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Chemical Structure| 129946-63-0

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Product Details of [ 129946-63-0 ]

CAS No. :129946-63-0
Formula : C7H5F2N3
M.W : 169.13
SMILES Code : NNC1=CC(F)=C(C=C1F)C#N
MDL No. :MFCD04972812
InChI Key :PCCAOKUPWXCHHG-UHFFFAOYSA-N
Pubchem ID :10920925

Safety of [ 129946-63-0 ]

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

Computational Chemistry of [ 129946-63-0 ] Show Less

Physicochemical Properties

Num. heavy atoms 12
Num. arom. heavy atoms 6
Fraction Csp3 0.0
Num. rotatable bonds 1
Num. H-bond acceptors 4.0
Num. H-bond donors 2.0
Molar Refractivity 38.28
TPSA ?

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

61.84 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.14
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

1.08
Log Po/w (WLOGP)?

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

1.77
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.

1.59
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

1.16
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.35

Water Solubility

Log S (ESOL):?

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

-1.87
Solubility 2.27 mg/ml ; 0.0134 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.

-1.97
Solubility 1.81 mg/ml ; 0.0107 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

-2.73
Solubility 0.316 mg/ml ; 0.00187 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.

-6.56 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)

1.94

Application In Synthesis of [ 129946-63-0 ]

* 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.

  • Downstream synthetic route of [ 129946-63-0 ]

[ 129946-63-0 ] Synthesis Path-Downstream   1~9

  • 1
  • [ 129946-63-0 ]
  • 4-cyano-2-fluoro-5-methoxyphenylhydrazine [ No CAS ]
YieldReaction ConditionsOperation in experiment
With sodium hydroxide; acetic acid; In methanol; water; Example II-3 5 g (0.125 mol) of powdered sodium hydroxide are added to 13 g (0.076 mol) of <strong>[129946-63-0]4-cyano-2,5-difluorophenylhydrazine</strong> in 100 ml of methanol, the mixture is then heated at reflux temperature for 6 hours and subsequently evaporated in vacuo, the residue is transferred to 50 ml of water, the mixture is rendered neutral by the dropwise addition of acetic acid, and any solids which have precipitated are filtered off with suction and recrystallized from toluene. 9 g (65% of theory) of 4-cyano-2-fluoro-5-methoxyphenylhydrazine of melting point 155-156 C. are obtained.
  • 2
  • [ 129946-63-0 ]
  • [ 136411-82-0 ]
  • [ 186142-40-5 ]
YieldReaction ConditionsOperation in experiment
With sodium acetate; In water; acetic acid; Example 3 At room temperature (about 20 C.), 7.9 g (0.047 mol) of <strong>[129946-63-0]2,5-difluoro-4-cyano-phenylhydrazine</strong> are added to 8.8 g (0.047 mol) of 4,4,4-trichloro-2-methyl-crotonaldehyde, 11.5 g (0.14 mol) of sodium acetate and 20 ml of water in 100 ml of acetic acid, and the mixture is stirred at 50 C. overnight. The mixture is allowed to cool to room temperature, stirred with water and filtered off with suction, and the residue is recrystallized from n-hexane. 7.2 g (62% of theory) of 2-(2,5-difluoro-4-cyano-phenyl)-5-methyl-pyridazin-3-one of melting point 223 C. are obtained.
  • 3
  • [ 129946-63-0 ]
  • [ 3282-30-2 ]
  • 1-(4-cyano-2,5-difluorophenyl)-2-pivaloylhydrazine [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine; In dichloromethane; STR116 12.05 g (0.1 mol) of pivaloyl chloride are added dropwise at 0 C. with stirring and ice-cooling to 16.9 g (0.1 mol) of <strong>[129946-63-0]4-cyano-2,5-difluorophenylhydrazine</strong> and 12.4 g (0.105 mol) of triethylamine in 50 ml of dichloromethane; when the addition is complete, the mixture is stirred at 20 C. for 10 hours and then evaporated in vacuo, the residue is distributed between dichloromethane and water, the organic phase is dried over sodium sulphate, and the solvent is removed in vacuo. 24.85 g (98% of theory) of 1-(4-cyano-2,5-difluorophenyl)-2-pivaloylhydrazine of melting point 167 C. are obtained.
With triethylamine; In dichloromethane; Example VIII-1 12.05 g (0.1 mol) of pivaloyl chloride are added dropwise at 0 C. with stirring and ice-cooling to 16.9 g (0.1 mol) of <strong>[129946-63-0]4-cyano-2,5-difluorophenylhydrazine</strong> and 12.4 g (0.105 mol) of triethylamine in 50 ml of dichloromethane; when the addition is complete, the mixture is stirred at 20 C. for 10 hours and then evaporated in vacuo, the residue is distributed between dichloromethane and water, the organic phase is dried over sodium sulphate, and the solvent is removed in vacuo. 24.85 g (98% of theory) of 1-(4-cyano-2,5-difluorophenyl)-2-pivaloylhydrazine of melting point 167 C. are obtained.
  • 4
  • [ 129946-63-0 ]
  • [ 123-54-6 ]
  • 4-(3,5-dimethylpyrazol-1-yl)-2,5-di-fluorobenzonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
In ethanol; Petroleum ether; STR58 1.1 g (0.125 mol) of <strong>[129946-63-0]4-cyano-2,5-difluorophenylhydrazine</strong> and 12.5 g (0.125 mol) of 2,4-pentanedione are stirred for 2 hours at room temperature in 250 ml of ethanol, and the mixture is subsequently heated at 70 C. for 15 hours and then evaporated in vacuo. The residue is stirred with petroleum ether and filtered off with suction. 28 g (96% of theory) of 4-(3,5-dimethyl-1-pyrazolyl)-2,5-difluorobenzonitrile of melting point 122 C. are obtained.
In ethanol; Petroleum ether; Example 1 (Process a) 21.1 g (0.125 mol) of <strong>[129946-63-0]4-cyano-2,5-difluorophenylhydrazine</strong> and 12.5 g (0.125 mol) of 2,4-pentanedione are stirred for 2 hours at room temperature in 250 ml of ethanol, and the mixture is subsequently heated at 70 C. for 15 hours and then evaporated in vacuo. The residue is stirred with petroleum ether and filtered off with suction. 28 g (96% of theory) of 4-(3,5-dimethyl-1-pyrazolyl)-2,5-difluorobenzonitrile of melting point 122 C. are obtained.
  • 5
  • [ 129946-63-0 ]
  • [ 874-23-7 ]
  • [ 129946-36-7 ]
YieldReaction ConditionsOperation in experiment
In ice-water; acetic acid; STR59 5.2 ml (0.04 mol) of 2-acetylcyclohexanone (cf., for example, J. org. Chem. 34, 1425-1429 [1969]) are added to 6.76 g (0.04 mol) of <strong>[129946-63-0]4-cyano-2,5-difluorophenylhydrazine</strong> in 40 ml of glacial acetic acid, the reaction mixture is stirred at room temperature for 2 hours and then stirred into 250 ml of ice-water, the mixture is extracted with dichloromethane, dried over sodium sulphate and evaporated in vacuo, and the residue is recrystallized from dichloromethane/n-hexane. 3.21 g (23.5% of theory) of 4-(5-methyl-3,4-tetramethylene -1-pyrazolyl)-2,5-difluorobenzonitrile of melting point 120 C. are obtained.
In ice-water; acetic acid; Example 2 (Process a) 5.2 ml (0.04 mol) of 2-acetylcyclohexanone (cf., for example, J. org. Chem. 34, 1425-1429 [1969]) are added to 6.76 g (0.04 mol) of <strong>[129946-63-0]4-cyano-2,5-difluorophenylhydrazine</strong> in 40 ml of glacial acetic acid, the reaction mixture is stirred at room temperature for 2 hours and then stirred into 250 ml of ice-water, the mixture is extracted with dichloromethane, dried over sodium sulphate and evaporated in vacuo, and the residue is recrystallized from dichloromethane/n-hexane. 3.21 g (23.5% of theory) of 4-(5-methyl-3,4-tetramethylene-1-pyrazolyl)-2,5-difluorobenzonitrile of melting point 120 C. are obtained.
  • 6
  • ethyl N-ethoxycarbonylethaneimidate [ No CAS ]
  • [ 129946-63-0 ]
  • [ 129946-38-9 ]
YieldReaction ConditionsOperation in experiment
In 5,5-dimethyl-1,3-cyclohexadiene; STR62 8.45 g (0.05 mol) of 4-cyano-2,5-difluorophenyl-hydrazine and 12.08 g (0.078 mol) of ethyl N-ethoxycarbonylethaneimidate (cf., for example, Chem. Ber. 119, 2444-2457 [1986]) are heated at reflux temperature for 8 hours in 50 ml of xylene, the mixture is then cooled to room temperature, and solids are filtered off with suction and recrystallized from dichloromethane/petroleum ether. 5.91 g (50% of theory) of 1-(4-cyano-2,5-difluorophenyl)3-methyl-4,5-dihydro-1,2,4-triazolin-5-one of melting point 174 C. are obtained
  • 7
  • [ 98349-22-5 ]
  • [ 129946-63-0 ]
YieldReaction ConditionsOperation in experiment
93% With hydrazine; In 1,4-dioxane; for 16.0h; 2,4,5-Trifluorobenzonitrile (1 g, 6.3 mmol) and hydrazine (610 mg, 19 mmol) were dissolved in dioxane (3 mL) and stirred for 16 h. The reaction mixture was partitioned between ethyl acetate (30 mL) and sat. NaHCO3 (20 mL). The organic layer was washed with brine (10 mL), dried (MgSO4), filtered and concentrated to give 4-hydrazino-2,5-difluorobenzonitrile (1.012 g, 93%) as a white solid. LC/MS: m/z (M+H)=170.0. 1H-NMR (400 MHz, DMSO-d6) delta (ppm): 4.41 (2H, br s), 6.93 (1H, dd), 7.51 (1H, dd), 8.22 (1H, br s).
With hydrazine hydrate; In ethanol; water; STR112 11 g (0.22 mol) of hydrazine hydrate are added to 30 g (0.19 mol) of 2,4,5-trifluorobenzonitrile (cf., for example, EP-A 191,181) in 120 ml of ethanol, the mixture is heated at reflux temperature for 2 hours, cooled to room temperature and concentrated in vacuo, the residue is stirred with 50 ml of water, and any product which has precipitated is filtered off with suction and dried. 24 g (75% of theory) of 4-cyano-2,5-difluorophenylhydrazine of melting point 158 C. are obtained.
With hydrazine hydrate; In ethanol; water; Example II-1 11 g (0.22 mol) of hydrazine hydrate are added to 30 g (0.19 mol) of 2,4,5-trifluorobenzonitrile (cf., for example, EP-A 191,181) in 120 ml of ethanol, the mixture is heated at reflux temperature for 2 hours, cooled to room temperature and concentrated in vacuo, the residue is stirred with 50 ml of water, and any product which has precipitated is filtered off with suction and dried. 24 g (75% of theory) of 4-cyano-2,5-difluorophenylhydrazine of melting point 158 C. are obtained.
  • 8
  • [ 19975-56-5 ]
  • [ 129946-63-0 ]
  • 1,3-thiazolin-2-one(2,5-difluoro-4-cyanophenyl) hydrazone [ No CAS ]
YieldReaction ConditionsOperation in experiment
With trifluoroacetic acid; In methanol; ethyl acetate; Reference Example 15 1,3-Thiazolin-2-one(2,5-difluoro-4-cyanophenyl) hydrazone (Compound No. 3-4) 2-Methylthio-2-thiazoline (1.0g, 7.52mmol), and <strong>[129946-63-0]2,5-difluoro-4-cyanophenylhydrazine</strong> (1.27g, 7.51mmol) were dissolved in methanol (20ml), and to the resulting mixture, trifluoroacetic acid (four drops) was added at room temperature, and then the resultant was stirred at 55 ØC for 48 hours. After cooling, the reaction mixture was evaporated, and the obtained residue was dissolved in ethyl acetate, washed with sodium bicarbonate solution and dried, and then the solvent was removed. The obtained residue was purified by silicagel column chromatography (chloroform:acetone=25:1) to give 1,3-thiazolin-2-one(2,5-difluoro-4-cyanophenyl) hydrazone(0.9g). 1H-NMR(CDCl3) delta:3.33(2H,t,J=6.6Hz), 3.70(2H, t, J=6.6Hz), 6.10(1H,br s), 6.60-6.78(1H,m), 7.09-7.17(1H, m).
  • 9
  • [ 129946-63-0 ]
  • [ 908117-02-2 ]
  • [ 1073973-25-7 ]
YieldReaction ConditionsOperation in experiment
70% 2-(2-Cyclopropylacetyl)-5,5-dimethylcyclohexane-1,3-dione (351 mg, 1.58 mol) and <strong>[129946-63-0]4-hydrazino-2,5-difluorobenzonitrile</strong> (267 mg, 1.58 mmol) were combined with ACOH (0.4 mL) and EtOH (1.2 mL). The reaction was stirred at 25 C. for 2 hours. It was diluted with EtOAc (20 mL) and washed with sat. NaHCO3 (20 mL) and sat. NaCl (20 mL). The organic layer was dried over Na2SO4 and concentrated. Purification by gradient flash chromatography eluting with 0% to 50% EtOAc in hexanes provided 4-(3-cyclopropylmethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydroindazol-1-yl)-2,5-difluorobenzonitrile (395 mg, 70%) as an orange solid (LC/MS m/z=356.0 [M+H]+).
 

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