g of RL-0106(Yield: about 93.1percent).
References: [1] Chemical Communications, 2017, vol. 53, # 31, p. 4339 - 4341.
[2] Patent: JP2018/118935, 2018, A, . Location in patent: Paragraph 0099; 0100.
[3] Journal of the American Chemical Society, 2016, vol. 138, # 33, p. 10413 - 10416.
  • 2
  • [ 4964-76-5 ]
  • [ 959121-99-4 ]
References: [1] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 14, p. 2358 - 2363.
 

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Technical Information

Categories

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