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Chemical Structure| 283173-80-8 Chemical Structure| 283173-80-8

Structure of 283173-80-8

Chemical Structure| 283173-80-8

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Product Details of [ 283173-80-8 ]

CAS No. :283173-80-8
Formula : C11H8BrFN2O
M.W : 283.10
SMILES Code : O=C1NCCC2=C(Br)NC3=C2C1=CC(F)=C3
MDL No. :MFCD23703297
InChI Key :DIUAWEVAOAYVBP-UHFFFAOYSA-N
Pubchem ID :22266717

Safety of [ 283173-80-8 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H317
Precautionary Statements:P280

Computational Chemistry of [ 283173-80-8 ] Show Less

Physicochemical Properties

Num. heavy atoms 16
Num. arom. heavy atoms 9
Fraction Csp3 0.18
Num. rotatable bonds 0
Num. H-bond acceptors 2.0
Num. H-bond donors 2.0
Molar Refractivity 65.72
TPSA ?

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

44.89 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.69
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

2.49
Log Po/w (WLOGP)?

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

2.39
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.

2.36
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

3.71
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.53

Water Solubility

Log S (ESOL):?

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

-3.58
Solubility 0.0744 mg/ml ; 0.000263 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.

-3.08
Solubility 0.237 mg/ml ; 0.000836 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

-5.18
Solubility 0.00187 mg/ml ; 0.00000659 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

Yes
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

Yes
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-6.26 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<0.0
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)

2.23

Application In Synthesis of [ 283173-80-8 ]

* 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.

  • Upstream synthesis route of [ 283173-80-8 ]
  • Downstream synthetic route of [ 283173-80-8 ]

[ 283173-80-8 ] Synthesis Path-Upstream   1~2

  • 1
  • [ 283173-80-8 ]
  • [ 518336-26-0 ]
  • [ 283173-50-2 ]
YieldReaction ConditionsOperation in experiment
6.82 g With bis(acetato)bis(triphenylphosphine)palladium(0); sodium carbonate In methanol; water at 60℃; for 4 h; Inert atmosphere 2-Bromo-8-fluoro-4,5-dihydro-lH-azepino[5,4,3-cd]indol-6(3H)-one (10 g; 35.3 mmol), prepared according to process described in Example 3, sodium carbonate (3.74 g; 35.3 mmol), bis(triphenylphosphine)palladium(II) diacetate (0.529 g; 0.71 mmol) and (4-((methylamino)methyl)phenyl)boronic acid solution (75 ml; 45.9 mmol), prepared according to process described in Example 2, are charged into a three-necked round bottom flask, followed by inertisation with nitrogen. A previously degassed mixture of methanol (130 mL) and water (40 mL) is added and the reaction mixture is stirred at 60°C for 4 hours. The reaction mixture is cooled to ambient temperature followed by addition of activated carbon. The mixture is stirred at ambient temperature for one hour, heated to 50 °C, stirred for another hour and then filtered through a layer of celite. The solution of 8-fluoro-2-(4- ((methylamino)methyl)phenyl)-4,5-dihydro-lH-azepino[5,4,3-cd]indol-6(3H)-one is concentrated to about 110 mL, heated to 40°C followed by dropwise addition of water (40 mL). Reaction mixture is cooled to ambient temperature and stirred for 17 hours at ambient temperature and additional one hour at 0-5°C. Solid is filtered off, washed with water and dried in vacuum oven at 50°C for 5 hours. Crude material (9.5 g) is suspended in methanol (95mL) at reflux temperature and stirred for 20 minutes. Suspension is than cooled down and stirred for 17 hours at ambient temperature and 1.5 hour at 0-5°C. Crystals are filtered off, washed with methanol and dried in vacuum oven at 50°C for 4 hours to obtain 6.82 g of Rucaparib base.
References: [1] Patent: WO2018/140377, 2018, A1, . Location in patent: Paragraph 00325; 00327.
  • 2
  • [ 283173-80-8 ]
  • [ 283173-50-2 ]
References: [1] Organic Process Research and Development, 2012, vol. 16, # 12, p. 1897 - 1904.
[2] Organic Process Research and Development, 2012, vol. 16, # 12, p. 1897 - 1904.
[3] ACS Chemical Neuroscience, 2018, vol. 9, # 6, p. 1259 - 1263.
 

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