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Chemical Structure| 188577-68-6

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4,5-Dichloropyridin-2-amine

CAS No.: 188577-68-6

4.5 *For Research Use Only !

Cat. No.: A135080 Purity: 97%

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Product Details of [ 188577-68-6 ]

CAS No. :188577-68-6
Formula : C5H4Cl2N2
M.W : 163.01
SMILES Code : NC1=NC=C(Cl)C(Cl)=C1
MDL No. :MFCD07437842
Boiling Point : No data available
InChI Key :CRRAQLWJVYODCL-UHFFFAOYSA-N
Pubchem ID :10773304

Safety of [ 188577-68-6 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302
Precautionary Statements:P280-P305+P351+P338

Calculated chemistry of [ 188577-68-6 ] Show Less

Physicochemical Properties

Num. heavy atoms 9
Num. arom. heavy atoms 6
Fraction Csp3 0.0
Num. rotatable bonds 0
Num. H-bond acceptors 1.0
Num. H-bond donors 1.0
Molar Refractivity 38.66
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.

1.45
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

1.76
Log Po/w (WLOGP)?

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

1.98
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.

1.43
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

1.99
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.72

Water Solubility

Log S (ESOL):?

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

-2.45
Solubility 0.575 mg/ml ; 0.00353 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.

-2.19
Solubility 1.04 mg/ml ; 0.00639 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

-2.89
Solubility 0.211 mg/ml ; 0.00129 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.

-6.04 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)

1.57

Application In Synthesis [ 188577-68-6 ]

* 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 [ 188577-68-6 ]
  • Downstream synthetic route of [ 188577-68-6 ]

[ 188577-68-6 ] Synthesis Path-Upstream   1~4

  • 1
  • [ 188577-71-1 ]
  • [ 188577-68-6 ]
YieldReaction ConditionsOperation in experiment
86% With hydrogenchloride In water at 100℃; for 17 h; A mixture of 4,5-dichloro-2-trimethylacetamido-pyridine (0.500 g, 2.02 mmol) and aqueous HCl (6N; 9.5 ml) was heated was heated at 100° C. for 17 h. The reaction mixture was allowed to cool to room temperature, diluted with ice-water (15 ml), and the pH of the mixture was adjusted to 7.0 with 10percent aqueous NaOH. The white precipitate was collected by filtration, washed with water (2.x.5 ml), and dried in vacuo over P2O5. The title compound was obtained as a white solid (0.284 g, 86percent); 1H-NMR (500 Mz, DMSO-d6) 6.44 (s, 2H, NH2, exchangeable with D2O), 6.64 (s, 1H), and 8.03 (s, 1H) (3-H, 6-H); LC-MS (ESI, m/z) 4.37 min-163, 165, 167 [(M+H)+, Cl2 isotopic pattern].
85% With hydrogenchloride In water at 100℃; for 10 h; A mixture of N-(4,5-dichloropyridin-2-yl)pivalamide (1.25 g, 5.04 mmol) in 6N HCl (20 mL) was stirred at 100° C. for 10 h. The mixture was cooled, combined with water (20 mL), and basified by the addition of sodium bicarbonate solution (20 mL). The mixture was extracted with ethyl acetate (3×40 mL), and the combined organic layers were dried over sodium sulfate, then evaporated under reduced pressure and purified by gradient column chromatography using ethyl acetate in n-hexane as eluent to afford 4,5-dichloropyridin-2-amine as a white solid (0.7 g, 85percent). 1HNMR (400 MHz, CDCl3): δ 8.06 (s, 1H), 6.60 (s, 1H), 4.48 (br s, 2H). LC-MS calcd exact mass 161.98, found m/z 162.8 [M+H]+.
References: [1] Synthetic Communications, 1997, vol. 27, # 5, p. 861 - 870.
[2] Patent: US2009/247507, 2009, A1, . Location in patent: Page/Page column 7.
[3] Patent: US2016/362407, 2016, A1, . Location in patent: Paragraph 0558-0559.
[4] Patent: WO2010/122151, 2010, A1, . Location in patent: Page/Page column 66.
  • 2
  • [ 19798-80-2 ]
  • [ 188577-68-6 ]
YieldReaction ConditionsOperation in experiment
69% With N-chloro-succinimide In N,N-dimethyl-formamide at -20 - 20℃; for 24 h; 5.2.2.30
7,8-Dichloro-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (30)
To a solution of 2-amino-4-chloropyridine (1.28 g, 10.0 mmol) in DMF (40 mL) at -20 °C was added NCS (2.67 g, 20.0 mmol).
This mixture was allowed to warm to room temperature and stirred for 24 h, and then poured into 300 mL ice-water and extracted with ethyl acetate.
The extracts were washed with 1 M NaOH and brine, dried and evaporated.
The residue was purified by column chromatography on silica gel to give 4,5-dichloropyridin-2-amine (1.12 g, 69.0percent).
66% With N-chloro-succinimide In ethyl acetate at 20℃; for 28 h; INTERMEDIATE 1 4,5-Dichloropyridin-2-amine To a solution of 4-chloropyridine-2-amine (50.00 g, 0.389 mol) in EtOAc (400 mL) was added N-chloro succinimide (53.50 g, 0.401 mol) in one portion. The mixture was stirred over night (28 h) at room temperature, and was then filtered to remove precipitated succinimide. The filtrate was washed with aqueous 0.5M NaOH (8x50 mL), water (2x50 mL) and brine (2x50 mL). The organic phase was dried (Na2S04), filtered and evaporated to furnish 59.4 g of crude light brown powder after vacuum drying. The dry isolated crude (with a purity of ca. 75percent of the title compound) was slurried in hexane (800 mL) and stirred at reflux temperature for 15 min. The mixture was allowed to cool to 35 °C and was then filtered using a G3 glass frit filter. The filter cake was washed with hexane (ca. 200 mL) and dried on the filter to furnish 42.1 g (66percent>) of brown solid. The product was pure enough (96percent>) to be taken to the next step. 1H NMR (600 MHz, DMSO-d6) δ ppm 8.02 (s, 1 H) 6.65 (s, 1 H) 6.42 (s, 2 H). MS: (ESI+) m z 163, 165, 167 [M+H]+, di-chlorine isotopic pattern.
66% With N-chloro-succinimide In ethyl acetate at 20℃; for 28 h; To a solution of 4-chloropyridine-2-amine (50.00 g, 0.389 mol) in EtOAc (400 mL) was added N-chloro succinimide (53.50 g, 0.401 mol) in one portion. The mixture was stirred over night (28 h) at room temperature, and was then filtered to remove precipitated succinimide. The filtrate was washed with aqueous 0.5M NaOH (8x50 mL), water (2x50 mL) and brine (2x50 mL). The organic phase was dried (Na2SO4), filtered and evaporated to furnish 59.4 g of crude light brown powder after vacuum drying. The dry isolated crude (with a purity of ca. 75percent of the title compound) was slurried in hexane (800 mL) and stirred at reflux temperature for 15 min. The mixture was allowed to cool to 35 C and was then filtered using a G3 glass frit filter. The filter cake was washed with hexane (ca.200 mL) and dried on the filter to furnish 42.1 g (66percent) of brown solid. The product was pure enough (96percent) to be taken to the next step.1H NMR (600 MHz, DMSO-d6) δ ppm 8.02 (s, 1 H) 6.65 (s, 1 H) 6.42 (s, 2 H). MS: (ESI+) m/z 163, 165, 167 [M+H]+ , di-chlorine isotopic pattern.
References: [1] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 1, p. 60 - 67.
[2] European Journal of Medicinal Chemistry, 2016, vol. 117, p. 19 - 32.
[3] Patent: WO2016/124553, 2016, A1, . Location in patent: Page/Page column 71-72.
[4] Patent: WO2018/11138, 2018, A1, . Location in patent: Page/Page column 69-70.
[5] Synthetic Communications, 1997, vol. 27, # 5, p. 861 - 870.
[6] Patent: WO2011/85126, , A1, . Location in patent: Page/Page column 162-163[6] Patent: , 2011, , . Location in patent: Page/Page column 162-163.
[8] Patent: US2016/362407, 2016, A1, .
  • 3
  • [ 19798-80-2 ]
  • [ 188577-69-7 ]
  • [ 55933-91-0 ]
  • [ 188577-68-6 ]
References: [1] Synthetic Communications, 1997, vol. 27, # 5, p. 861 - 870.
[2] Synthetic Communications, 1997, vol. 27, # 5, p. 861 - 870.
  • 4
  • [ 188577-70-0 ]
  • [ 188577-68-6 ]
References: [1] Synthetic Communications, 1997, vol. 27, # 5, p. 861 - 870.
[2] Patent: US2016/362407, 2016, A1, .
 

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