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Chemical Structure| 64321-24-0

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Product Details of [ 64321-24-0 ]

CAS No. :64321-24-0
Formula : C6H6ClN3O
M.W : 171.58
SMILES Code : NC(=O)C1=CC=C(Cl)N=C1N
MDL No. :MFCD12024435
InChI Key :RZXHKUYBBAQDGZ-UHFFFAOYSA-N
Pubchem ID :22607643

Safety of [ 64321-24-0 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H317-H319
Precautionary Statements:P280-P305+P351+P338

Computational Chemistry of [ 64321-24-0 ] Show Less

Physicochemical Properties

Num. heavy atoms 11
Num. arom. heavy atoms 6
Fraction Csp3 0.0
Num. rotatable bonds 1
Num. H-bond acceptors 2.0
Num. H-bond donors 2.0
Molar Refractivity 41.75
TPSA ?

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

82.0 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

0.71
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

0.89
Log Po/w (WLOGP)?

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

0.42
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.

0.01
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

0.45
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

0.5

Water Solubility

Log S (ESOL):?

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

-1.8
Solubility 2.71 mg/ml ; 0.0158 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.

-2.2
Solubility 1.09 mg/ml ; 0.00636 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

-1.87
Solubility 2.33 mg/ml ; 0.0136 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

No
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.

-6.71 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)

1.69

Application In Synthesis of [ 64321-24-0 ]

* 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 [ 64321-24-0 ]

[ 64321-24-0 ] Synthesis Path-Upstream   1~2

  • 1
  • [ 58584-92-2 ]
  • [ 64321-24-0 ]
YieldReaction ConditionsOperation in experiment
93% With thionyl chloride In tetrahydrofuran 2-Amino-6-chloronicotinamide (Inter. 3)
To a 0.3 M solution of 2-amino-6-chloronicotinic acid (Inter. 2) (1 equiv) in anhydrous THF, under an inert atmosphere, was added thionyl chloride (3.3 equiv) in a dropwise fashion.
The reaction mixture was stirred at room temperature for 2 hours.
After this time the reaction was concentrated in vacuo to give a crude yellow solid residue.
The crude solid was dissolved in THF (equal to initial reaction volume) and concentrated in vacuo again to give a yellow solid residue.
The residue was dissolved once more in THF and concentrated as before to give a solid residue which was then dissolved in THF (to give a solution of 0.3M) and ammonia gas bubbled through the solution for 1 hour.
The resultant precipitate was removed by filtration and the filtrate concentrated in vacuo to give a yellow precipitate which was triturated with water at 50° C. then dried to give the title compound (92percent yield, 93percent purity), suitably clean to be used without any further purification. m/z (LC-MS, ESP): 172 [M+H]+R/T=3.19 mins
92%
Stage #1: With thionyl chloride In tetrahydrofuran at 20℃; for 2 h;
Stage #2: With ammonia In tetrahydrofuran for 1 h;
b) 2-Amino-6-chloronicotinamide (Inter. 3); To a 0.3 M solution of 2-amino-6-chloronicotinic acid (Inter. 2)(1 equiv) in anhydrous THF, under an inert atmosphere, was added thionyl chloride (3.3 equiv) in a dropwise fashion. The reaction mixture was stirred at room temperature for 2 hours. After this time the reaction was concentrated in vacuo to give a crude yellow solid residue. The crude solid was dissolved in THF (equal to initial reaction volume) and concentrated in vacuo again to give a yellow solid residue. The residue was dissolved once more in THF and concentrated as before to give a solid residue which was then dissolved in THF (to give a solution of 0.3M) and ammonia gas bubbled through the solution for 1 hour. The resultant precipitate was removed by filtration and the filtrate concentrated in vacuo to give a yellow precipitate which was triturated with water at 50°C then dried to give the title compound (92percent yield, 93percent purity), suitably clean to be used without any further purification, m/z (LC- MS, ESP): 172 [M+H]+ R/T = 3.19 mins
90%
Stage #1: With thionyl chloride In tetrahydrofuran at 20℃; for 2 h;
Stage #2: With ammonia In tetrahydrofuran for 1 h;
To a 0.3 M solution of amino acid (1 equiv) in anhydrous THF, under an inert atmosphere, was added thionyl chloride (3.3 equiv) in a dropwise fashion. The reaction mixture was stirred at room temperature for 2 hours. After this time the reaction was concentrated in vacuo to give a crude yellow solid residue. The crude solid was dissolved in THF (equal to initial reaction volume) and concentrated in vacuo again to give a yellow solid residue. The residue was dissolved once more in THF and concentrated as before to give a solid residue which was then dissolved in THF (to give a solution of 0.3M) and ammonia gas bubbled through the solution for 1 hour. The resultant precipitate was removed by filtration and the filtrate concentrated in vacuo to give a yellow precipitate which was triturated with water at 50 0C then dried to give the title compound (typically 90-95 percent) yield and suitably clean enough to be used without any further purification.2-Amino-6-chloronicotinamide - X=N, Y=C, Z=C: (92 percent yield, 93 percent purity) m/z (LC-MS, ESP): 172 [M+H]+ R/T = 3.19 min
81% With ammonium chloride; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 25℃; for 16 h; To a solution of 2-amino-6-chloronicotinic acid (1.0 g, 5.79 mmol), HOBT (932 mg, 6.95 mmol) and EDCI (2.22 g, 11.6 mmol) in 15 mL of DMF was added triethylamine (5.86 g, 57.9mmol) and NH4C1 (1.55 g, 28.9 mmol). Then the mixture was stirred at room temperature for 16 h. The solution was concentrated in vacuo to remove DMF and the residue was suspended in saturated NaHCO3. Finally the 2-amino-6-chloronicotinamide (800 mg, yield: 81percent) was obtained by filtration without further purification. ‘H-NMR (DMSO-d6, 400 MHz) 7.95 (d, J = 8.4 Hz, 1H), 7.62 (s, 2H), 7.39 (s, 2H), 6.59 (d, J = 8.4 Hz, 1H). MS (M+H): 172 / 174.
78% With thionyl chloride In 1,2-dichloro-ethane; N,N-dimethyl-formamide Example 140B
2-Amino-6-chloro-nicotinamide
To a mixture of Example 140A (11.9 g, 69.2 mmol) in 1,2-dichloroethane (100 mL) was added thionyl chloride (30 mL, 411 mmol) and DMF (catalytic).
The mixture was refluxed for 4 h then evaporated.
The residue was taken in ether (200 mL) and ammonia was bubbled through for 15 min.
The mixture was stirred overnight at rt then washed with water (100 mL) and brine (100 ml).
The ether was evaporated off to yield 9.2 g of product (78percent). MS (DCI/NH3) m/z 172 (M+1)+.
78%
Stage #1: With thionyl chloride In 1,2-dichloro-ethane for 4 h; Heating / reflux
Stage #2: With ammonia In diethyl ether at 20℃;
Example 140B
2-Amino-6-chloro-nicotinamide
To a mixture of Example 140A (11.9 g, 69.2 mmol) in 1,2-dichloroethane (100 mL) was added thionyl chloride (30 mL, 411 mmol) and DMF (catalytic).
The mixture was refluxed for 4 h then evaporated.
The residue was taken in ether (200 mL) and ammonia was bubbled through for 15 min.
The mixture was stirred overnight at rt then washed with water (100 mL) and brine (100 ml).
The ether was evaporated off to yield 9.2 g of product (78percent). MS (DCI/NH3) m/z 172 (M+1)+.

References: [1] Patent: US2009/99174, 2009, A1, .
[2] Patent: WO2007/60404, 2007, A1, . Location in patent: Page/Page column 57-58.
[3] Patent: WO2008/23161, 2008, A1, . Location in patent: Page/Page column 100.
[4] Patent: WO2014/205593, 2014, A1, . Location in patent: Page/Page column 59.
[5] Patent: US2003/187026, 2003, A1, .
[6] Patent: US2003/199511, 2003, A1, . Location in patent: Page/Page column 46.
[7] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 5, p. 1212 - 1216.
[8] Patent: WO2014/209727, 2014, A1, . Location in patent: Page/Page column 56.
  • 2
  • [ 38496-18-3 ]
  • [ 64321-24-0 ]
References: [1] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 5, p. 1212 - 1216.
 

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