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Chemical Structure| 1015070-56-0 Chemical Structure| 1015070-56-0

Structure of 1015070-56-0

Chemical Structure| 1015070-56-0

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Product Details of [ 1015070-56-0 ]

CAS No. :1015070-56-0
Formula : C9H6BrNO
M.W : 224.05
SMILES Code : OC1=CN=CC2=C1C=C(Br)C=C2
English Name :6-Bromoisoquinolin-4-ol
MDL No. :MFCD18257891
InChI Key :KXGSBBRPEPMUTK-UHFFFAOYSA-N
Pubchem ID :57346151

Safety of [ 1015070-56-0 ]

Computational Chemistry of [ 1015070-56-0 ] 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 1.0
Molar Refractivity 51.47
TPSA ?

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

33.12 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.81
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

2.44
Log Po/w (WLOGP)?

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

2.7
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.

1.64
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

2.64
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.24

Water Solubility

Log S (ESOL):?

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

-3.38
Solubility 0.0928 mg/ml ; 0.000414 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.

-2.78
Solubility 0.373 mg/ml ; 0.00166 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

-3.98
Solubility 0.0232 mg/ml ; 0.000104 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.

-5.93 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

0.0
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)

1.38

Application In Synthesis of [ 1015070-56-0 ]

* 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 [ 1015070-56-0 ]

[ 1015070-56-0 ] Synthesis Path-Downstream   1~10

  • 1
  • [ 1015070-56-0 ]
  • [ 3061741-76-9 ]
  • [ 1015069-74-5 ]
YieldReaction ConditionsOperation in experiment
34% Stage #1: 6-bromoisoquinolin-4-ol; diazomethyl-trimethyl-silane In hexanes; N,N-dimethyl-formamide at 20℃; for 2.5h; Stage #2: With acetic acid In hexanes; N,N-dimethyl-formamide for 0.333333h; 5.1.42.E E. 6-Bromo-4-methoxyisoquinoline. To a solution of 6-bromoisoquinolin-4-ol (293 mg, 1.31 mmol) in DMF (6 mL) was added methanol (0.6 mL), and (trimethylsilyl)diazomethane (0.658 mL, 1.31 mmol, 2.0 M in hexanes). The reaction was stirred at room temperature for 90 minutes then additional (trimethylsilyl)diazomethane (1.32 mL, 2.62 mmol, 2.0 M in hexanes) was added. The reaction was stirred at room temperature for 60 minutes, quenched with acetic acid (3 mL), and stirred an additional 20 minutes. The mixture was neutralized with saturated aqueous sodium bicarbonate and extracted three times with dichloromethane. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solution was filtered and the volatiles were evaporated. The resulting material was purified using chromatography on a normal phase silica gel column with 0 to 45% ethyl acetate in hexanes. Fractions containing clean product were combined and the solvent evaporated. The material was dried under vacuum at room temperature to provide the title compound (312 mg, 34%). MS (ESI) m/z 238 [M+1]+ and MS (ESI) m/z 238 [M+1]+.
31 % In methanol; hexane; dichloromethane at 20℃; 1 Step 1. Synthesis of 6-bromo-4-methoxyisoquinoline To a solution of compound Int-3 (50 mg, 0.22 mmol) in DCM (3 mL) and MeOH (0.75 mL) was added TMSCHN2 (0.9 mL, 0.45 mmol, 2 M in hexane). The mixture was stirred at 20 °C for 2 hours. The reaction mixture was concentrated and the residue was purified by flash silica gel column (PE/EtOAc = 1/2) to give 6-bromo-4-methoxyisoquinoline (25 mg, yield: 31%) as an off- white solid.’H NMR (400 MHz, DMSO-d6) δ 4.06 (3H, s), 7.84-7.88 (1H, m), 8.09 (1H, d, J= 8.8 Hz), 8.22-8.31 (2H, m), 8.98 (1H, s).
31 % In methanol; hexane; dichloromethane at 20℃; 1 Step 1. Synthesis of 6-bromo-4-methoxyisoquinoline To a solution of compound Int-3 (50 mg, 0.22 mmol) in DCM (3 mL) and MeOH (0.75 mL) was added TMSCHN2 (0.9 mL, 0.45 mmol, 2 M in hexane). The mixture was stirred at 20 °C for 2 hours. The reaction mixture was concentrated and the residue was purified by flash silica gel column (PE/EtOAc = 1/2) to give 6-bromo-4-methoxyisoquinoline (25 mg, yield: 31%) as an off- white solid.’H NMR (400 MHz, DMSO-d6) δ 4.06 (3H, s), 7.84-7.88 (1H, m), 8.09 (1H, d, J= 8.8 Hz), 8.22-8.31 (2H, m), 8.98 (1H, s).
  • 2
  • [ 2916-68-9 ]
  • [ 1015070-56-0 ]
  • [ CAS Unavailable ]
  • [ 1235382-35-0 ]
YieldReaction ConditionsOperation in experiment
85.4% With N-ethyl-N,N-diisopropylamine at 60℃; for 8h; carbon monoxide atmosphere; 15.15b 6-Bromo-4-hydroxyisoquinoline (15.7 g, 70.0 mmol) produced in Example 15 (15a) was dissolved in dimethylformamide (100 mL), to which 2-trimethylsilylethanol (100 mL), diisopropylethylamine (27.1 g, 210 mmol), 1,3-bis(diphenylphosphino)propane (8.57 g, 21.0 mmol), and palladium chloride (3.72 g, 21.0 mmol) were then added, followed by stirring at 60°C for eight hours under a carbon monoxide atmosphere. The solvent was distilled off under reduced pressure. Water was added to the residue thus obtained, and the resulting mixture was extracted with dichloromethane. The resulting organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue thus obtained was purified by silica gel column chromatography((a mixed solvent of hexane : ethyl acetate - 1 : 1) : methanol, 100 : 0 - 70 : 30, V/V) to give the desired title compound (17.3 g, yield 85.4%). 1H-NMR (CDCl3 δ: 0. 11 (9H, s), 1.11-1.24 (2H, m), 4.46-4.55 (2H, m), 8.02 (1H, d, J = 8.4 Hz), 8.24 (1H, d, J = 8.4 Hz), 8.38 (1H, s), 8.87 (1H, s), 9.09 (1H, s).
  • 3
  • [ 1015070-56-0 ]
  • [ 1235380-73-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine / 1,3-bis-(diphenylphosphino)propane; palladium dichloride / 8 h / 60 °C / carbon monoxide atmosphere 2.1: pyridine / dichloromethane / 1 h / -25 - 20 °C 3.1: potassium carbonate / DavePhos; tris-(dibenzylideneacetone)dipalladium(0) / toluene / 1.5 h / Reflux; Inert atmosphere 4.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 1.5 h / 20 °C 4.2: 13 h / 20 °C / Inert atmosphere
  • 4
  • [ 1015070-56-0 ]
  • [ 1235382-39-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / 1,3-bis-(diphenylphosphino)propane; palladium dichloride / 8 h / 60 °C / carbon monoxide atmosphere 2: pyridine / dichloromethane / 1 h / -25 - 20 °C 3: potassium carbonate / DavePhos; tris-(dibenzylideneacetone)dipalladium(0) / toluene / 1.5 h / Reflux; Inert atmosphere
  • 5
  • [ 1015070-56-0 ]
  • [ 1235382-38-3 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / 1,3-bis-(diphenylphosphino)propane; palladium dichloride / 8 h / 60 °C / carbon monoxide atmosphere 2: pyridine / dichloromethane / 1 h / -25 - 20 °C
  • 6
  • [ 1235382-79-2 ]
  • [ 1015070-56-0 ]
YieldReaction ConditionsOperation in experiment
75% Stage #1: 6-Bromo-2-(phenylsulfonyl)-2,3-dihydroisoquinoline-4(1H)-one With sodium ethanolate In ethanol at 20℃; for 1h; Stage #2: With hydrogenchloride In ethanol; water 15.15a 6-Bromo-2-(phenylsulfonyl)-2,3-dihydroisoquinoline-4(1H)-one (29 g, 79.2 mmol) was produced from 4-bromobenzyl bromide in accordance with the method described in Tetrahedron 61 (2005) 8282 to 8287, and then suspended in ethanol (300 ml). To the resulting mixture, a 21% sodium ethoxide/ethanol solution (88.6 ml, 238 mmol) was added, followed by stirring at room temperature for one hour. To the resulting reaction liquid, 5M hydrochloric acid (approximately 50 ml) was added for neutralization, and then ethanol was distilled off under reduced pressure. A solid precipitate was collected by filtration. The solid was dried and then purified by silica gel column chromatography (dichloromethane : methanol, 100 : 0 - 50 : 50, V/V) to give the desired title compound (13.2 g, yield 75%). 1H-NMR (DMSO-D6) δ: 7.79 (1H, dd, J = 8.7, 1.8 Hz), 8.03 (1H, d, J = 8.7 Hz), 8.11 (1H, s), 8.25-8.27 (1H, m), 8.82 (1H, s), 10.62 (1H, s).
  • 7
  • [ 1015070-56-0 ]
  • [ 6226-25-1 ]
  • [ 2735689-02-6 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 3h; Intermediate 201. 6-bromo-4-(2,2,2-trifluoroethoxy)isoquinoline To a solution of 6-bromoisoquinolin-4-ol (0.5 g, 2.23 mmol, 1 equiv) in DMF (5mL) was added potassium carbonate (925 mg, 6.69 mmol, 3 equiv) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (777 mg, 3.35 mmol, 1.5 equiv). The reaction mixture was heated to 80oC. After 3 hours, the reaction mixture was diluted with brine (50 mL) and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. Purification was accomplished by SiO2 chromatography (0-100% EtOAc/Hex), affording 6- bromo-4-(2,2,2-trifluoroethoxy)isoquinoline. ES/MS m/z: 306.00 [M+H];1H NMR (400 MHz, Chloroform-d) δ 8.98 (s, 1H), 8.42 - 8.37 (m, 1H), 8.13 (s, 1H), 7.87 (d, J = 8.7 Hz, 1H), 7.78 (dd, J = 8.7, 1.9 Hz, 1H), 4.63 (q, J = 7.9 Hz, 2H).19F NMR (376 MHz, Chloroform-d) δ -74.28 (t, J = 7.9 Hz).
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 3h; Intermediate 201. 6-bromo-4-(2,2,2-trifluoroethoxy)isoquinoline To a solution of 6-bromoisoquinolin-4-ol (0.5 g, 2.23 mmol, 1 equiv) in DMF (5mL) was added potassium carbonate (925 mg, 6.69 mmol, 3 equiv) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (777 mg, 3.35 mmol, 1.5 equiv). The reaction mixture was heated to 80oC. After 3 hours, the reaction mixture was diluted with brine (50 mL) and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. Purification was accomplished by SiO2 chromatography (0-100% EtOAc/Hex), affording 6- bromo-4-(2,2,2-trifluoroethoxy)isoquinoline. ES/MS m/z: 306.00 [M+H];1H NMR (400 MHz, Chloroform-d) δ 8.98 (s, 1H), 8.42 - 8.37 (m, 1H), 8.13 (s, 1H), 7.87 (d, J = 8.7 Hz, 1H), 7.78 (dd, J = 8.7, 1.9 Hz, 1H), 4.63 (q, J = 7.9 Hz, 2H).19F NMR (376 MHz, Chloroform-d) δ -74.28 (t, J = 7.9 Hz).
  • 8
  • [ 1015070-56-0 ]
  • [ 2941124-04-3 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: azodicarboxylic acid bis(dimethylamide); tributylphosphine / toluene / 16 h / 110 °C / Inert atmosphere 2: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane / 12 h / 80 °C / Inert atmosphere
  • 9
  • [ 1015070-56-0 ]
  • [ 2941124-05-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: azodicarboxylic acid bis(dimethylamide); tributylphosphine / toluene / 16 h / 110 °C / Inert atmosphere 2: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane / 12 h / 80 °C / Inert atmosphere 3: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate / 1,4-dioxane; water / 12 h / 90 °C / Inert atmosphere
  • 10
  • [ 1015070-56-0 ]
  • [ 2941119-36-2 ]
  • [ 2941119-37-3 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: azodicarboxylic acid bis(dimethylamide); tributylphosphine / toluene / 16 h / 110 °C / Inert atmosphere 2: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane / 12 h / 80 °C / Inert atmosphere 3: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate / 1,4-dioxane; water / 12 h / 90 °C / Inert atmosphere 4: lithium hydroxide monohydrate; water / tetrahydrofuran; methanol / 2 h / 25 °C
 

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Technical Information

Categories

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