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Chemical Structure| 456-14-4 Chemical Structure| 456-14-4

Structure of 456-14-4

Chemical Structure| 456-14-4

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Product Details of [ 456-14-4 ]

CAS No. :456-14-4
Formula : C7H8ClFN2
M.W : 174.60
SMILES Code : N=C(N)C1=CC=C(F)C=C1.[H]Cl
MDL No. :MFCD04114421
Boiling Point : No data available
InChI Key :JQDATBKJKUWNGA-UHFFFAOYSA-N
Pubchem ID :12456160

Safety of [ 456-14-4 ]

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

Computational Chemistry of [ 456-14-4 ] 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 44.63
TPSA ?

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

49.87 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

0.0
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

1.09
Log Po/w (WLOGP)?

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

2.33
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.

2.36
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

1.53
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.46

Water Solubility

Log S (ESOL):?

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

-1.95
Solubility 1.97 mg/ml ; 0.0113 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.

-1.73
Solubility 3.25 mg/ml ; 0.0186 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

-2.38
Solubility 0.726 mg/ml ; 0.00416 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.

-6.59 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

2.0 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)

1.19

Application In Synthesis of [ 456-14-4 ]

* 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 [ 456-14-4 ]

[ 456-14-4 ] Synthesis Path-Downstream   1~35

  • 1
  • [ 456-14-4 ]
  • [ 34461-00-2 ]
  • [ 324-98-1 ]
  • 2
  • [ 1194-02-1 ]
  • [ 456-14-4 ]
YieldReaction ConditionsOperation in experiment
35.5% With ammonia; In diethyl ether; ethanol; EXAMPLE 40 4-Fluorobenzamidine Hydrochloride 4-Fluorobenzonitrile (10 g, 83 mmol) is dissolved in a mixture of anhydrous ethanol (5 mL) and diethyl ether (70 mL). The reaction mixture is cooled to ice-bath temperature and saturated with gaseous hydrogen chloride for 90 minutes. The mixture is allowed to warm to ambient temperature and stirred overnight. The colorless precipitates are filtered off, washed with diethyl ether and dissolved in anhydrous ethanol (20 mL). Diethyl ether (100 mL) saturated with gaseous ammonia is added and the solution is stirred for 3 hours. The resulting suspension is filtered and the solvent of the filtrate is removed in vacuo. The residue is washed with diisopropyl ether. After drying colourless crystals (5.15 g, 35.5percent) of melting point 210° C. are obtained.
2.9 g (100%) EXAMPLE 4A 4-Fluorobenzenecarboximidamide Hydrochloride In analogy to the procedure for Example 3A, 2,0 g (16,5 mmol) 4-fluorobenzonitrile and proportionate amounts of the other reagents are used. Yield: 2.9 g (100percent) 1H-NMR (DMSO-d6, 200 MHz): delta=7,5 (m, 2H), 8,0 (m, 2H) ppm.
  • 3
  • [ 56108-05-5 ]
  • [ 456-14-4 ]
  • 4
  • [ 456-14-4 ]
  • [ 146379-79-5 ]
  • [ 1026696-94-5 ]
  • 5
  • [ 456-14-4 ]
  • [ 459-57-4 ]
  • [ 7152-15-0 ]
  • [ 123837-56-9 ]
  • 8
  • [ 87937-54-0 ]
  • [ 456-14-4 ]
  • [ 203914-77-6 ]
  • 9
  • [ 50897-91-1 ]
  • [ 456-14-4 ]
  • 6-(p-anisyl)-2-(p-fluorophenyl)-4-oxo-3,4-dihydropyrimidine-5-carbonitrile [ No CAS ]
  • 10
  • [ 456-14-4 ]
  • [ 947739-65-3 ]
  • 2,6-bis-(p-fluorophenyl)-4-oxo-3,4-dihydropyrimidine-5-carbonitrile [ No CAS ]
  • 11
  • [ 4360-68-3 ]
  • [ 5815-08-7 ]
  • [ 456-14-4 ]
  • [ 76128-69-3 ]
  • 12
  • [ 456-14-4 ]
  • [2-(4-Fluoro-phenyl)-quinazolin-8-yl]-acetic acid methyl ester [ No CAS ]
  • 13
  • [ 456-14-4 ]
  • [ 203914-84-5 ]
  • 14
  • [ 456-14-4 ]
  • Bromo-[8-bromo-2-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-quinazolin-8-yl]-acetic acid methyl ester [ No CAS ]
  • 15
  • [ 456-14-4 ]
  • [2-(4-Fluoro-phenyl)-4-methyl-6-(3-nitro-phenyl)-pyrimidin-5-yl]-(4-methyl-piperazin-1-yl)-methanone [ No CAS ]
  • 16
  • [ 456-14-4 ]
  • [ 122253-41-2 ]
  • 17
  • [ 456-14-4 ]
  • [ 122253-18-3 ]
  • 18
  • [ 456-14-4 ]
  • [ 122252-95-3 ]
  • 19
  • [ 456-14-4 ]
  • [ 122254-31-3 ]
  • 20
  • [ 456-14-4 ]
  • [ 122254-02-8 ]
  • 21
  • [ 456-14-4 ]
  • [ 122253-62-7 ]
  • 22
  • [ 456-14-4 ]
  • [ 122253-83-2 ]
  • 23
  • [ 456-14-4 ]
  • [ 123930-31-4 ]
  • 24
  • [ 456-14-4 ]
  • [ 477879-42-8 ]
YieldReaction ConditionsOperation in experiment
1.47 g (44%) EXAMPLE 11A N-{1-[3-(4-Fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]propyl} acetamide In analogy to the procedure for Example 10A, 2,0 g (11,4 mmol) <strong>[456-14-4]4-fluorobenzenecarboximidamide hydrochloride</strong> and proportionate amounts of the other reagents are used. Yield: 1.47 g (44percent) 1H-NMR (DMSO-d6, 300 MHz): delta=0,9 (t, 3H), 1,6 (m, 1H), 1,8 (m, 1H), 1,9 (s, 3H), 4,9 (m, 1H), 7,5 (m, 2H), 8,1 (m, 3H), 14,1 (br. s, 1H) ppm.
  • 25
  • [ 51673-64-4 ]
  • [ 456-14-4 ]
  • 2-(4-'-Fluorophenyl)-5-methyl-4-pyrimidinone [ No CAS ]
YieldReaction ConditionsOperation in experiment
10.3% In sodium hydroxide; ethanol; Example 38 2-(4-'-Fluorophenyl)-5-methyl-4-pyrimidinone Sodium hydride (0.52 g, 13 mmol) is added to 20 ml of anhydrous ethanol and stirred for 30 minutes at ambient temperature. To this, <strong>[456-14-4]4-fluorobenzamidine hydrochloride</strong> (1.47 g, 8.5 mmol) (from example 1) is added and the mixture is stirred for further 30 minutes. Methyl 2-formylpropionate (1 g, 10.6 mmol) is added dropwise and the reaction mixture is left for 4 days under stirring at ambient temperature. After cooling, the solvent is removed in vacuo and the residue is dissolved in aqueous sodium hydroxide (10 ml, 1M). Then the mixture is brought to pH 5 with 2 molar hydrochloric acid. The precipitate is filtered off and washed with diisopropyl ether. After drying, colorless crystals (0.44 g, 10.3percent) of melting point >250° C. are obtained.
  • 26
  • [ 51673-64-4 ]
  • [ 456-14-4 ]
  • [ 180606-36-4 ]
YieldReaction ConditionsOperation in experiment
10.3% In sodium hydroxide; ethanol; EXAMPLE 51 2-(4'Fluorophenyl)-5-methyl-4-pyrimidinone Sodium hydride (0.52 g, 13 mmol) is added to 20 mL of anhydrous ethanol and stirred for 30 minutes at ambient temperature. To this, <strong>[456-14-4]4-fluorobenzamidine hydrochloride</strong> (1.47 g, 8.5 mmol) (from example 40) is added and the mixture is stirred for further 30 minutes. Methyl 2-formylpropionate (1 g, 10.6 mmol) is added dropwise and the reaction mixture is left for 4 days under stirring at ambient temperature. After cooling, the solvent is removed in vacuo and the residue is dissolved in aqueous sodium hydroxide (10 mL, 1M). Then the mixture is brought to pH 5 with 2 molar hydrochloric acid. The precipitate is filtered off and washed with diisopropyl ether. After drying, colorless crystals (0.44 g, 10.3percent) of melting point >250° C. are obtained.
  • 27
  • [ 456-14-4 ]
  • [ 87234-37-5 ]
  • 5-propyl-2-(4-fluorophenyl)pyrimidine [ No CAS ]
YieldReaction ConditionsOperation in experiment
55% With sodium methylate; In methanol; ethanol; toluene; EXAMPLE 1 Preparation of 5-propyl-2-(4-fluorophenyl)pyrimidine To a sodium methylate solution under agitation obtained by dissolving Na (2.8 g, 0.12 mol) in anhydrous methanol (20 c.c.) was added <strong>[456-14-4]4-fluorobenzamidine hydrochloride</strong> (10.5 g, 0.06 mol), followed by adding alpha-propyl-beta-dimethylaminoacrolein (9.2 g, 0.06 mol), thereafter refluxing on heating for 3 hours with stirring, distilling off methanol under the atmospheric pressure after completion of the reaction, adding toluene (20cc) to the reaction residue to extract the resulting product, washing the extraction liquid with water, drying with anhydrous sodium sulfate, distilling off toluene and recrystallizing the remaining oily substance from ethanol (20 c.c.) to obtain the objective 5-propyl-2-(4-fluorophenyl)pyrimidine (7.0 g). Yield: 55%. M.P. 52.7 C.
  • 28
  • [ 75-70-7 ]
  • [ 456-14-4 ]
  • [ 138426-27-4 ]
YieldReaction ConditionsOperation in experiment
85% With sodium hydroxide; In dichloromethane; water; at 0 - 20℃; for 2h; General procedure: To a stirred solution of 2-fluorobenzenecarboximidamide (1.38 g, 10.0 mmol) and perchloromethyl mercaptan (1.07 mL, 10.0 mmol) in CH2Cl2 (10 mL) was added a solution of NaOH (1.60 g, 40.0 mmol) in H2O (4.0 mL) dropwise at 0 C. The mixture was stirred at 0 C for 1.0 h and at room temperature for 1.0 h. The organic layer was washed with water, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane?EtOAc) to give 9
With sodium hydroxide; In dichloromethane; water; at 0℃; for 0.5h; Intermediate 13; 5-Chloro-3-(4-fluoro-phenyl)-[1,2,4]thiadiazole; To a suspension of <strong>[456-14-4]4-fluorobenzamidine hydrochloride</strong> (0.385 g) in DCM (5 mL) was added perchloromethyl mercaptan (0.219 mL). The resulting mixture was cooled to 0° C., treated with 6 N NaOH (2 mL) and stirred for 30 min. The resulting mixture was diluted with water (10 mL) and extracted with DCM (20 mL). The organic layer was dried (MgSO4) and concentrated. Chromatography of the residue (0-20percent EtOAc-hexanes) gave the title compound as a yellow-orange solid (0.43 g).
  • 29
  • [ 456-14-4 ]
  • 2-dimethylaminomethylene-1,3-bis(dimethylimmonio)propane bistetrafluoroborate [ No CAS ]
  • [ 944904-93-2 ]
YieldReaction ConditionsOperation in experiment
With ethanol; potassium tert-butylate; for 8h;Heating / reflux; Example 132 3-[2-(4-Fluoro-phenyl)-pyrimidin-5-yl]-N-(thiazol-2-yl)-acrylamide [Show Image] (a) 2-(4-Fluoro-phenyl)-pyrimidine-5-carbaldehyde; 2 g (11.45 mmol) of <strong>[456-14-4]4-fluorobenzamidine hydrochloride</strong>, 4.09 g (11.45 mmol) of 2-dimethylaminomethylene-1,3-bis(dimethylimmonio)propane-bis(tetrafluoroborate) and 3.86 g (34.36 mmol) of potassium tert-butylate in 70 ml of ethanol were heated under reflux for 8 h. After concentration, water and ethyl acetate were added. The organic phase was washed with a potassium hydrogensulfate solution and water, dried and evaporated. Yield: 1.87 g.
  • 30
  • [ 110-85-0 ]
  • [ 456-14-4 ]
  • [ 594-42-3 ]
  • [ 1062512-45-1 ]
  • 32
  • [ 134653-70-6 ]
  • [ 456-14-4 ]
  • ethyl 2-(4-fluorophenyl)-4-methyl-pyrimidine-5-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
87% Example 42; 2-f4-Difluorophenyl)-4-methylpyrimidine-5-carboxylic acid-3-methylsulfamoyl-benzylamide; Step 1; <strong>[456-14-4]4-Fluorobenzamidine hydrochlorid</strong>e (1.25 g, 7.16 mmol) is added to a solution of sodium metal (0.17 g, 7.39 mmol) in dry ethanol (25 mL) and stirred at room temperature for 20 min. Ethyl-2- acetyl-3-(dimethylamino)acrylate (1.35 g, 7.16 mmol) is added. The mixture is heated to reflux for 3 hours. The solvent is removed in vacuo. The residue is dissolved in EtOAc, washed with water and brine, dried (MgSO4), filtered and concentrated in vacuo to afford ethyl-2-(4-fluorophenyl)-4-methyl- pyrirnidine-5-carboxylate (1.65 g, 87percent) as a solid. MS: 261 (M+H)
  • 33
  • [ 22179-78-8 ]
  • [ 456-14-4 ]
  • 34
  • [ 456-14-4 ]
  • [ 289-96-3 ]
  • [ 68049-17-2 ]
  • 35
  • [ 899694-59-8 ]
  • [ 456-14-4 ]
  • [ 1430808-99-3 ]
 

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