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Chemical Structure| 63489-58-7 Chemical Structure| 63489-58-7

Structure of 4-Amino-2,6-difluoropyridine
CAS No.: 63489-58-7

Chemical Structure| 63489-58-7

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Product Details of [ 63489-58-7 ]

CAS No. :63489-58-7
Formula : C5H4F2N2
M.W : 130.10
SMILES Code : NC1=CC(F)=NC(F)=C1
MDL No. :MFCD08436089
InChI Key :OWXBXLGJIFPPMS-UHFFFAOYSA-N
Pubchem ID :11286475

Safety of [ 63489-58-7 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Computational Chemistry of [ 63489-58-7 ] 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 3.0
Num. H-bond donors 1.0
Molar Refractivity 28.56
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.

1.09
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

1.04
Log Po/w (WLOGP)?

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

1.79
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.

0.67
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

1.55
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.23

Water Solubility

Log S (ESOL):?

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

-1.8
Solubility 2.09 mg/ml ; 0.016 mol/l
Class?

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

Very soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-1.45
Solubility 4.64 mg/ml ; 0.0357 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

-2.19
Solubility 0.846 mg/ml ; 0.0065 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.

-6.36 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)

1.67

Application In Synthesis of [ 63489-58-7 ]

* 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 [ 63489-58-7 ]
  • Downstream synthetic route of [ 63489-58-7 ]

[ 63489-58-7 ] Synthesis Path-Upstream   1~6

  • 1
  • [ 2840-00-8 ]
  • [ 63489-58-7 ]
YieldReaction ConditionsOperation in experiment
63.5% With palladium 10% on activated carbon; triethylamine In ethanol at 25℃; for 24 h; Autoclave In a 500 mL autoclave, 49.8 g (0.25 mol) of 2,6-difluoro-3,5-dichloro-4-aminopyridine,200mL ethanol,5.61 g (0.55 mol) of triethylamine,10.0 g of 10percent palladium on carbon,Keep the temperature at 25 ,Filled with hydrogen pressure 0.46 MPa,Reaction for 24 hours.After cooling, the hydrogen was released, suction filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 3: 1)20.6 g of 2,6-difluoro-4-aminopyridine was obtained as a white solid,Liquid normalized content of 99.7percent, yield 63.5percent.
References: [1] Journal of Medicinal Chemistry, 1987, vol. 30, # 2, p. 340 - 347.
[2] Patent: CN104610250, 2017, B, . Location in patent: Paragraph 0076; 0077; 0079.
  • 2
  • [ 2840-00-8 ]
  • [ 63489-58-7 ]
  • [ 405230-78-6 ]
YieldReaction ConditionsOperation in experiment
57% With hydrogen; triethylamine In ethanol for 18 h; 4-Amino-3-chloro-2,6-difluoropyridine (6) and 4-amino-2,6-difluoropyridine (7). A suspension of 19.9 g (100 mmol) of 5, 2.2 g of 10percent Pd/C and 27 mL (190 mmol) of triethylamine in 100 mL of anhydrous ethanol was hydrogenated at 50 psi in a Parr hydrogenation apparatus overnight (about 18 h). The catalyst was filtered and carefully washed with ethanol. The combined filtrate and washings were evaporated to dryness in vacuo. The residue was partitioned between ether and water, and the water layer was extracted with ether. The combined ether layers were dried (MgSO4) and concentrated to dryness. The residue was dissolved in ethanol and the solution was treated with 50 g of silica gel. The solvent was removed in vacuo to give a powder, which was purified by silica gel column chromatography, eluted with CH2Cl2 to afford 9.4 g (57percent) of 6 and 4.3 g (33percent) of 7. [0129] Compound 6 was isolated as a white solid: mp 8485° C.; TLC, Rf 0.55 (CH2Cl2); 1H NMR (CDCl3) δ 5.15 (br s, 2H, NH2, D2O exchangeable), 6.20 (s, 1H, 5-H). Analysis calculated for C5H3ClF2N2: C, 36.49; H, 1.84; N, 17.02. Found: C, 36.78; H, 2.09; N, 16.89. [0130] Compound 7 was isolated as a white solid: mp 126-128° C. (Lit., Secrist, et al., J. Med. Chem. 1988 31, 405-410 mp 125-127° C.); TLC, Rf 0.37 (CH2Cl2); 1H NMR (DMSO-d6) δ 6.00 (s, 2H, 3- and 5-H), 6.70 (br s, 2H, NH2, D2O exchangeable). Analysis calculated for C5H4F2N2: C, 46.16; H, 3.10; N, 21.54. Found: C, 46.01; H, 3.39; N, 21.29.
References: [1] Nucleosides, Nucleotides and Nucleic Acids, 2001, vol. 20, # 12, p. 1975 - 2000.
[2] Patent: US2004/116362, 2004, A1, . Location in patent: Page/Page column 11; Figure 11.
  • 3
  • [ 1352830-73-9 ]
  • [ 1352830-76-2 ]
  • [ 63489-58-7 ]
YieldReaction ConditionsOperation in experiment
37%
Stage #1: With potassium fluoride; [2.2.2]cryptande In dimethyl sulfoxide at 160℃; for 72 h;
Stage #2: With hydrogenchloride In methanol for 1 h;
Anhydrous F (300 mg, 5. 16 mmol) was added to a mixture of 1 (700 mg, 1.72 mmol) and kryptofix (1.0 g, 2.65 mmol) in DM SO (2.5 mL) and the mixture was stirred at 160 °C for 72 h. After the reaction, water was added and the solid formed was filtered and dried. The solid was dissolved in ethyl acetate (25.0 mL) and washed with water and dried (Na2S04). Evaporation of the solvent gave a dark oil, which was purified by silica gel column chromatography using hexane /ethyl acetate (7/3). UV visible fractions were collected and evaporated to give an yellow oil, which solidified on standing. Yield 0.5 g. (88percent). This was found to be a mixture of 63, 64 and 62 in the ratio (13:51 : 14) by HPLC analysis. A portion of the solid (80.0 mg) was purified by preparative HPLC using CH3CN / water /0.1percent TFA. Fractions containing the pure product were collected and evaporated to give the compound 64 as a while solid. Yield 32.0 mg (42percent). MS: 389.2 (M+H)+. The trityl derivatives 63, 63 and 64 obtained in the above reaction (600 mg, 1.5 mmol) was dissolved in methanolic HQ (5.0 inL) and stirred for 1 h. Methanol was removed and the residue was triturated with ethyl acetate to remove the trityl chloride and the resulting hydrochloride was dissolved in methanol and stirred with anion exchange resin. The pH of the solution (7.0) tested and the methanolic solution was filtered and concentrated to give the free amine mixture 65, 66 and 61. Yield 200 mg (89percent). A portion of the solid (38.0 mg) was purified by preparative HPLC (Ci8 column (0.46 x 5 cm, gradient 0- 1 0 percent) CH3CN / water/ 0.1 percent) TFA. Fractions containing the pure product were collected and concentrated to give the compound 65. Yield 10.0 mg (37percent). MS: (M+H f 147.0. 1HNMR (DMSO-d6) d 6.06 (s, I H ).6.46 (s, 1 H ). 6.80 (bs, 2H).
References: [1] Patent: WO2011/159864, 2011, A1, . Location in patent: Page/Page column 41-42.
  • 4
  • [ 1737-93-5 ]
  • [ 63489-58-7 ]
References: [1] Nucleosides, Nucleotides and Nucleic Acids, 2001, vol. 20, # 12, p. 1975 - 2000.
[2] Patent: CN104610250, 2017, B, .
  • 5
  • [ 2587-02-2 ]
  • [ 1352830-76-2 ]
  • [ 63489-58-7 ]
References: [1] Patent: WO2011/159864, 2011, A1, .
  • 6
  • [ 1737-93-5 ]
  • [ 63489-58-7 ]
  • [ 2840-00-8 ]
  • [ 405230-78-6 ]
References: [1] Journal of Fluorine Chemistry, 2004, vol. 125, # 12, p. 1829 - 1834.
 

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