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Structure of 38186-82-2

Chemical Structure| 38186-82-2

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Product Details of [ 38186-82-2 ]

CAS No. :38186-82-2
Formula : C6H7ClN2
M.W : 142.59
SMILES Code : NC1=CC(C)=C(Cl)N=C1
MDL No. :MFCD03095087
InChI Key :VSBISZPNLZFTPG-UHFFFAOYSA-N
Pubchem ID :12295607

Safety of [ 38186-82-2 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H312-H332
Precautionary Statements:P280

Computational Chemistry of [ 38186-82-2 ] Show Less

Physicochemical Properties

Num. heavy atoms 9
Num. arom. heavy atoms 6
Fraction Csp3 0.17
Num. rotatable bonds 0
Num. H-bond acceptors 1.0
Num. H-bond donors 1.0
Molar Refractivity 38.62
TPSA ?

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

38.91 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.37
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

1.5
Log Po/w (WLOGP)?

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

1.63
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.

0.75
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

1.74
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.4

Water Solubility

Log S (ESOL):?

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

-2.16
Solubility 0.981 mg/ml ; 0.00688 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.

-1.92
Solubility 1.7 mg/ml ; 0.0119 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

-2.64
Solubility 0.324 mg/ml ; 0.00227 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.

-6.1 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)

1.6

Application In Synthesis of [ 38186-82-2 ]

* 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 [ 38186-82-2 ]
  • Downstream synthetic route of [ 38186-82-2 ]

[ 38186-82-2 ] Synthesis Path-Upstream   1~4

  • 1
  • [ 22280-56-4 ]
  • [ 38186-82-2 ]
YieldReaction ConditionsOperation in experiment
97% With iron; acetic acid In water for 3 h; Iron (Fe) powder (9.75 g, 0.174 mol, Sigma-Aldrich) was added in portions over a period of 2h to a stirred solution of 2-chloro-3-methyl-5-nitropyridine (10 g, 0.058 mol, Combi-blocks) in acetic acid/water (29 mL: 88 mL). After 3h, the reaction mixture was filtered through celite and the filter cake was washed with ethyl acetate. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with aqueous sodium bicarbonate, brine and dried over Na2S04. The solvent was removed under reduced pressure to yield 6-chloro-5-methylpyridine-3-amine as a brown solid (8.0g; 97percent). MS m/z = 142.03 [M+H]+.1H-NMR (300MHZ, DMSO-d6): 7.54 (d, J=30 Hz, 1H), 6.91-6.90 (dd, J = 0.6 Hz & 2.7 Hz, 1H), 5.39 (s, 2H), 2.17 (s, 3H)
97% With iron; acetic acid In water for 5 h; Iron powder (9.75 g, 0.17 mol) was added in portions over a period of 2 h to a stirred solution of 2-chloro-3-methyl-5-nitropyridine (10 g, 58.00 mmol, Combi-blocks) in HOAc/water (29 mL : 88 mL). After 3 h, the reaction mixture was filtered through Celite® filter aid and the filter cake was washed with EtOAc. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with aqueous sodium bicarbonate, brine and dried over Na2SO4. The solvent was removed under reduced pressure to yield 6-chloro-5- methylpyridine-3-amine as a brown solid (269A, 8.00 g; 97percent). MS m/z = 142.03 [M+H]+. 1H-NMR (300MHz, DMSO-d6): 7.54 (d, J=30 Hz, 1 H), 6.91 -6.90 (dd, J = 0.6 Hz & 2.7 Hz, 1 H), 5.39 (s, 2H), 2.17 (s, 3H)
42% With water; iron; ammonium chloride In methanol at 20 - 50℃; for 3.08333 h; Heating / reflux Reference Example 33 6-chloro-5-methylpyridine-3-amine; Reduced iron (793 mg) was added to an aqueous solution (25 mL) of ammonium chloride (1.27 g), and the mixture was stirred at room temperature for 5 min. A solution (10 mL) of 2-chloro-3-methyl-5-nitropyridine (816 mg) in methanol was added dropwise over 10 min. The reaction mixture was stirred at 40° C. for 20 min and at 50° C. for 1.5 hr and further refluxed for 1 hr. The reaction mixture was filtered through celite, and celite was washed with methanol. Methanol was mostly removed by concentration under reduced pressure, and saturated aqueous sodium hydrogencarbonate solution was added. The mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1-->7:3) to give the title compound as a solid (yield 280 mg, 42percent). 1H-NMR (CDCl3) δ: 3.62 (2H, br), 6.88-6.89 (1H, m), 7.70-7.71 (1H, m).
42% With iron; ammonium chloride In methanol at 40℃; for 2.83333 h; Heating Reference Example 136
6-Chloro-5-methylpyridine-3-amine
Reduced iron (793 mg) was added to an aqueous solution (25 mL) of ammonium chloride (1.27 g), and the mixture was stirred at room temperature for 5 min.
A solution (10 mL) of 2-chloro-3-methyl-5-nitropyridine (816 mg) in methanol was added dropwise over 10 min.
The reaction mixture was stirred at 40°C for 20 min and at 50°C for 1.5 hr and further refluxed under heating for 1 hr.
The reaction mixture was filtered through celite, and celite was washed with methanol.
Methanol was mostly removed by concentrated under reduced pressure, and saturated aqueous sodium hydrogencarbonate solution was added.
The mixture was extracted with ethyl acetate.
The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→7:3) to give the title compound as a solid (yield 280 mg, 42percent).
1H-NMR (CDCl3)δ: 2.29 (3H, s), 3.62 (2H, br), 6.88-6.89 (1H, m), 7.70-7.71 (1H, m).

References: [1] Patent: WO2014/138484, 2014, A1, . Location in patent: Page/Page column 156.
[2] Patent: WO2016/22724, 2016, A1, . Location in patent: Page/Page column 296.
[3] Journal of Organic Chemistry, 2011, vol. 76, # 23, p. 9841 - 9844.
[4] Synthetic Communications, 2006, vol. 36, # 9, p. 1235 - 1245.
[5] Organic Letters, 2016, vol. 18, # 11, p. 2774 - 2776.
[6] Chemistry of Heterocyclic Compounds, 1996, vol. 32, # 10, p. 1173 - 1177.
[7] Patent: US2007/60623, 2007, A1, . Location in patent: Page/Page column 24.
[8] Patent: WO2006/36024, 2006, A1, . Location in patent: Page/Page column 162.
[9] Patent: EP2336107, 2015, B1, . Location in patent: Paragraph 0310.
[10] Patent: WO2007/65662, 2007, A2, . Location in patent: Page/Page column 44.
[11] Patent: US2014/249104, 2014, A1, . Location in patent: Page/Page column.
[12] Patent: WO2005/123668, 2005, A1, . Location in patent: Page/Page column 46-47.
  • 2
  • [ 22280-56-4 ]
  • [ 7732-18-5 ]
  • [ 7439-89-6 ]
  • [ 38186-82-2 ]
YieldReaction ConditionsOperation in experiment
89% With acetic acid In ethyl acetate 19a.
5-Amino-2-chloro-3-methylpyridine
2-Chloro-3-methyl-5-nitropyridine (15 g, 86.9 mmol; from Maybridge Chemical Co.) was dissolved in a solution of H2 O/AcOH (5:1, 60 mL).
Iron powder was added to the reaction mixture while maintaining the temperature below 40° C., and the mixture was stirred for 5 hours.
The mixture was filtered through celite and the aqueous filtrate was extracted with EtOAc (4*).
The filter cake was washed with EtOAc, and the EtOAc solutions were combined, dried (MgSO4), concentrated and chromatographed (silica gel; CHCl3 /MeOH, 98:2) to afford an orange solid (2.3 g, 89percent): 1 H NMR (CD3 OD, 300 MHz) δ2.25 (s, 3H), 7.01 (d, J=2.0 Hz, 1H), 7.58 (d, J=2.0 Hz, 1H); MS (CI/NH3) m/z: 243/245 (M+H)+.
References: [1] Patent: US5733912, 1998, A, .
  • 3
  • [ 22280-56-4 ]
  • [ 7732-18-5 ]
  • [ 7439-89-6 ]
  • [ 54232-03-0 ]
  • [ 38186-82-2 ]
References: [1] Patent: US6133253, 2000, A, .
  • 4
  • [ 22280-56-4 ]
  • [ 144-55-8 ]
  • [ 38186-82-2 ]
References: [1] Patent: EP1803709, 2007, A1, .
 

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