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Chemical Structure| 13091-23-1 Chemical Structure| 13091-23-1

Structure of 13091-23-1

Chemical Structure| 13091-23-1

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Product Citations

Product Citations

Augustine N. Vu ; Santana P. Garcia ; Jenny H. Tran ; Adrian A. Godoy ; Joaquin M. Mesa ; Cassidy M. DiTirro , et al.

Abstract: An efficient synthesis of the exorbitantly priced Lambert–Eaton myasthenic syndrome drug amifampridine was developed and applied in the second-semester undergraduate organic chemistry laboratory. The two-step synthesis entails a nucleophilic aromatic substitution reaction of commercial 4-chloro-3-nitropyridine with methanolic ammonia to afford 4-amino-3-nitropyridine. Subsequent palladium-catalyzed nitro reduction provides amifampridine in high yield and purity. Amifampridine can alternatively be prepared by advanced undergraduate students in four linear steps beginning with 4-hydroxypyridine. Nitration of 4-hydroxypyridine to 4-hydroxy-3-nitropyridine and subsequent treatment with phosphoryl chloride provides the intermediate 4-chloro-3-nitropyridine, which is then subjected to the SNAr and reduction reactions to cleanly afford amifampridine without the need for column chromatography.

Keywords: Second-Year Undergraduate ; Upper-Division Undergraduate ; Organic Chemistry ; Hands-On Learning ; Drugs/Pharmaceuticals ; Ethics ; Heterocycles

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Alternative Products

Product Details of [ 13091-23-1 ]

CAS No. :13091-23-1
Formula : C5H3ClN2O2
M.W : 158.54
SMILES Code : C1=NC=CC(=C1[N+]([O-])=O)Cl
MDL No. :MFCD02683025
InChI Key :JOTRPRKONYTVBV-UHFFFAOYSA-N
Pubchem ID :2735781

Safety of [ 13091-23-1 ]

GHS Pictogram:
Signal Word:Danger
Hazard Statements:H301-H318
Precautionary Statements:P280-P301+P310-P305+P351+P338
Class:8(6.1)
UN#:2923
Packing Group:

Computational Chemistry of [ 13091-23-1 ] Show Less

Physicochemical Properties

Num. heavy atoms 10
Num. arom. heavy atoms 6
Fraction Csp3 0.0
Num. rotatable bonds 1
Num. H-bond acceptors 3.0
Num. H-bond donors 0.0
Molar Refractivity 38.07
TPSA ?

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

58.71 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

0.92
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

1.31
Log Po/w (WLOGP)?

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

1.64
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.

-0.13
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

-0.09
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

0.73

Water Solubility

Log S (ESOL):?

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

-2.03
Solubility 1.49 mg/ml ; 0.00941 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.

-2.14
Solubility 1.14 mg/ml ; 0.00719 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

-2.01
Solubility 1.55 mg/ml ; 0.00979 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.

-6.34 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

2.0 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)

1.74

Application In Synthesis of [ 13091-23-1 ]

* 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 [ 13091-23-1 ]

[ 13091-23-1 ] Synthesis Path-Downstream   1~10

  • 2
  • [ 124-41-4 ]
  • [ 13091-23-1 ]
  • [ 31872-62-5 ]
  • 3
  • [ 13091-23-1 ]
  • [ 273-34-7 ]
  • [ 201029-08-5 ]
  • 4
  • [ 110-71-4 ]
  • [ 13091-23-1 ]
  • [ 132038-21-2 ]
  • [ 31872-62-5 ]
  • 5
  • [ 13091-23-1 ]
  • [ 98-80-6 ]
  • [ 132038-21-2 ]
  • [ 31872-62-5 ]
  • 6
  • [ 929302-18-1 ]
  • [ 13091-23-1 ]
  • [ 1023299-47-9 ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 60℃; for 15h;Product distribution / selectivity; Example 78; Preparation of Compound 78B; Step A; To a vial were added 4-chloro-3-nitro pyridine (2 mmol) and spirocyclic amine (2 mmol). The starting materials were dissolved in 4 ml. of dichloromethane followed by the addition of DIPEA (6 mmol). The reaction was stirred at 60° for about 15 hours, then the reaction mixture was concentrated and using preparative liquid chromatography (0-5percent methanol in ethyl acetate) to provide compound 78A. Recovered 1.6 mmol (80percent) of 274. Mass calculated for formula C17H24N4O4 348.18, observed LCMS m/z 348.20 (M+H).; Using the methods described in Steps A and B above, and using the appropriate reactants, the following intermediate compounds were made:
  • 7
  • [ 13091-23-1 ]
  • [ 146950-68-7 ]
  • 8
  • [ 13091-23-1 ]
  • [ 21642-98-8 ]
  • 4-methoxy-3'-nitro-2-oxo-2H-[1,4'-bipyridine]-3-carbonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
5 g With caesium carbonate; In N,N-dimethyl-formamide; at 10 - 35℃; for 16.0h; A mixture of <strong>[21642-98-8]4-methoxy-2-oxo-1,2-dihydropyridine-3-carbonitrile</strong> (3.00 g), 4-chloro-3-nitropyridine (6.34 g), cesium carbonate (13.02 g) and N,N-dimethylformamide (30 mL) was stirred at room temperature for 16 hr. The reaction mixture was slowly poured into saturated sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To the residue was added isopropyl ether (20 mL), and the mixture was stirred for 15 min. The precipitate was collected by filtration to give the title compound (5.00 g). MS (ESI+): [M+H]+ 273.2
  • 9
  • [ 13091-23-1 ]
  • [ 7205-46-1 ]
  • 10
  • [ 13091-23-1 ]
  • [ 172478-01-2 ]
  • C16H24N4O4 [ No CAS ]
 

Historical Records

Technical Information

Categories

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Related Parent Nucleus of
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