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Structure of 384-16-7

Chemical Structure| 384-16-7

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Product Details of [ 384-16-7 ]

CAS No. :384-16-7
Formula : C7H3BrClF3
M.W : 259.45
SMILES Code : FC(C1=C(Br)C(Cl)=CC=C1)(F)F
MDL No. :MFCD00673988
Boiling Point : No data available
InChI Key :GMUWNTUONIQRFP-UHFFFAOYSA-N
Pubchem ID :17750574

Safety of [ 384-16-7 ]

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

Computational Chemistry of [ 384-16-7 ] Show Less

Physicochemical Properties

Num. heavy atoms 12
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 44.15
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.

2.31
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

4.13
Log Po/w (WLOGP)?

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

5.27
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.

4.66
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

4.17
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

4.11

Water Solubility

Log S (ESOL):?

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

-4.35
Solubility 0.0115 mg/ml ; 0.0000442 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.

-3.84
Solubility 0.0378 mg/ml ; 0.000146 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

-4.75
Solubility 0.00456 mg/ml ; 0.0000176 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

Yes
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.

-4.95 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)

1.5

Application In Synthesis of [ 384-16-7 ]

* 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 [ 384-16-7 ]

[ 384-16-7 ] Synthesis Path-Downstream   1~21

  • 1
  • [ 384-16-7 ]
  • C7H2(2)HClF3Li [ No CAS ]
  • 3
  • [ 384-16-7 ]
  • 4-(4-(1-(phenylsulfonyl)-3-vinyl-1H-pyrrolo[2,3-b]pyridine-5-yl)-1H-pyrazole-1-yl)piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]
  • C35H33ClF3N5O4S [ No CAS ]
YieldReaction ConditionsOperation in experiment
With tri-tert-butyl phosphine; tetrabutylammomium bromide; palladium diacetate; potassium carbonate; In N,N-dimethyl-formamide; toluene; at 150℃; for 1.5h;Microwave irradiation; To a microwave vial were added tert-butyl 4-(4-(l-(phenylsulfonyl)-3-vinyl-lH- pyrrolo[2,3-b]pyridin-5-yl)-lH-pyrazol-l-yl)piperidine-l-carboxylate (1.07 g, 2.0 mmol), 2- bromo-l-chloro-3-(trifluoromethyl)benzene (780 mg, 3.0 mmol), Pd(OAc)2 (9 mg, 40 mumol), TBAB (650 mg, 2.0 mmol), K2C03 (930 mg, 6.0 mmol), DMF (10 mL) and P(t-Bu)3 (36 mg, 74 umol, 1 M in toluene). The mixture was stirred and microwaved at 150 C for 90 minutes, then cooled to rt, washed with brine (150 mL) and extracted with DCM (150 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous Na2S04, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 4/1) to give the PhS02-protected product (purity: 88%).
  • 4
  • [ 384-16-7 ]
  • 2-(2-chloro-6-(trifluoromethyl)phenyl)-2-oxoacetic acid [ No CAS ]
  • 5
  • [ 384-16-7 ]
  • 2-(2-chloro-6-(trifluoromethyl)phenyl)-2-oxo-N-(pyridin-2-ylmethyl)acetamide [ No CAS ]
  • 6
  • [ 384-16-7 ]
  • (2-chloro-6-(trifluoromethyl)phenyl)(imidazo[1,5-a]pyridin-3-yl)methanone [ No CAS ]
  • 7
  • [ 384-16-7 ]
  • (1-bromoimidazo[1,5-a]pyridin-3-yl)(2-chloro-6-(trifluoromethyl)phenyl)methanone [ No CAS ]
  • 8
  • [ 384-16-7 ]
  • 4-(3-(2-chloro-6-(trifluoromethyl)benzoyl)imidazo[1,5-a]pyridin-1-yl)-2-methoxybenzoic acid [ No CAS ]
  • 9
  • [ 384-16-7 ]
  • 4-[3-[2-chloro-6-(trifluoromethyl)benzoyl]imidazo[1,5-a]pyridin-1-yl]-2-hydroxybenzoic acid [ No CAS ]
  • 10
  • [ 384-16-7 ]
  • [ 95-92-1 ]
  • ethyl 2-(2-chloro-6-(trifluoromethyl)phenyl)-2-oxoacetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
95% To a solution of <strong>[384-16-7]2-bromo-1-chloro-3-(trifluoromethyl)benzene</strong> (29, 2.45 g, 9.5 mmol) in dry THF (75 mL) at -78 C was added dropwise n-BuLi (4 mL,10 mmol) over 1 h under N2. The slurry was stirred at -78 C for 45 min, then a solution of the diethyl oxalate(1.46 g, 10 mmol) in THF (25 mL) was added dropwise over 1 h at -78 C and the mixture was stirred at -78 C for 45 min. The cooling bath was removed, and the temperature was allowed to rise to-20 C. A solution of NH4Cl (4 g) in water (75 mL) was then added over 5 min and the resulting mixture was concentrated under reduced pressure. The residue was partitioned between EtOAc (75 mL) andbrine (30 mL). The organic phase was separated, washed with brine (50 mL), dried and concentrated under reduced pressure to afford the title compound as a brown oil (2.5 g, 95%). LCMS (ESI): m/z = 298.0 [M+18]+.
  • 11
  • [ 384-16-7 ]
  • methyl (S,Z)-3-(6-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-1-en-1-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoate [ No CAS ]
  • methyl (S,E)-3-(6-(2-(2-chloro-6-(trifluoromethyl)phenyl)prop-1-en-1-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
22% With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In methanol; water; toluene; at 90℃; A mixture o met y , - - - - , , , -tetramethyl-1,3,2-dioxaborolan-2- yl)prop-1-en-1-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoate (1 g, 2.58 mmol), 2- bromo-1-chloro-3-(trifluoromethyl)benzene (1 g, 3.85 mmol), sodium carbonate (800 mg, 7.48 mmol), tetrakis(triphenylphosphine)palladium(0) (300 mg, 0.26 mmol), toluene (20 mL), methanol (10 mL) and water (5 mL) was stirred overnight at 90 C. The mixture was diluted with water, and extracted twice with dichloromethane. The combined organic layers were dried (Na2SO4) and concentrated. The resulting residue was purified via MPLC eluting with 20% ethyl acetate in petroleum ether to afford methyl (S,E)-3-(6-(2-(2-chloro-6- (trifluoromethyl)phenyl)prop-1 -en-1-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoate (250 mg, 22%) as a colorless oil.
  • 12
  • [ 384-16-7 ]
  • 4-(4-(1-(phenylsulfonyl)-3-vinyl-1H-pyrrolo[2,3-b]pyridine-5-yl)-1H-pyrazole-1-yl)piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]
  • C35H33ClF3N5O4S [ No CAS ]
YieldReaction ConditionsOperation in experiment
With tri-tert-butyl phosphine; tetrabutylammomium bromide; palladium diacetate; potassium carbonate; In N,N-dimethyl-formamide; toluene; at 150℃; for 1.5h;Microwave irradiation; The compound 4 - (4 - (1 - (phenyl-sulfonyl) -3 - vinyl - 1H - pyrrolo [2, 3 - b] pyridine -5 - yl) - 1H - pyrazole -1 - yl) piperidine -1 - carboxylic acid tert-butyl ester (1.07 g, 2.0 mmol), 2 - bromo -1 - chloro -3 - (trifluoromethyl) benzene (780 mg, 3.0 mmol), Pd (OAc)2 (9 Mg, 40 mumol), TBAB (650 mg, 2.0 mmol), K2 CO3 (930 Mg, 6.0 mmol), DMF (10 ml) and P (t - Bu)3 (36 Mg, 74 mumol, 1 M toluene solution) are sequentially placed in the microwave in the bottle, the mixture under microwave conditions, for 150 C stirring for 90 minutes, cooled to the room temperature, and then the salt water (150 ml) washing, for DCM (150 mLx 3) extraction, the combined organic phase for salt water (100 ml x 2) washing, anhydrous Na2 SO4 Drying, concentrated under reduced pressure, the residue by silica gel column chromatography (PE/EtOAc (v/v)=4/1) purified PhSO2 Protection of the product (HPLC: 88%). The upper step of the obtained compounds are dissolved in EtOH (40 ml) in, then to the reaction solution is added in an aqueous solution of NaOH (20 ml, 10%), the reaction liquid 90 C stirring for 1.5 hours, cooling to room temperature, concentrated under reduced pressure, the residual aqueous phase for EtOAc (50 ml x 3) extraction. The combined organic phase with anhydrous Na2 SO4 Drying, concentrated under reduced pressure, the residue by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to obtain the title compound as yellow solid (270 mg, 24%).
  • 13
  • [ 384-16-7 ]
  • 4-(4-(1-(phenylsulfonyl)-3-vinyl-1H-pyrrolo[2,3-b]pyridine-5-yl)-1H-pyrazole-1-yl)piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]
  • (E)-4-(4-(3-(2-chloro-6-(trifluoromethyl)styryl)-1H-pyrrolo[2,3-b]pyridine-5-yl)-1H-pyrazole-1-yl)piperidine-1-carboxylic acid tert-butyl [ No CAS ]
  • 14
  • [ 384-16-7 ]
  • 4-(3-formyl-1H-indazol-1-yl)benzoic acid ethyl ester [ No CAS ]
  • 4-(3-[2-chloro-6-(trifluoromethyl)phenyl](hydroxy)methyl}-1H-indazol-1-yl)benzoic acid ethyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
71 mg Under nitrogen substitution,2-Bromo-3-chlorobenzotrifluoride (212 mg)Of tetrahydrofuran (0.7 mL)Was added isopropyl magnesium chloride / lithium chloride complex / tetrahydrofuran solution (1.3 M, 0.63 mL) dropwise at room temperature and stirred for 1 hour.This solution was added to the ice-cooled compound (172 mg) obtained in Example 46c,In diethyl ether (3 mL) over 5 minutes.Thereafter, the mixture was stirred under ice-cooling for 2 hours and at room temperature for 2.5 hours.Since the reaction was not completed,Again <strong>[384-16-7]2-bromo-3-chlorobenzotrifluoride</strong> (212 mg),From isopropyl magnesium chloride / lithium chloride complex / tetrahydrofuran solution (1.3 M, 0.63 mL)Grignard reagent was prepared by the same operation as above,Was added dropwise to the ice-cooled reaction solution over 5 minutes.After stirring for 1 hour under ice cooling, 0.5N hydrochloric acid was added and the mixture was extracted with ethyl acetate.The extract layer was washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine,After drying with anhydrous sodium sulfate and filtration, the solvent was distilled off under reduced pressure.The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (71.0 mg) as a colorless transparent gummy solid.
  • 15
  • [ 384-16-7 ]
  • 4-{3-[2-chloro-6-(trifluoromethyl)benzoyl]imidazo[1,5-a]pyridin-1-yl}benzoic acid methyl ester [ No CAS ]
  • 16
  • [ 384-16-7 ]
  • {3-[2-chloro-6-(trifluoromethyl)benzoyl]imidazo[1,5-a]pyridin-1-yl}boronic acid [ No CAS ]
  • 17
  • [ 384-16-7 ]
  • methyl 6-{3-[2-chloro-6-(trifluoromethyl)benzoyl]imidazo[1,5-a]pyridin-1-yl}pyridine-3-carboxylate [ No CAS ]
  • 18
  • [ 384-16-7 ]
  • 4-[3-[2-chloro-6-(trifluoromethyl)benzoyl]imidazo[1,5-a]pyridin-1-yl]benzoic acid [ No CAS ]
  • 19
  • [ 384-16-7 ]
  • 6-{3-[2-chloro-6-(trifluoromethyl)benzoyl]imidazo[1,5-a]pyridin-1-yl}pyridine-3-carboxylic acid [ No CAS ]
  • 20
  • [ 384-16-7 ]
  • [ 56671-66-0 ]
  • [2-chloro-6-(trifluoromethyl)phenyl](imidazo[1,5-a]pyridin-3-yl)methanol [ No CAS ]
YieldReaction ConditionsOperation in experiment
1.22 g 2-Bromo-1-chloro-3-trifluoromethylbenzene (2.49 g)In tetrahydrofuran (25 mL) at -78 C.,n-Butyllithium (1.58 N hexane solution, 6.10 mL) was added,And the mixture was stirred at the same temperature for 30 minutes.Then, the obtained lithio compoundAt -78 C.,Imidazo [1,5-a] pyridine-3-carboxaldehyde (700 mg) in tetrahydrofuran (25 mL), and the mixture was stirred at -78 C. for 1 hour. Water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and then purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (1.22 g) as a pale yellow solid.
  • 21
  • [ 61676-62-8 ]
  • [ 384-16-7 ]
  • 2-(3-bromo-2-chloro-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ No CAS ]
YieldReaction ConditionsOperation in experiment
52% Lithium 2,2,6,6-tetramethylpiperidin-1-ide (2.84 g, 19.27 mmol) was placed in an oven-dried 250-mL round-bottomed flask in a glovebox and removed. Diethyl ether (75 mL) was added and the solution was cooled to -78 C (reaction mixture is not homogeneous). 2-Bromo-1-chloro-3-(trifluoromethyl)benzene (5.00 g, 19.3 mmol, 1.0 equiv) was added as solution in ether (25 mL) dropwise over 10 minutes and the mixture was allowed to stir at -78 C for 1 hour. 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.9 mL, 19.27 mmol, 1.0 equiv) was then added to the non-homogeneous reaction mixture over 10 minutes and the reaction was allowed to warm slowly to room temperature overnight. The reaction was quenched with saturated NH4C1 at 0 C and warmed to room temperature, layers separated. The aqueous was further extracted with diethyl ether (2) and the combined organics dried over sodium sulfate, filtered and concentrated. Purification over silica gel using a 0 to 5% ethyl acetate/hexane gradient afforded the title compound (3.87 g, 52% yield) as a viscous yellow oil.
 

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