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Structure of 116369-24-5

Chemical Structure| 116369-24-5

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Product Details of [ 116369-24-5 ]

CAS No. :116369-24-5
Formula : C6H4BrClFN
M.W : 224.46
SMILES Code : NC1=CC(Cl)=C(Br)C=C1F
MDL No. :MFCD09878173
Boiling Point : No data available
InChI Key :SKJMNEFZWYBTHT-UHFFFAOYSA-N
Pubchem ID :14129196

Safety of [ 116369-24-5 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302
Precautionary Statements:P280-P305+P351+P338

Computational Chemistry of [ 116369-24-5 ] 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 1.0
Num. H-bond donors 1.0
Molar Refractivity 43.51
TPSA ?

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

26.02 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.87
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

2.66
Log Po/w (WLOGP)?

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

3.25
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.

3.26
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

2.88
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.78

Water Solubility

Log S (ESOL):?

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

-3.35
Solubility 0.0999 mg/ml ; 0.000445 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.

-2.86
Solubility 0.311 mg/ml ; 0.00139 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

-3.79
Solubility 0.0362 mg/ml ; 0.000161 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.

-5.78 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)

1.57

Application In Synthesis of [ 116369-24-5 ]

* 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 [ 116369-24-5 ]

[ 116369-24-5 ] Synthesis Path-Downstream   1~18

  • 1
  • [ 116369-24-5 ]
  • [ 1332333-18-2 ]
  • [ 1332333-75-1 ]
YieldReaction ConditionsOperation in experiment
60% a) N-(4-bromo-5-chloro-2-fluorophenyl)-2-[(35)-l-(cyclopropylcarbonyl)-3- pyrrolidinyl]acetyl}hydrazinecarboxamideTo a round bottom flask was added triphosgene (2.66 mmol) and dichloromethane (20 mL) under nitrogen, and the solution was cooled to -78 C. In a separate vial, 4- bromo-5-chloro-2-fluoroaniline (6.83 mmol) was dissolved in dichloromethane (20 mL) and Hunig's base (17.1 mmol) was added. This solution was slowly added to the cooled solution and then the reaction was allowed to warm to room temperature. After 10 min, analysis by LCMS indicated desired intermediate formation. The reaction was cooled again to -78 C and 2-[(35)-l-(cyclopropylcarbonyl)-3-pyrrolidinyl]acetohydrazide (3.98 mmol) in dichloromethane (5 mL) was added slowly. The reaction was allowed to warm to room temperature and stirred for 30 min. Analysis by LCMS indicated desired product formation. The reaction was poured into a separatory funnel and partitioned with saturated aq sodium bicarbonate. The aqueous layer was extracted with dichloromethane (3x) and the combined organic layers were dried over Na2S04, filtered, and concentrated to an oil. The residue was purified by silica gel chromatography (0-15%isopropanol/ethyl acetate). The desired fractions were combined and concentrated to afford the title product as an oil (1.12 g, 60%). MS(ES)+ m/e 461.1, 463.0 [M+H]+.
  • 2
  • [ 116369-24-5 ]
  • [ 1332333-76-2 ]
  • 3
  • [ 116369-24-5 ]
  • [ 1332332-75-8 ]
  • 4
  • [ 2106-05-0 ]
  • [ 116369-24-5 ]
YieldReaction ConditionsOperation in experiment
91% With N-Bromosuccinimide; In acetonitrile; at 25℃; for 1h; 4-Bromo-5-chloro-2-fluoroaniline To a mixture of 5-chloro-2-fluoroaniline (1 equiv.) in acetonitrile (0.5 M) was added N-bromosuccinimide (1 equiv.) at 25 C. The mixture was stirred at 25 C. for 1 h. The mixture was concentrated to a residue, the residue was purified via silica gel chromatography to give 4-bromo-5-chloro-2-fluoroaniline (91%) as a yellow oil. 1H NMR (400 MHz, CDCl3) delta ppm: 7.23 (d, J=10.2 Hz, 1H), 6.88 (d, J=8.4 Hz, 1H), 3.92-2.64 (br, 2H).
  • 5
  • [ 116369-24-5 ]
  • 4-bromo-2,3-dichloro-6-fluoroaniline [ No CAS ]
YieldReaction ConditionsOperation in experiment
76% With N-chloro-succinimide; In acetonitrile; at 90℃; for 0.5h; 4-Bromo-2,3-dichloro-6-fluoroaniline To a mixture of <strong>[116369-24-5]4-bromo-5-chloro-2-fluoroaniline</strong> (1 equiv.) in acetonitrile (0.36 M) was added NCS (1 equiv.) portion-wise at 90 C. over 30 min. The mixture was stirred at 90 C. for 1 h. The residue was purified by chromatography to give 4-bromo-2,3-dichloro-6-fluoroaniline (76%) as a brown solid. 1H NMR (400 MHz, CDCl3) delta ppm: 7.35 (d, J=10.5 Hz, 1H).
  • 6
  • [ 116369-24-5 ]
  • [ 1017777-51-3 ]
  • 7
  • [ 116369-24-5 ]
  • 1,2-dichloro-4-fluoro-3-isothiocyanatobenzene [ No CAS ]
  • 8
  • [ 116369-24-5 ]
  • (1s,4s)-4-(8-(2,3-dichloro-6-fluorophenylamino)-2-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl)cyclohexanecarboxamide [ No CAS ]
  • 9
  • [ 1027833-17-5 ]
  • [ 116369-24-5 ]
YieldReaction ConditionsOperation in experiment
88.75% With hydrogenchloride; iron; In ethanol; water; at 0℃; for 0.5h; To a stirred solution of 99 (23 g, 90.39 mmol) in EtOH (90 mL) and cone HC1 (90 mL) cooled to 0 C was added Fe powder (47.52 g, 848.5 mmol) in small portions over 30 min. After addition was complete, the reaction mixture was stirred at RT for another 30 min. The solvent was distilled off under reduced pressure. Water was added to the resulting residue and the mixture neutralized with NaHC03 and diluted with EtOAc. The resulting biphasic reaction mixture was filtered through Celite and washed with EtOAc. The phases of the filtrate were separated and the organic layer was washed with water and brine solution, dried over Na2S04 and concentrated to afford 100 (18 g, 88.75 %) as a yellow solid.
  • 10
  • [ 116369-24-5 ]
  • 2-chloro-4-(diallylamino)-5-fluorobenzonitrile [ No CAS ]
  • 11
  • [ 116369-24-5 ]
  • 2-chloro-4-(diallylamino)-5-fluorobenzoic acid [ No CAS ]
  • 12
  • [ 116369-24-5 ]
  • copper(l) cyanide [ No CAS ]
  • 4-amino-2-chloro-5-fluoro-benzonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
74% In N,N-dimethyl-formamide; at 150℃; for 5h; Copper(I) cyanide (3.99 g, 44.55 mmol) was added to a mixture of <strong>[116369-24-5]4-bromo-5-chloro-2-fluoroaniline</strong> (5.0 g, 22.28 mmol) in DMF (30 mL) at room temperature, and the mixture was stirred at 150C for 5 hr. To the reaction mixture were added water and ethyl acetate, and the mixture was filtered. The organic layer was washed with water and brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 4-amino-2-chloro-5-fluorobenzonitrile (2.81 g, 16.47 mmol, 74.0%) as a grayish white solid. 1H NMR (300 MHz, CDCl3):delta 4.34(2H,brs), 6.82(1H,d,J=7.6 Hz), 7.21-7.29(1H,m).
51.2% In N,N-dimethyl-formamide; at 140℃; for 10h; To a stirred solution of 100 (18 g, 80.19 mmol) in DMF (100 mL) was added cuprous cyanide (1 1.49 g, 128.2 mmol) and the resulting mixture was heated to 140 C for 10 h. The reaction mixture was cooled to RT and and DMF was evaporated under reduced pressure. The resulting residue was partitioned between DCM and water and the resulting biphasic mixture was filtered. The phases of the filtrate were separated and the organic layer was washed with brine, dried over Na2S04 and concentrated in vacuo. The crude compound was purified by column chromatography (4% EtOAc/hexane) to afford 101 (7 g, 51.20%) as a white solid.
  • 13
  • 2-bromo-1-chloro-4-fluorobenzene [ No CAS ]
  • [ 116369-24-5 ]
  • 14
  • [ 116369-24-5 ]
  • (R)-tert-butyl 2-((5-chloro-4-cyano-2-fluorophenyl)carbamoyl)morpholine-4-carboxylate [ No CAS ]
  • 15
  • [ 827614-66-4 ]
  • [ 116369-24-5 ]
  • 5-chloro-2-fluoro-4-(1-isobutyl-1H-pyrazol-4-yl)aniline [ No CAS ]
YieldReaction ConditionsOperation in experiment
67 mg With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 110℃; for 1h;Inert atmosphere; Irradiation; <strong>[116369-24-5]4-bromo-5-chloro-2-fluoroaniline</strong> (100mg, 0.446mmol),Isobutyl-1H-pyrazole-4-boronic acid pinacol ester(223 mg, 0.891 mmol),Pd (dppf) Cl2 (163 mg, 0.223 mmol)And potassium carbonate (123 mg, 0.890 mmol) were stirred in 1,4-dioxane / water (10 mL / 2 mL)Under nitrogen atmosphere, the temperature was raised to 110 C for 1 hour under microwave irradiation.Cool to room temperature,add water,Dichloromethane extraction,dry,Purification by column chromatography gave 5-chloro-2-fluoro-4- (1-isobutyl-1H-pyrazol-4-yl) aniline(67.0 mg).
  • 16
  • [ 827614-66-4 ]
  • [ 116369-24-5 ]
  • 1-((5H-imidazo[5,1-a]isoindol-5-yl) methyl)-3-(5-chloro-2-fluoro-4-(1-isobutyl-1H-pyrazol-4-yl)phenyl)urea [ No CAS ]
  • 17
  • [ 1233526-47-0 ]
  • [ 116369-24-5 ]
  • 5-chloro-2-fluoro-4-(1-cyclobutylmethyl-1H-pyrazol-4-yl)aniline [ No CAS ]
YieldReaction ConditionsOperation in experiment
47 mg With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 110℃; for 1h;Inert atmosphere; Irradiation; <strong>[116369-24-5]4-bromo-5-chloro-2-fluoroaniline</strong> (86mg, 0.383mmol),Cyclobutylmethyl-1H-pyrazole-4-boronic acid pinacol ester (200 mg, 0.763 mmol),Pd (dppf) Cl2 (140mg, 0.191mmol) and potassium carbonate (105mg, 0.760mmol) stirring in 1,4-dioxane / water (10mL / 2mL),Under nitrogen atmosphere, the temperature was raised to 110 C for 1 hour under microwave irradiation.Cool to room temperature,add water,Dichloromethane extraction,dry,Purification by column chromatography gave 5-chloro-2-fluoro-4- (1-cyclobutylmethyl-1H-pyrazol-4-yl) benzeneAmine (47.0 mg).
  • 18
  • [ 1349151-98-9 ]
  • [ 116369-24-5 ]
  • 5-(4-amino-2-chloro-5-fluorophenyl)-1-isopropylpyridine-2(1H)-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
64% With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); potassium carbonate; In 1,4-dioxane; water; at 80℃; for 10h;Inert atmosphere; Add <strong>[116369-24-5]4-bromo-5-chloro-2-fluoroaniline</strong> (0.5 g, 2.24 mmol) to 1,4-dioxane (8.0 mL) and water (4.0 mL), and then add 1-isopropyl-5 in this order. -(4,4,5,5-tetramethyl-1,3,2-dioxorane-2-yl) pyridine-2 (1H) -one (0.65 g, 2.46 mmol),Potassium carbonate (0.94g, 6.72mmol) and Pd (dppf) Cl2 (0.1g, 0.12mmol),After replacing with nitrogen three times, the reaction was carried out at 80 C for 10 hours.After the reaction is completed, cool to room temperature, pour the reaction solution into water, extract with ethyl acetate, combine the organic phases, dry, filter, and concentrate. The residue is purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether). = 3/1),The title compound (0.4 g, yield: 64%) was obtained in this step.
 

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