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Chemical Structure| 21524-39-0

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Product Details of [ 21524-39-0 ]

CAS No. :21524-39-0
Formula : C7H3F2N
M.W : 139.10
SMILES Code : N#CC1=CC=CC(F)=C1F
MDL No. :MFCD00009976
InChI Key :GKPHNZYMLJPYJJ-UHFFFAOYSA-N
Pubchem ID :88935

Safety of [ 21524-39-0 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302+H312+H332-H315-H319-H335
Precautionary Statements:P261-P280-P305+P351+P338

Computational Chemistry of [ 21524-39-0 ] Show Less

Physicochemical Properties

Num. heavy atoms 10
Num. arom. heavy atoms 6
Fraction Csp3 0.0
Num. rotatable bonds 0
Num. H-bond acceptors 3.0
Num. H-bond donors 0.0
Molar Refractivity 31.07
TPSA ?

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

23.79 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.61
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

1.84
Log Po/w (WLOGP)?

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

2.68
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.

2.32
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

2.64
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.22

Water Solubility

Log S (ESOL):?

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

-2.31
Solubility 0.688 mg/ml ; 0.00495 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.

-1.96
Solubility 1.52 mg/ml ; 0.011 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

-3.01
Solubility 0.135 mg/ml ; 0.000971 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

Yes
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.

-5.84 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

2.0
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)

1.58

Application In Synthesis of [ 21524-39-0 ]

* 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 [ 21524-39-0 ]

[ 21524-39-0 ] Synthesis Path-Downstream   1~7

  • 1
  • [ 2785-78-6 ]
  • [ 21524-39-0 ]
  • 1-cyano-6,9-dimethyldibenzo[1,4]dioxine [ No CAS ]
  • 2
  • [ 21524-39-0 ]
  • [ 425379-16-4 ]
  • 3
  • [ 21524-39-0 ]
  • [ 1247885-40-0 ]
YieldReaction ConditionsOperation in experiment
13% With sulfuric acid; potassium nitrate; at 0℃; for 3.0h;Inert atmosphere; 2,3-difluoro-5-nitrobenzonitrile (0272) At 0 C., to a solution of 2,3-difluorobenzonitrile (20.8 g, 149.82 mmol) in sulfuric acid (100 mL) was added potassium nitrate (30.3 g, 299.59 mmol) in portions over 1 h period. The resulting solution was kept stirring for 2 h at 0 C. and then ice water (500 mL) was added. The resulting mixture was extracted with ethyl acetate (300 mL×3). The organic phases were combined, washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with ethyl acetate in hexane (0% to 10% gradient) to yield 2,3-difluoro-5-nitrobenzonitrile as brown solid (3.6 g, 13%).
11% With sulfuric acid; potassium nitrate; at 0℃; for 2.0h; Potassium nitrate (404 mg, 4.0 mmol) to a solution of 2,3- difluorobenzonitrile (278 mg, 2.0 mmol) in sulfuric acid (2 mL) at 00C. After stirring at 00C for 2 h the reaction was quenched with ice water (5 mL). The mixture was extracted with ethyl acetate (3x10 mL). The organic layer was dried and concentrated to give the crude product which was purified by silica gel (PE : EA = 40 : 1) to give the title compound as a yellow solid. (40 mg, 11%). 1H NMR (400 MHz, CDCl3): delta 8. 25-8.22 (m, IH), 7.69-7.63 (m, IH). LC/MS: m/e = 185 (M+H)+.
  • 4
  • [ 21524-39-0 ]
  • [ 85290-78-4 ]
  • C14H12FN3O2 [ No CAS ]
  • [ 1307314-29-9 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 2.5h; A mixture of 3 -methyl- lH-pyrazole-4-carboxylic acid ethyl ester (1.25 g, 8.1 1 mmol), potassium carbonate (1.68 g, 12.16 mmol), 2,3-difluorobenzonitrile (1.08 mL, 9.73 mmol) in dimethylformamide (12 mL) is heated at 100C with the aid of a magnetic stirred. After 2.5 hr. the reaction mixture is treated with water and extracted with ethyl acetate. The organic layer is decanted, washed with brine, dried over magnesium sulfate and the solvent evaporated under reduced pressure to give 2.3 g of l-(2-cyano-6-fluoro- phenyl)-3 -methyl- lH-pyrazole-4-carboxylic acid ethyl ester (this compound is contaminated with the other pyrazole regioisomer in a ratio 75:25). MS (m/z): 274 (M+1).
  • 5
  • [ 21524-39-0 ]
  • [ 85290-78-4 ]
  • [ 109-81-9 ]
  • [ 1307314-30-2 ]
  • C17H19FN4O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
A mixture of 3 -methyl- lH-pyrazole-4-carboxylic acid ethyl ester (1.25 g, 8.1 1 mmol), potassium carbonate (1.68 g, 12.16 mmol), 2,3-difluorobenzonitrile (1.08 mL, 9.73 mmol) in dimethylformamide (12 mL) is heated at 100C with the aid of a magnetic stirred. After 2.5 hr. the reaction mixture is treated with water and extracted with ethyl acetate. The organic layer is decanted, washed with brine, dried over magnesium sulfate and the solvent evaporated under reduced pressure to give 2.3 g of l-(2-cyano-6-fluoro- phenyl)-3 -methyl- lH-pyrazole-4-carboxylic acid ethyl ester (this compound is contaminated with the other pyrazole regioisomer in a ratio 75:25). MS (m/z): 274 (M+1). A capped vial is charged with ethyl l-(2-cyano-6-fluoro-phenyl)-3-methyl- pyrazole-4-carboxylate (1.97 g, 7.21 mmol) (contaminated with the other pyrazole regioisomer in a ratio of 75:25, 1,2-ethanediamine, N-methyl- (6 mL, 68.02 mmol) and phosphorus pentasulfide (229 mg, 1,01 mmol) and the mixture is stirred at 1 10C for 30 min and then allow to reach rt. Solvent is evaporated in vacuo and the residue purified by normal phase Isco chromatography using dichloromethane/2M ammonia in methanol from 95/5 to 85/15 as eluent to yield 2.1 1 g of ethyl l-[2-fluoro-6-(l-methyl-4,5- dihydroimidazol-2-yl)phenyl]-3-methyl-pyrazole-4-carboxylate (contaminated with the other pyrazole regioisomer in a ratio 75:25). MS (m/z): 331 (M+1).
  • 6
  • [ 21524-39-0 ]
  • [ 85290-78-4 ]
  • [ 109-81-9 ]
  • [ 1307314-31-3 ]
  • C17H17FN4O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
A mixture of 3 -methyl- lH-pyrazole-4-carboxylic acid ethyl ester (1.25 g, 8.1 1 mmol), potassium carbonate (1.68 g, 12.16 mmol), 2,3-difluorobenzonitrile (1.08 mL, 9.73 mmol) in dimethylformamide (12 mL) is heated at 100C with the aid of a magnetic stirred. After 2.5 hr. the reaction mixture is treated with water and extracted with ethyl acetate. The organic layer is decanted, washed with brine, dried over magnesium sulfate and the solvent evaporated under reduced pressure to give 2.3 g of l-(2-cyano-6-fluoro- phenyl)-3 -methyl- lH-pyrazole-4-carboxylic acid ethyl ester (this compound is contaminated with the other pyrazole regioisomer in a ratio 75:25). MS (m/z): 274 (M+1). A capped vial is charged with ethyl l-(2-cyano-6-fluoro-phenyl)-3-methyl- pyrazole-4-carboxylate (1.97 g, 7.21 mmol) (contaminated with the other pyrazole regioisomer in a ratio of 75:25, 1,2-ethanediamine, N-methyl- (6 mL, 68.02 mmol) and phosphorus pentasulfide (229 mg, 1,01 mmol) and the mixture is stirred at 1 10C for 30 min and then allow to reach rt. Solvent is evaporated in vacuo and the residue purified by normal phase Isco chromatography using dichloromethane/2M ammonia in methanol from 95/5 to 85/15 as eluent to yield 2.1 1 g of ethyl l-[2-fluoro-6-(l-methyl-4,5- dihydroimidazol-2-yl)phenyl]-3-methyl-pyrazole-4-carboxylate (contaminated with the other pyrazole regioisomer in a ratio 75:25). MS (m/z): 331 (M+1). Potassium permanganate (1.58 g, 10 mmmol) and montmorillonite K- 10 (3.16 g) are grounded together in a mortar until a fine homogeneous powder is obtained.KMn04-montmorillonite K-10 (3.2 g, 6.78 mmol) is added portionwise to a solution of ethyl l-[2-fluoro-6-(l-methyl-4,5-dihydroimidazol-2-yl)phenyl]-3-methyl-pyrazole-4- carboxylate (1.12 g, 3.39 mmol) (contaminated with the other pyrazole regioisomer in a ratio 75:25) in acetonitrile (84.76 mL, 1.62 moles). The mixture is stirred at room temperature for 6.5 hr. and more KMn04-montmorillonite K-10 (0.8 g, 1.69 mmol) is added portionwise and the mixture stirred at room temperature overnight. Ethanol is added and stirred for additional 20 min. Then the reaction mixture is filtered through a short pad of celite and the solid material is washed with acetonitrile. The solvent is evaporated under reduced pressure and the crude mixture is purified normal phase Isco chromatography using ethyl acetate as eluent to yield 518 mg of l-[2-fluoro-6-(l- methylimidazol-2-yl)phenyl]-3-methyl-pyrazole-4-carboxylate (contaminated with the other pyrazole regioisomer in a ratio 75:25). MS (m/z): 329 (M+1).
  • 7
  • [ 21524-39-0 ]
  • [ 1307248-44-7 ]
  • [ 85290-78-4 ]
  • [ 109-81-9 ]
  • [ 1307313-52-5 ]
YieldReaction ConditionsOperation in experiment
A mixture of 3 -methyl- lH-pyrazole-4-carboxylic acid ethyl ester (1.25 g, 8.1 1 mmol), potassium carbonate (1.68 g, 12.16 mmol), 2,3-difluorobenzonitrile (1.08 mL, 9.73 mmol) in dimethylformamide (12 mL) is heated at 100C with the aid of a magnetic stirred. After 2.5 hr. the reaction mixture is treated with water and extracted with ethyl acetate. The organic layer is decanted, washed with brine, dried over magnesium sulfate and the solvent evaporated under reduced pressure to give 2.3 g of l-(2-cyano-6-fluoro- phenyl)-3 -methyl- lH-pyrazole-4-carboxylic acid ethyl ester (this compound is contaminated with the other pyrazole regioisomer in a ratio 75:25). MS (m/z): 274 (M+1). A capped vial is charged with ethyl l-(2-cyano-6-fluoro-phenyl)-3-methyl- pyrazole-4-carboxylate (1.97 g, 7.21 mmol) (contaminated with the other pyrazole regioisomer in a ratio of 75:25, 1,2-ethanediamine, N-methyl- (6 mL, 68.02 mmol) and phosphorus pentasulfide (229 mg, 1,01 mmol) and the mixture is stirred at 1 10C for 30 min and then allow to reach rt. Solvent is evaporated in vacuo and the residue purified by normal phase Isco chromatography using dichloromethane/2M ammonia in methanol from 95/5 to 85/15 as eluent to yield 2.1 1 g of ethyl l-[2-fluoro-6-(l-methyl-4,5- dihydroimidazol-2-yl)phenyl]-3-methyl-pyrazole-4-carboxylate (contaminated with the other pyrazole regioisomer in a ratio 75:25). MS (m/z): 331 (M+1). Potassium permanganate (1.58 g, 10 mmmol) and montmorillonite K- 10 (3.16 g) are grounded together in a mortar until a fine homogeneous powder is obtained.KMn04-montmorillonite K-10 (3.2 g, 6.78 mmol) is added portionwise to a solution of ethyl l-[2-fluoro-6-(l-methyl-4,5-dihydroimidazol-2-yl)phenyl]-3-methyl-pyrazole-4- carboxylate (1.12 g, 3.39 mmol) (contaminated with the other pyrazole regioisomer in a ratio 75:25) in acetonitrile (84.76 mL, 1.62 moles). The mixture is stirred at room temperature for 6.5 hr. and more KMn04-montmorillonite K-10 (0.8 g, 1.69 mmol) is added portionwise and the mixture stirred at room temperature overnight. Ethanol is added and stirred for additional 20 min. Then the reaction mixture is filtered through a short pad of celite and the solid material is washed with acetonitrile. The solvent is evaporated under reduced pressure and the crude mixture is purified normal phase Isco chromatography using ethyl acetate as eluent to yield 518 mg of l-[2-fluoro-6-(l- methylimidazol-2-yl)phenyl]-3-methyl-pyrazole-4-carboxylate (contaminated with the other pyrazole regioisomer in a ratio 75:25). MS (m/z): 329 (M+1). 4. Gamma 1 - r2-Fruoro-6-C 1 -methylimidazol-2-yl phenyl1-3 -methyl-pyrazol-4-yllmethanolThis compound is essentially prepared as described in Preparation 29 by using ethyl l-[2-fluoro-6-(l-methylimidazol-2-yl)phenyl]-3-methyl-pyrazole-4-carboxylate (contaminated with the other pyrazole regioisomer in a ratio 75:25) in 99% yield. MS (m/z): 287 (M+l).5. l-r2-Fluoro-6-(l-methylimidazol-2-yl phenyl1-3-methyl-pyrazole-4-carbaldehvdeThe following compound is essentially prepared as described in Preparation 30 by using [l-[2-fluoro-6-(l-methylimidazol-2-yl)phenyl]-3-methyl-pyrazol-4-yl]methanol (contaminated with the other pyrazole regioisomer in a ratio 75:25). Residue is purified by normal phase Isco chromatography using ethyl acetate as eluent to give 64% yield of the title compound (contaminated with the other pyrazole regioisomer in a ratio 75:25). MS (m/z): 285 (M+l). To a screw-cap test tube containing a mixture of l-[2-fluoro-6-(l- methylimidazol-2-yl)phenyl]-3-methyl-pyrazole-4-carbaldehyde (288 mg, 1.01 mmol) (contaminated with the other pyrazole regioisomer in a ratio 75:25) and 2-chloro-4,4- difluoro-spiro[5H-thieno[2,3-c]pyran-7,4'-piperidine] (31 1.72 mg, 1.1 1 mmol) in 1,2- dichloroethane (3 mL) is stirred at room temperature for 1 hr. and then sodium triacetoxyborohydride (429.41 mg, 2.03 mmol) is added. The reaction tube is sealed and stirred at room temperature for 18 hr. with the aid of a magnetic stirrer. Then, the reaction is quenched by addition of sodium bicarbonate saturated solution and the compound is extracted with ethyl acetate. The organic layer is separated, dried over magnesium sulfate and the solvent removed under reduced pressure. The compound is purified by supercritical fluid chromatography using AD-H as stationary phase to provide 230 mg (41%) of the title compound as white solid. MS (m/z): 548 (M+l).
 

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