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Chemical Structure| 109-04-6

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Togo, Takaya ; Tram, Linh ; Denton, Laura G. ; ElHilali-Pollard, Xochina ; Gu, Jun ; Jiang, Jinglei , et al.

Abstract: Heteroaromatic stacking interactions are important in drug binding, supramolecular chemistry, and materials science, making protein-ligand model systems of these interactions of considerable interest. Here we studied 30 congeneric ligands that each present a distinct heteroarene for stacking between tyrosine residues at the dimer interface of procaspase-6. Complex X-ray crystal structures of 10 analogs showed that stacking geometries were well conserved, while high-accuracy computations showed that heteroarene stacking energy was well correlated with predicted overall ligand binding energies. Empirically determined KD values in this system thus provide a useful measure of heteroarene stacking with tyrosine. Stacking energies are discussed in the context of torsional strain, the number and positioning of heteroatoms, tautomeric state, and coaxial orientation of heteroarene in the stack. Overall, this study provides an extensive data set of empirical and high-level computed binding energies in a versatile new protein-ligand system amenable to studies of other intermolecular interactions.

Purchased from AmBeed: ; ; ;

Comins, Daniel L ;

Abstract: A short and economical synthesis of various 2-methylaminopyidine amides (MAPA) from 2-bromopyridine has been developed using the catalytic Goldberg reaction. The effective catalyst was formed in situ by the reaction of CuI and 1,10-phenanthroline in a 1/1 ratio with a final loading of 0.5–3 mol%. The process affords high yields and can accommodate multigram-scale reactions. A modification of this method provides a new preparation of 2-N-substituted aminopyridines from various secondary N-alkyl(aryl)formamides and 2-bromopyridine. The intermediate aminopyridine formamide is cleaved in situ through methanolysis or hydrolysis to give 2-alkyl(aryl)aminopyridines in high yields.

Keywords: N-methyl-N-(2-pyridyl)formamide ; 2-methylaminopyridine amides ; 2-alkyl(aryl)aminopyridines ; Goldberg reaction ; copper-catalyzed reactions ; cross-coupling reactions ; 1,10-phenanthroline

Purchased from AmBeed: ;

Alternative Products

Product Details of [ 109-04-6 ]

CAS No. :109-04-6
Formula : C5H4BrN
M.W : 158.00
SMILES Code : C1=CC=C(N=C1)Br
MDL No. :MFCD00006219
InChI Key :IMRWILPUOVGIMU-UHFFFAOYSA-N
Pubchem ID :7973

Safety of [ 109-04-6 ]

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 [ 109-04-6 ] Show Less

Physicochemical Properties

Num. heavy atoms 7
Num. arom. heavy atoms 6
Fraction Csp3 0.0
Num. rotatable bonds 0
Num. H-bond acceptors 1.0
Num. H-bond donors 0.0
Molar Refractivity 31.94
TPSA ?

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

12.89 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.62
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

1.42
Log Po/w (WLOGP)?

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

1.84
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.

1.24
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

2.18
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.66

Water Solubility

Log S (ESOL):?

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

-2.35
Solubility 0.708 mg/ml ; 0.00448 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.

-1.3
Solubility 8.0 mg/ml ; 0.0506 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Very 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

-2.86
Solubility 0.217 mg/ml ; 0.00137 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.

-6.26 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

2.0
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)

1.61

Application In Synthesis of [ 109-04-6 ]

* 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 [ 109-04-6 ]
  • Downstream synthetic route of [ 109-04-6 ]

[ 109-04-6 ] Synthesis Path-Upstream   1~5

  • 1
  • [ 109-04-6 ]
  • [ 14305-17-0 ]
YieldReaction ConditionsOperation in experiment
55% at 20℃; for 16 h; Example 20; 4-Cyano- lH-imidazole-2-carboxylic acid [2-cyclohex- 1 -enyl-4-( 1 -oxy-pyridin-2-yl)-phenyl] - amide; a) 2-Bromo-pyridine 1 -oxide; A solution of 2-bromopyridine (158 mg, 1.00 mmol) and urea hydrogen peroxide (658 mg, 7.00 mmol) in 2.5 mL of formic acid was stirred at RT for 16 h. The resulting mixture was treated with H2O (30 mL) and extracted with DCM (3 x 15). The combined organic layers were dried (Na2SO4) and concentrated to give 96 mg (55 percent) of the title compound as a brown oil. Mass spectrum (ESI, m/z): Calcd. for C5H4BrNO, 174.0 (M+H), found 174.2.
20% With dihydrogen peroxide; acetic acid In water i)
2-Bromopyridine-N-oxide (Den Hertog, Kolder and Combe, 1951)
2-Bromopyridine (12 g), hydrogen peroxide (30percent, 90 ml) and acetic acid (90 ml) were heated at 55-60° C. for 8 days with stirring.
The solvent was then reduced under vacuum, water added, and the process repeated 3 or 4 times, to remove all solvent.
A greenish oil/solid of 2-Bromopyridine-N-oxide (2.2 g,20percent) was obtained.
References: [1] Tetrahedron Letters, 2008, vol. 49, # 48, p. 6933 - 6935.
[2] Inorganic Chemistry, 2018, vol. 57, # 9, p. 5486 - 5498.
[3] Organic and Biomolecular Chemistry, 2014, vol. 12, # 19, p. 3026 - 3036.
[4] Catalysis Science and Technology, 2014, vol. 4, # 7, p. 2099 - 2106.
[5] Organic Letters, 2014, vol. 16, # 12, p. 3336 - 3339.
[6] Polish Journal of Chemistry, 2000, vol. 74, # 2, p. 227 - 230.
[7] Synthesis and Reactivity in Inorganic, Metal-Organic and Nano-Metal Chemistry, 2010, vol. 40, # 10, p. 912 - 915.
[8] Patent: WO2007/123516, 2007, A1, . Location in patent: Page/Page column 55.
[9] Green Chemistry, 2016, vol. 18, # 24, p. 6630 - 6636.
[10] Journal of the American Chemical Society, 2017, vol. 139, # 16, p. 5998 - 6007.
[11] Advanced Synthesis and Catalysis, 2019, vol. 361, # 4, p. 725 - 738.
[12] Patent: US5929082, 1999, A, .
[13] Journal of the American Chemical Society, 1957, vol. 79, p. 2236.
[14] Journal of the American Chemical Society, 1950, vol. 72, p. 4362.
[15] Journal of the American Chemical Society, 1950, vol. 72, p. 4362.
[16] Chemische Berichte, 1992, vol. 125, # 5, p. 1131 - 1140.
[17] Heterocycles, 2008, vol. 75, # 1, p. 57 - 64.
[18] Journal of Organic Chemistry, 2009, vol. 74, # 2, p. 939 - 942.
[19] Journal of Organic Chemistry, 2011, vol. 76, # 19, p. 7842 - 7848.
[20] Journal of Inorganic Biochemistry, 2013, vol. 121, p. 10 - 15.
[21] RSC Advances, 2016, vol. 6, # 63, p. 58118 - 58124.
  • 2
  • [ 109-04-6 ]
  • [ 178039-84-4 ]
References: [1] Journal of the Chemical Society, 1938, p. 1662,1669.
  • 3
  • [ 109-04-6 ]
  • [ 201230-82-2 ]
  • [ 141-43-5 ]
  • [ 16347-06-1 ]
References: [1] Organic Letters, 2014, vol. 16, # 16, p. 4296 - 4299.
  • 4
  • [ 109-04-6 ]
  • [ 5188-07-8 ]
  • [ 74134-42-2 ]
References: [1] Phosphorus and Sulfur and the Related Elements, 1987, vol. 34, p. 123 - 132.
  • 5
  • [ 109-04-6 ]
  • [ 927-74-2 ]
  • [ 395652-44-5 ]
YieldReaction ConditionsOperation in experiment
90% With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In 1,4-dioxane at 20℃; Inert atmosphere Under nitrogen atmosphere, and at r.t., CuT (0.06 g, 0.31 mmol), dry Et3N (1.32 mL, 9.49 mmol) and bis-(triphenylphosphine)-palladium chloride (0.13 g, 0.18 mmol) were sequentially added to a solution of 2-bromopyridine (0.60 mL, 6.33 mmol) in 1,4-dioxane (10 mL). Then, but-3-yn-1-ol (0.57 mL, 7.59 mmol) was added dropwise at the same temperature.The resulting reaction mixture was left stirred overnight, then concentrated under reduced pressure, dissolved in EtOAc (80 mL) and washed with H20 (3 x 10 mL). The organic layer was dried over Na2504 and concentrated to dryness to give an oily crude (1.1 g). Purification by typical silica gel flash chromatography using a Teledyne ISCO apparatus (Cy/EtOAc from 90:10 to 30:70) afforded the pure title compound (0.84 g, 90percent), as a white solid. R= 1.25 mm. MS(ESI) m/z: 148 EM-H], 170 EM-Na], 186 EM-K]. ‘H NMR (DMSO-d6): ö 8.55—8.49 (m, 1H),7.76 (td, 1H, J= 7.8, 1.8 Hz), 7.44 (d, 1H, J= 7.8 Hz), 7.33 (ddd, 1H, J= 7.8, 4.9, 1.8 Hz), 4.92 (t, 1H, J= 5.2 Hz), 3.62-3.58 (m, 2H), 2.58 (t, 2H, J= 6.8 Hz).
77% at 0 - 70℃; Example 199 ;3 -Methoxy- N -methyl- N -( 4-(pyridin- 2-yl)but - 3 -ynyl)benzamide; 199(A) 4-(Pyridin-2-yl)but-3-yn-1-01; To a suspension of CuI (301 mg, 1.58 mmol) in TEA (40 mL) were added 2- bromopyridine (5 g, 31.6 mmol), followed by Pd2Cl2(PPh3)2 (1.11 g, 1.58 mmol) to give a yellow orange suspension. After cooling down to 0°C under N2, 3-butyn-l-ol (2.28 g, 31.6 mmol) was added. The resulting reaction mixture turned black and it was stirred overnight at 70°C. The reaction mixture was quenched at 0°C with water, TEA was removed under low pressure, and the organic layer was extracted 3x using DCM, washed with Ammonia, water, brine, dried over MgS04, filtered and concentrated. The crude residue was purified over silicagel chromatography (prepacked 250 g silicagel column, DCM/MeOH : from 99/1 to 95/5 as eluent) to afford 3.60 g of 4- (pyridin-2-yl)but-3-yn-1-ol as a brown oil (Yield : 77percent). LCMS (RT) : 1.58min; MS (ES+) gave m/z : 148 Rf (DCM/MeOH : 95/5) =0.23
References: [1] Tetrahedron Letters, 2005, vol. 46, # 10, p. 1717 - 1720.
[2] Journal of Organic Chemistry, 2003, vol. 68, # 3, p. 762 - 769.
[3] Patent: WO2014/144836, 2014, A2, . Location in patent: Paragraph 0526; 0527.
[4] European Journal of Organic Chemistry, 2011, # 2, p. 271 - 279.
[5] Patent: WO2005/123703, 2005, A2, . Location in patent: Page/Page column 207.
[6] Molecules, 2010, vol. 15, # 12, p. 9157 - 9173.
[7] Journal of Organic Chemistry, 2003, vol. 68, # 8, p. 3327 - 3329.
[8] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 8, p. 1077 - 1080.
 

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