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Chemical Structure| 32247-96-4 Chemical Structure| 32247-96-4
Chemical Structure| 32247-96-4

3,5-Bis(trifluoromethyl)benzyl bromide

CAS No.: 32247-96-4

4.5 *For Research Use Only !

Cat. No.: A891640 Purity: 98%

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Product Citations

Product Citations

La Rosa, Chris ; Sharma, Pankaj ; Dar, M Junaid ; Jin, Yiru ; Qin, Lingli ; Roy, Anuradha , et al.

Abstract: CYP5122A1, an enzyme involved in sterol biosynthesis in Leishmania, was recently characterized as a sterol C4-methyl oxidase. Screening of a library of compounds against CYP5122A1 and from Leishmania resulted in the identification of two structurally related classes of inhibitors of these enzymes. Analogs of screening hit N-(3,5-dimethylphenyl)-4-(pyridin-4-ylmethyl)piperazine-1-carboxamide (4a) were generally strong inhibitors of but were less potent against CYP5122A1 and typically displayed weak inhibition of L. donovani promastigote growth. Analogs of screening hit N-(4-(benzyloxy)phenyl)-4-(2-(pyridin-4-yl)ethyl)piperazine-1-carboxamide (18a) were stronger inhibitors of both CYP5122A1 and L. donovani promastigote proliferation but also remained selective for inhibition of . Two compounds in this series, N-(4-((3,5-bis(trifluoromethyl)benzyl)oxy)phenyl)-4-(2-(pyridin-4-yl)ethyl)piperazine-1-carboxamide (18e) and N-(4-((3,5-di-tert-butylbenzyl)oxy)phenyl)-4-(2-(pyridin-4-yl)ethyl)piperazine-1-carboxamide (18i) showed modest selectivity for inhibiting L. donovani promastigote proliferation compared to J774 macrophages and were effective against intracellular L. donovani with EC50 values in the low micromolar range. Replacement of the 4-pyridyl ring present in 18e with imidazole resulted in a compound (4-(2-(1H-imidazol-1-yl)ethyl)-N-(4-((3,5-bis(trifluoromethyl)benzyl)oxy)phenyl)piperazine-1-carboxamide, 18p) with approximately fourfold selectivity for CYP5122A1 over that inhibited both enzymes with IC50 values ≤ 1 µM, although selective potency against L. donovani promastigotes was lost. Compound 18p also inhibited the proliferation of L. major promastigotes and caused the accumulation of 4-methylated sterols in L. major membranes, indicating that this compound blocks sterol demethylation at the 4-position in Leishmania parasites. The molecules described here may therefore be useful for the future identification of dual inhibitors of and CYP5122A1 as potential antileishmanial drug candidates and as probes to shed further light on sterol biosynthesis in Leishmania and related parasites.

Keywords: Leishmaniasis ; drug discovery ; ; CYP5122A1

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Product Details of [ 32247-96-4 ]

CAS No. :32247-96-4
Formula : C9H5BrF6
M.W : 307.03
SMILES Code : FC(F)(F)C1=CC(C(F)(F)F)=CC(CBr)=C1
MDL No. :MFCD00009905
InChI Key :ATLQGZVLWOURFU-UHFFFAOYSA-N
Pubchem ID :122573

Safety of [ 32247-96-4 ]

GHS Pictogram:
Signal Word:Danger
Hazard Statements:H225-H314
Precautionary Statements:P280-P305+P351+P338-P310
Class:8(3)
UN#:2920
Packing Group:

Calculated chemistry of [ 32247-96-4 ] Show Less

Physicochemical Properties

Num. heavy atoms 16
Num. arom. heavy atoms 6
Fraction Csp3 0.33
Num. rotatable bonds 3
Num. H-bond acceptors 6.0
Num. H-bond donors 0.0
Molar Refractivity 49.28
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.

2.61
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

4.25
Log Po/w (WLOGP)?

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

6.77
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.

5.08
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

4.94
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

4.73

Water Solubility

Log S (ESOL):?

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

-4.5
Solubility 0.0097 mg/ml ; 0.0000316 mol/l
Class?

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

Moderately soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-3.96
Solubility 0.0336 mg/ml ; 0.000109 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

-5.41
Solubility 0.00119 mg/ml ; 0.00000386 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

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.

-5.16 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

1.0
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)

2.11

Application In Synthesis of [ 32247-96-4 ]

* 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 [ 32247-96-4 ]

[ 32247-96-4 ] Synthesis Path-Downstream   1~5

  • 1
  • [ 2478-38-8 ]
  • [ 32247-96-4 ]
  • 1-[4-(3,5-Bis-trifluoromethyl-benzyloxy)-3,5-dimethoxy-phenyl]-ethanone [ No CAS ]
  • 2
  • [ 32707-89-4 ]
  • [ 32247-96-4 ]
YieldReaction ConditionsOperation in experiment
99.1% With sulfuric acid; hydrogen bromide; In water; at 50 - 105℃; for 10h;Heating / reflux; EXAMPLE 2 Preparation of 3, 5-bis (trifluoromethyl)-benzyl bromide; In a 4-neck flask with capacity 1000 ml equipped with mechanical agitator, thermometer, bubble condenser and 100 ml loading funnel, 262.2 g of the product of Example 1 (ii) at 92. 8% (0. 988 moles), 550,2 g HBr 48% (3.2645 moles) are loaded; this is heated at 50C so as to melt the alcohol, then one starts to dose 113 g of concentrated His04 (1.153 moles). Pouring is accomplished in 30 minutes, noting an increase of the internal temperature. This is heated to 100-105C and left to react for 8 hours. The reaction is completed by reflux heating for per 1.5 hours. the mixture is left to settle and the phases are separated; the solvents are removed from the organic phase and the product in the title is obtained with a yield of 99.1 %.
  • 3
  • [ 32247-96-4 ]
  • [ 186663-74-1 ]
  • tert-butyl (2-((3,5-bis(trifluoromethyl)benzyl)oxy)phenyl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
89% With potassium carbonate; In N,N-dimethyl-formamide; at 60℃;Inert atmosphere; General procedure: To a solution of the corresponding N-Boc-aminophenol (1 mmol) in DMF (2 mL), K2CO3 (207 mg,1.5 mmol) and the required benzyl bromide (1 mmol) were added. The mixture was stirred at 60 Cuntil no starting material was observed by TLC. A saturated aqueous solution of ammonium chloridewas added (5 mL) and the resulting mixture extracted with EtOAc (10 mL ×3), the organic extractswashed with brine (20 mL) and dried over MgSO4. The crude product was purified by FC eluting withhexane/EtOAc (95:5 ? 9:1).
  • 4
  • [ 32247-96-4 ]
  • [ 436-77-1 ]
  • C64H54F18N2O6(2+)*2Br(1-) [ No CAS ]
YieldReaction ConditionsOperation in experiment
11.22g With diethylamine; In dichloromethane; at 60℃; for 12h; Weigh 6.10g of <strong>[436-77-1]fangchinoline</strong>base dissolved in 150mL of dichloromethane in a 500mL three-necked flask, then add diethylamine10.50g of 10mL, 3,5-bis(trifluoromethyl)benzyl bromide, stirred, and kept at 60 C for 12 h, TLC detection of <strong>[436-77-1]fangchinoline</strong> all the reactions, distill off the dichloromethane, cool to room temperature, add 200 mL of water to dissolve, use 500g of H-type 732 type cationic resinWashed, washed with dilute ammonia water, distilled under reduced pressure to a liquid volume of about 50 mL, crystallized at room temperature overnight, filtered, TLC tracking reactionSeparation and purification from the product, the solid was dried at 60 C for 4 h to give 11.22 g of product as a yellow powder. Target productMelting point: 216.1-218.3 C, TOF-HRMS: M / e (1448.9020), molecular formula: C64H54O6N2F18Br2, that is, the chemical in Table 2Compound III74.
  • 5
  • [ 32247-96-4 ]
  • [ 436-77-1 ]
  • C46H44F6N2O6 [ No CAS ]
YieldReaction ConditionsOperation in experiment
69.6% General procedure: The mixture of stirred DTET (100 mg, 0.16 mmol) and NaH (20 mg,0.83 mmol) was dissolved in 2 mL DMF at 0 C. Then, R1Br (0.18 mmol)dissolved in 0.5 mL DMF was added to the DTET solution, and themixture was stirred until the TLC analysis showed that the reaction wascompleted. The temperature of the mixture was cooled to room temperatureand vacuum evaporated. The residue was purified using aluminumcolumn chromatography, and 3a-3m were obtained usingCH2Cl2/CH3OH as the eluent
4.65 g With diethylamine; In dichloromethane; at 0℃; for 48h; Weigh 6.10g of <strong>[436-77-1]fangchinoline</strong> dissolved in 100mL of dichloromethane in a 500mL three-necked flask.Then add 10 mL of diethylamine,3.10g of 3,5-bis(trifluoromethyl)benzyl bromide, stirred, and kept at 0 C for 48 h.HPLC to detect the total reaction of the <strong>[436-77-1]fangchinoline</strong>, distill off the dichloromethane to reduce the volume of the liquid to 1/4, cool to 5 C for crystallization overnight, filter,HPLC separates the separation and purification process of the reaction and the product,The solid was dried at 60 C for 4 h to give 4.65 g of product as a yellow powder.
 

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