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Chemical Structure| 445303-69-5 Chemical Structure| 445303-69-5

Structure of 445303-69-5

Chemical Structure| 445303-69-5

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Product Details of [ 445303-69-5 ]

CAS No. :445303-69-5
Formula : C7H4BrF3
M.W : 225.01
SMILES Code : FC(F)C1=C(F)C=CC(Br)=C1
MDL No. :MFCD06411633
InChI Key :YHQZVEGLXIBPRA-UHFFFAOYSA-N
Pubchem ID :2761161

Safety of [ 445303-69-5 ]

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

Computational Chemistry of [ 445303-69-5 ] Show Less

Physicochemical Properties

Num. heavy atoms 11
Num. arom. heavy atoms 6
Fraction Csp3 0.14
Num. rotatable bonds 1
Num. H-bond acceptors 3.0
Num. H-bond donors 0.0
Molar Refractivity 39.17
TPSA ?

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

0.0 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.11
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

3.33
Log Po/w (WLOGP)?

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

4.46
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.

4.37
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

3.79
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

3.61

Water Solubility

Log S (ESOL):?

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

-3.67
Solubility 0.048 mg/ml ; 0.000214 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.

-3.01
Solubility 0.222 mg/ml ; 0.000985 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

-4.14
Solubility 0.0162 mg/ml ; 0.0000719 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Moderately soluble

Pharmacokinetics

GI absorption?

Gatrointestinal absorption: according to the white of the BOILED-Egg

Low
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.

-5.31 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

1.0
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

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)

1.61

Application In Synthesis of [ 445303-69-5 ]

* 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 [ 445303-69-5 ]

[ 445303-69-5 ] Synthesis Path-Downstream   1~13

  • 1
  • [ 93777-26-5 ]
  • [ 445303-69-5 ]
YieldReaction ConditionsOperation in experiment
70% With diethylamino-sulfur trifluoride; In dichloromethane;Heating / reflux; 5-Bromo-2-fluorobenzaldehyde (2 g, 9.8 mmol) in CH2Cl2 (50 ml) was treated at 0C. with (diethylamino)sulfur trifluoride (2 ml, 14.8 mmol). The reaction mixture was refluxed overnight and then quenched with saturated solution of NaHCO3. The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed over silica gel (hexane-ethyl acetate 99 : 01) to provide 4-bromo-2-difluoromethyl-1-fluoro-benzene (1.55 g, 70%) as a colorless oil, MS: m/e=226.0 (M+H+).
61% With diethylamino-sulfur trifluoride; In dichloromethane; at 20.0℃; for 18.0h;Inert atmosphere; [143] To a solution of 5-bromo-2-fluoro-benzaldehyde (4.06 g, 20 mmol) in DCM (50 mL) was added DAST (diethylaminosulfur trifluoride) (4.03 g, 25 mmol) and the mixture was stirred at room temperature for 18 hours under nitrogen atmosphere. The reaction mixture was quenched into ice-water and extracted with DCM. The organic layer was dried and concentrated. Yield: 2.74 g (61 %)
With diethylamino-sulfur trifluoride; In dichloromethane; at 20.0℃; for 1.0h; Preparation 3:4-BROMO-2-(DIFLUOROMETHYL)-l-FLUOROBENZENE5-bromo-2-fluorobenzaldehyde (2.0 g, 9.85 mmol) and diethylaminosulfur trifluo?de (2.2 ml) was stirred at ambient temperature for 1 hour. Methylene chloride (100 ml) was added and the solution was cooled to 0 0C. Aqueous sodium bicarbonate (10%, 50 ml) was added slowly and the phases were separated. The organic phase was washed with water (50 ml), dried (MgSO4), filtered and evaporated to dryness to yield the crude product (1.79 g). MS m/z (rel. intensity, 70 eV) 226 (M+, 98), 224 (M+, bp), 207 (17), 145 (79), 125 (22).
  • 2
  • [ 144-55-8 ]
  • [ 93777-26-5 ]
  • [ 445303-69-5 ]
YieldReaction ConditionsOperation in experiment
70% With diethylaminosulfur trifluoride; In dichloromethane; 4-Bromo-2-difluoromethyl-1-fluoro-benzene 5-Bromo-2-fluorobenzaldehyde (2 g, 9.85 mmol) was dissolved in CH2Cl2 (50 ml). The reaction mixture was put under an argon atmosphere and cooled to 0 C. Diethylaminosulfur trifluoride (2.04 ml, 14.78 mmol) was added dropwise. The mixture was allowed to warm up to room temperature and stirred overnight. It was then quenched with a saturated aqueous NaHCO3 solution. The layers were separated and the aqueous one was extracted with CH2Cl2. The combined organic phases were dried with Na2SO4 and the solvent evaporated. The brown oil was chromatographed (silica, elution hexane/AcOEt) to afford the title compound (1.55 g, 70%) as a colorless oil. MS: m/e=226.0 (M+H+).
  • 3
  • [ 445303-69-5 ]
  • [ 73183-34-3 ]
  • 2-(3-(difluoromethyl)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ No CAS ]
YieldReaction ConditionsOperation in experiment
54% 2-(3-Difluoromethyl-4-fluoro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane The title compound was obtained according to example 342 as a colorless oil (54% yield) using <strong>[445303-69-5]4-bromo-2-difluoromethyl-1-fluoro-benzene</strong> and bis(pinacolato)diboron as the starting materials. MS: m/e=272 (M+).
With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 90.0℃; for 21.0h;Inert atmosphere; A stirred mixture of 4-bromo-2-(difluoromethyl)-l-fluorobenzene (0.53 g, 2.3 mmol), bis(pinacolato)diboron (0.72 g, 2.8 mmol), l,l'-bis(diphenylphosphino)- ferrocene-palladium dichloride (0.2 g, 0.24 mmol), and potassium acetate (0.7 g, 7.09 mmol) in dry 1,4-dioxane (7.0 mL) was purged three times with argon and placed under vacuum three times. The mixture was heated to 90 C and monitored with LC-MS and TLC. After 21 h, the reactions were cooled to rt then filtered through celite. The organic solvent was removed under reduced pressure, and the residue was purified on silica gel (0-10% EtOAc in hexanes) to yield a yellow liquid as 2-(3-(difluoromethyl)-4-fluorophenyl)-4,4,5,5-tetramethyl-l,3,2- dioxaborolane. .H NMR (500 MHz,CDCl3) delta ppm 8.22 (1 H, d, J=7.6 Hz), 8.12(1 H, m), 7.29 (1 H, ddd, J=9.8, 8.8, 0.7 Hz), 7.05 (1 H, t), 1.52 (12 H, s). Mass Spectrum (pos.) m/e: 273.1 (M+H)+.
  • 4
  • [ 445303-69-5 ]
  • [ 1692-15-5 ]
  • [ 941711-20-2 ]
YieldReaction ConditionsOperation in experiment
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; for 16.0h;Heating / reflux; Preparation 4:4-[3-(DIFLUOROMETHYL)-4-FLUOROPHENYL]PYRIDINETo a mixture of 4-bromo-2-(diotafluoromethyl)-l-fluorobenzene (0.5 g, 2.24 mmol), 1- pyriotadyl-4-boroniotac acid (0.33 g, 2.69 mmol) and sodium carbonate (0.64 g, 5.6 mmol) in toluene/ethanol (1 : 1, 20 ml) under nitrogen, was added palladium tetrakis (0.13 g , 5 mol%). The mixture was heated at reflux for 16 h, cooled to ambient temperature and <n="30"/>diluted with water (50 ml) and ethyl acetate (100 ml). The organic layer was separated and the aqueous phase was extracted with ethyl acetate (2x50 ml). The combined organic phases was evaporated to dryness and dissolved in aqueous hydrochloric acid (10%, 50 ml). The solution was washed with diethyl ether (2x40 ml), basified with aqueous sodium hydroxide (2M) and extracted with ethyl acetate (2x50 ml). The combined organic phases was dried (MgSO4) and evaporated to dryness to give the crude product. Purification by flash column chromatography (ethyl acetate/isooctane 2: 1) gave the title compound (0.34 g). MS m/z (rel. intensity, 70 eV) 223 (M+, bp), 222 (12), 204 (7), 172 (12), 145 (8).
  • 5
  • [ 445303-69-5 ]
  • [ 1354286-92-2 ]
  • 6
  • [ 445303-69-5 ]
  • 4-(4-fluorophenyl)-1-(1-methyl-1H-imidazol-4ylsulfonyl)pyrrolidin-3-amine hydrochloride [ No CAS ]
  • N-[3-(difluoromethyl)-4-fluorophenyl]-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]pyrrolidin-3-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In 1,2-dimethoxyethane; at 130.0℃; for 0.25h;Microwave irradiation; Sealed tube; To a 10 mL microwave vial was added 4-(4-fluorophenyl)-l-(l-methyl-lH-imidazol-4- ylsulfonyl)pyrrolidin-3 -amine hydrochloride (100 mg, 0.277 mmol) and premixed tris(dibenzylidene- acetone)dipalladium(0)/sodium tert-butoxide/ 2,2'-bis(diphenylphosphino)-l ,1 '-binaphthyl (100 mg, 0.05:0.15:2), aldrich 715530). The solids were suspended in 1 ,2-dimethoxyethane, and 4-bromo-2- (difluoromethyl)-l -fluorobenzene (74.8 mg, 0.333 mmol) was added. The reaction vessel was capped and the reaction mixture was heated in a microwave (Biotage Initiator, maximum 400 Watts) for 15 min at 130C. The mixture was filtered through celite, concentrated, dissolved in 2 ml 50% methanol/dimethylsulfoxide, and purified by HPLC to provide the title compound. MS (ESI) m/z 469 (M+H)+.
  • 7
  • [ 445303-69-5 ]
  • [ 77-71-4 ]
  • 3-[3-(difluoromethyl)-4-fluorophenyl]-5,5-dimethylimidazolidine-2,4-dione [ No CAS ]
  • 8
  • [ 445303-69-5 ]
  • [ 73183-34-3 ]
  • (3-(difluoromethyl)-4-fluorophenyl)boronic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
78% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 90.0℃;Inert atmosphere; A solution of 4-bromo-2-(difluoromethyl)-l-fluorobenzene (1.2 g, 5.33 mmol), bis(pinacolato)diboron (1.490 g, 5.87 mmol) and potassium acetate (1.570 g, 16.00 mmol) in 1 ,4-dioxane (20 mL) was flushed with nitrogen. PdCl2(dppf)-CH2Cl2 adduct (0.218 g, 0.267 mmol) was added and the reaction mixture was heated at 90 C overnight. The reaction mixture was then filtered through diatomaceous earth (Celite) and washed with ethyl acetate (100 mL). The filtrate was concentrated under reduced pressure and the crude product was purified by silica gel chromatography (0-25% EtOAc in hexanes) to afford (3-(difluoromethyl)-4- fluorophenyl)boronic acid (1.2 g, 4.17 mmol, 78% yield). NMR (400 MHz, CDCh): delta 8.04 (m, 1H), 7.90 (m, 1H), 7.1 1 (m, 1H), 6.87 (t, J = 15.2 Hz, 1H) ppm.
  • 9
  • [ 762262-09-9 ]
  • [ 445303-69-5 ]
  • 4-(3-(difluoromethyl)-4-fluorophenyl)-2-methoxypyridine [ No CAS ]
YieldReaction ConditionsOperation in experiment
74% With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 90.0℃; for 4.0h;Inert atmosphere; A solution of (2-methoxypyridin-4-yl)boronic acid (75 mg, 0.490 mmol), 4- bromo-2-(difluoromethyl)-l-fluorobenzene (121 mg, 0.539 mmol), potassium phosphate tribasic (312 mg, 1.471 mmol) and PdCl2(dppf)-CH2Cl2 adduct (20.02 mg, 0.025 mmol) in 1,4-dioxane (3 mL) and water (0.5 mL) was purged with nitrogen and heated to 90 C for 4 h. The reaction mixture was diluted with ethyl acetate (10 mL). The black suspension was filtered through diatomaceous earth (Celite) and the bed was washed with ethyl acetate (10 mL). The residue was purified via silica gel chromatography (15% pet ether: ethyl acetate) to afford 4-(3-(difluoromethyl)-4- fluorophenyl)-2-methoxypyridine (100 mg, 0.363 mmol, 74% yield) as a brown solid. LCMS (ESI) m/e 254.0 [(M+H)+, calcd for C13H11F3NO 254.1]; LC/MS retention time (Method C): tR = 1.02 min.
  • 10
  • [ 762262-09-9 ]
  • [ 445303-69-5 ]
  • (S)-1-(2-(difluoromethyl)-4-(2-methoxypyridin-4-yl)phenoxy)-2,4-dimethylpentan-2-amine [ No CAS ]
  • 11
  • [ 445303-69-5 ]
  • 3-(3-Difluoromethyl-4-fluoro-phenyl)-5-(2-methyl-imidazol-1-ylmethyl)-pyridine [ No CAS ]
  • 12
  • [ 445303-69-5 ]
  • (E)-3-(difluoroboraneyl)-3-phenyl-1-(pyrrolidin-1-yl)prop-2-en-1-one [ No CAS ]
  • (Z)-3-(3-(difluoromethyl)-4-fluorophenyl)-3-phenyl-1-(pyrrolidin-1-yl)prop-2-en-1-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
In ethanol; dichloromethane; at 20.0℃; for 48.0h; General procedure: To a solution of 4-bromo-2-methoxybenzaldehyde (1.0 g, 4.6 mmol) in anhydrous dichloromethane (4.7 mL) was added N-ethyl-N-(trifluoromethylsulfanyl)ethanamine (1.84 mL, 13.91 mmol) and anhydrous ethanol (500 muL) and the reaction mixture was stirred at room temperature for 48 h. The reaction was quenched with 2M aqueous sodium hydroxide (4.5 mL) at 0 C. The mixture was extracted with dichloromethane (3 x 15 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography eluting with n-heptane to afford the title compound (529 mg, 2.24 mmol, 48%) as a colorless oil. (0584) LCMS Method F: 100%, tR=2.348 min, no ion 1H NMR (300 MHz, Chloroform-d) d 7.44 (d, J = 8.1 Hz, 1H), 7.31- 7.14 (m, 1H), 7.13- 7.09 (m, 1H), 6.80 (t, J = 55.5 Hz, 1H), 4.11- 3.64 (m, 3H).
 

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