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Structure of 1133115-78-2

Chemical Structure| 1133115-78-2

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Product Details of [ 1133115-78-2 ]

CAS No. :1133115-78-2
Formula : C9H5BrFN
M.W : 226.05
SMILES Code : FC1=C2N=CC=CC2=C(Br)C=C1
MDL No. :MFCD11855895
InChI Key :KXPOUFUCFZQOQE-UHFFFAOYSA-N
Pubchem ID :46739263

Safety of [ 1133115-78-2 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Computational Chemistry of [ 1133115-78-2 ] Show Less

Physicochemical Properties

Num. heavy atoms 12
Num. arom. heavy atoms 10
Fraction Csp3 0.0
Num. rotatable bonds 0
Num. H-bond acceptors 2.0
Num. H-bond donors 0.0
Molar Refractivity 49.4
TPSA ?

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

12.89 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.08
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

3.35
Log Po/w (WLOGP)?

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

3.56
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.

2.98
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

3.54
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

3.1

Water Solubility

Log S (ESOL):?

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

-3.97
Solubility 0.0243 mg/ml ; 0.000107 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.

-3.3
Solubility 0.114 mg/ml ; 0.000503 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

-4.84
Solubility 0.00327 mg/ml ; 0.0000145 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

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.

-5.3 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

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)

1.59

Application In Synthesis of [ 1133115-78-2 ]

* 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 [ 1133115-78-2 ]

[ 1133115-78-2 ] Synthesis Path-Downstream   1~11

  • 1
  • [ 2924-09-6 ]
  • [ 56-81-5 ]
  • [ 1133115-78-2 ]
YieldReaction ConditionsOperation in experiment
INTERMEDIATE 4 5-BROMO-8-FLUORO-2-METHOXYQUINOLINE25MRL DOB-00006Step A. 5-Bromo-8-fluoroquinolme5-Bromo-2-fluoroaniline (1.0 g, 5.3 mmol) was mixed with glycerol (2.0 raL, 27 mmoi), sodium 3 -nitrobenzene sulfonate (1.2 g, 5.3 mmol) and concentrated sulfuric acid (85 mL), then the mixture was heated to 14O0C for 2 hours. The inital suspension became a dark brown solution. The mixture was allowed to cool to room temperature. The solution was made basic with 5N NaOH (30 mL), then extracted with EtOAc. The combined organic phase was washed with water then saturated NaCl (aq), dried over MgSO4, filtered, then concentrated to afford the title compound as a white solid:. 1H NMR (500 MHz, CDCl3): delta 9.00 (d, J = 4.2 Hz, 110 H); 8.54 (d, J = 8.6 Hz, 1 H); 7.77 (dd, J = 8.3, 4.5 Hz, 1 H); 7.59 (dd, J - 8.6, 4.2 Hz, 1 H); 7.32 (dd, J - 9.9, 8.3 Hz, 1 H). LC4 1.81 min. (M+H) = 226.
  • 2
  • [ 1133115-78-2 ]
  • C9H5BrFNO [ No CAS ]
YieldReaction ConditionsOperation in experiment
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 20.0℃; for 16.0h; Step B. 5-Bromo-2-chloro-8-fluoroquinolme15 3-Chloroperoxybenzoic acid (8.72 g, 35.4 mmol) was added to 5-bromo-8- fluoroquinoline (4.0 g, 18 mmol) in CH2Cl2 (50 mL) at room temperature. After stirring for 16 hours, the solution was diluted with CH2Cl2 (200 mL) and washed with 4 M NaOH (aq) (100 mL), then saturated NaCl (aq) (100 mL). The organic layer was dried over Na2SO4, filtered, then concentrated. The residue was purified by silica gel chromatography eluting with 0-100%20 EtOAc/hexanes to afford the N-oxide as a white solid. 1H NMR (600 MHz, CDCl3): delta 8.45 (d, J = 6.1 Hz, 1 H); 7.98 (d, J - 8.8 Hz, 1 H); 7.78 (dd, J = 8.5, 3.8 Hz, 1 H); 7.36 (dd, J - 8.8, 6.1 Hz5 1 H); 7.21 (dd, J - 12.5, 8.4 Hz, 1 H); LC4: 1.25 min. (M+H) 244.A solution of the N-oxide from the previous step (1.0 g, 4.1 mmol) and POCl3 (1.2 mL, 12 mmol) in CHCl3 (10 mL) was refluxed for one hour, then allowed to cool to room25 temperature. The solution was washed with saturated NaHCO3 (aq), dried over MgSO4, filtered, then concentrated to afford the title compound as an off-white solid. 1H NMR (500 MHz, CDCl3): delta 8.51 (d, J = 8.9 Hz, 1 H); 7.81 (dd, J = 8.4, 4.4 Hz, 1 H); 7.59 (d, J = 8.9 Hz, 1 H); 7.38 (t, J - 9.0 Hz, 1 H). LCl 1.67 min. (M+H) = 260. MRLDOB-00006
  • 3
  • [ 2924-09-6 ]
  • [ 107-02-8 ]
  • [ 1133115-78-2 ]
YieldReaction ConditionsOperation in experiment
Intermediate 47 5-Bromo-8-fluoroquinoline A mixture of 5-bromo-2-fluoroaniline (commercially available, for example, from Fluorochem) (21.45 g, 113 mmol) and 6M hydrochloric acid (90 ml) at -50 0C was treated with toluene (150 ml). The mixture was warmed to -60 0C and acrolein (15.1 ml, 226 mmol) was added slowly over 20 min.The mixture was then heated at reflux for 1 h 45 min. The cooled mixture was made alkaline with1OM NaOH aq and extracted with EtOAc. The extracts were washed with brine, dried and evaporated to give a brown oil that was purified by flash column chromatography on silica using mixtures of EtOAc and cyclohexane (1 :9 to 1 :6 ratio) as eluent. Evaporation of the solvent from appropriate fractions gave the title compound (6.69 g). LCMS RT= 2.84 min, ES+ve m/z 226/228[M+H]+.
  • 4
  • [ 1133115-78-2 ]
  • [ 109384-19-2 ]
  • [ 954235-85-9 ]
  • [ 1241746-01-9 ]
YieldReaction ConditionsOperation in experiment
Intermediate 48 1,1-Dimethylethyl 4-[(5-bromo-8-quinolinyl)oxy]-1-piperidinecarboxylate and 1,1-dimethylethyl 4-(8-quinolinyloxy)-1-piperidinecarboxylate (55:45 mixture) A stirring solution of t-butyl 4-hydroxy-1-piperidinecarboxylate (commercially available, for example, from Aldrich) (1.7817 g, 13.275 mmol) in NMP (8 ml) was treated portion-wise with NaH (531 mg of60% dispersion in mineral oil, 4.65 mmol). After effervescence had ceased, <strong>[1133115-78-2]5-bromo-8-fluoroquinoline</strong> (for example, as prepared for Intermediate 47) (2 g, 8.85 mmol) was added and the mixture was heated at 80 0C for 64 h. The mixture was partitioned between EtOAc and water and the organic layer was washed with water (twice) and brine, dried over anhydrous magnesium sulphate and evaporated to give a brown oil. This material was purified by Flashmaster Il on a silica cartridge (100 g) using a 0-100% EtOAc in DCM gradient over 60 min. Evaporation of the solvent from appropriate fractions gave a 55:45 mixture of the title compounds. LCMS RT= 3.47 min and 2.76 min, ES+ve m/z 407/409 [M+H]+ and 329 [M+H]+.
  • 5
  • [ 1133115-78-2 ]
  • (7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(piperidin-4-yl)methanone 2,2,2-trifluoroacetate [ No CAS ]
  • (7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(1-(8-fluoroquinolin-5-yl)piperidin-4-yl)methanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
22% With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; In toluene; at 95.0℃; To a solution of (7-cyclopropylimidazo [1, 5-a] pyridin-8-yl) (piperidin-4-yl) methanone 2, 2, 2-trifluoroacetate (3.83 g, 10 mmol, 1.00 eq) dissolved in toluene (150 mL) was added <strong>[1133115-78-2]5-bromo-8-fluoroquinoline</strong> (2.25 g, 10 mmol, 1.00 eq), Pd2 (dba) 3 (0.915 g, 1 mmol, 0.10 eq), s-phos (0.952 g, 1 mmol, 0.20 eq) and Cs2CO3 (8.13 g, 25 mmol, 2.50 eq). Then the mixture was stirred at 95 for overnight. The solvent was evaporated under reduced pressure. The crude was purified by column chromatography on silica gel 50g (PE/EA = 1/2) to give compound 8 (907 mg, 22% yield) as a yellow solid. 1H NMR (CDCL3) deltaH8.96 (dd, J= 1.6 Hz, J= 4.4 Hz, 1H), 8.52 (d, J = 8.8 Hz, 1H), 8.17 (s, 1H), 7.91 (d, J= 7.6 Hz, 1H), 7.46-7.51 (m, 1H), 7.27-7.36 (m, 2H), 7.00-7.09 (m, 1H), 6.16 (d, J= 7.6 Hz, 1H), 3.20-3.43 (m, 3H), 2.75-2.90 (m, 2H), 2.10-2.15 (m, 2H), 1.93-1.99 (m, 1H), 1.69-1.75 (m, 1H), 1.05-1.11 (m, 2H) and 0.77-0.85 (m, 2H).
  • 6
  • [ 1133115-78-2 ]
  • (7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(1-(8-fluoroquinolin-5-yl)piperidin-4-yl)methanol [ No CAS ]
  • 7
  • [ 1133115-78-2 ]
  • (S)-(7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(1-(8-fluoroquinolin-5-yl)piperidin-4-yl)methanol [ No CAS ]
  • (R)-(7-cyclopropylimidazo[1,5-a]pyridin-8-yl)(1-(8-fluoroquinolin-5-yl)piperidin-4-yl)methanol [ No CAS ]
  • 8
  • [ 557-21-1 ]
  • [ 1133115-78-2 ]
  • 8-fluoroquinoline-5-carbonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
94% With tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 150.0℃; for 0.5h;Microwave irradiation; 5-Bromo-8-fluoroquinoline (0.50 g, 2.21 muMol) was dissolved DMF (11 mL), and tetrakis(triphenylphosphine)palladium(0) (0.26 g, 0.22 muMol) and zinc cyanide (0.39 g, 3.32 muMol) were added to the solution. The mixturewas subjected to a reaction at a temperature of 150C for 30 minutes using a microwave reactor, Initiator, manufacturedby Biotage. The mixture was cooled to room temperature, and a saturated aqueous sodium bicarbonate solution wasadded to the mixture. The mixture was filtered with Celite(R). The organic layer was extracted with ethyl acetate, washedwith saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (heptane/ethyl acetate = 90/10 -> 60/40) to obtain compound 54-1(0.36 g, 94%).1H NMR (400 MHz, CDCl3, delta): 9.12 (dd, J = 4.5, 1.5 Hz, 1H), 8.58 (dt, J = 8.5, 1.5 Hz, 1H), 7.99 (dd, J = 8.3, 4.5 Hz,1H), 7.72 (dd, J = 8.5, 4.0 Hz, 1H), 7.50 (dd, J = 9.6, 8.3 Hz, 1H)ESIMS m/z: [M + H]+ 173.
  • 9
  • [ 1133115-78-2 ]
  • iodo(3-methoxycarbonylcyclobutyl)zinc [ No CAS ]
  • C15H14FNO2 [ No CAS ]
  • 10
  • [ 1133115-78-2 ]
  • (3-cyanocyclobutyl)iodozinc [ No CAS ]
  • C14H11FN2 [ No CAS ]
  • 11
  • [ 1133115-78-2 ]
  • N-(4-fluorophenyl)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide [ No CAS ]
  • N‐(4‐fluorophenyl)‐2‐[4‐(8‐fluoroquinolin‐5‐yl)phenyl]acetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
53% With tetrakis(triphenylphosphine) palladium(0); cesium fluoride; In 1,4-dioxane; at 100.0℃; for 6.0h; Compound 17 (30 mg, 0.085 mmol),<strong>[1133115-78-2]5-bromo-8-fluoroquinoline</strong> (19 mg, 0.085 mmol),Pd[PPh3]4 (10mg, 0.0085mmol)And CsF (38 mg, 0.255 mmol) was heated to 100 C in dioxane (2 mL) for 6 hours.Concentrated and added water (100 mL), EtOAc (EtOAc)The organic phase was separated and dried over anhydrous Na 2 SO 4Filter and concentrate, and the residue was purified by silica gel column chromatography.Elution with ethyl acetate/petroleum ether (2:3) gave the desired compound I-42 (17 mg, 53%).
 

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