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Structure of 215184-78-4

Chemical Structure| 215184-78-4

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Product Details of [ 215184-78-4 ]

CAS No. :215184-78-4
Formula : C14H18BrNO2
M.W : 312.20
SMILES Code : BrC1=C2C(=CC=C1)CN(CC2)C(=O)OC(C)(C)C
MDL No. :MFCD08752227
InChI Key :YSAAGRAKROVFRY-UHFFFAOYSA-N
Pubchem ID :18315369

Safety of [ 215184-78-4 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H332-H335
Precautionary Statements:P280-P305+P351+P338-P310

Computational Chemistry of [ 215184-78-4 ] Show Less

Physicochemical Properties

Num. heavy atoms 18
Num. arom. heavy atoms 6
Fraction Csp3 0.5
Num. rotatable bonds 3
Num. H-bond acceptors 2.0
Num. H-bond donors 0.0
Molar Refractivity 79.33
TPSA ?

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

29.54 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

3.4
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

3.33
Log Po/w (WLOGP)?

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

3.21
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.

3.18
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

3.11
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

3.24

Water Solubility

Log S (ESOL):?

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

-3.92
Solubility 0.0373 mg/ml ; 0.00012 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.

-3.63
Solubility 0.0737 mg/ml ; 0.000236 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

-4.3
Solubility 0.0157 mg/ml ; 0.0000504 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

Yes
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

Yes
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.

-5.84 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)

2.39

Application In Synthesis of [ 215184-78-4 ]

* 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 [ 215184-78-4 ]

[ 215184-78-4 ] Synthesis Path-Downstream   1~2

  • 1
  • [ 215184-78-4 ]
  • [ 73183-34-3 ]
  • [ 1035235-26-7 ]
YieldReaction ConditionsOperation in experiment
100% With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 80℃; for 2h;Inert atmosphere; 1 ,1-Dimethylethyl 5-bromo-3,4-dihydro-2(1 H)-isoquinolinecarboxylate (Preparation 53) (2.7g, 8.7 mmol), potassium acetate (2.55g, 26 mmol), [1 ,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (0.63g, 0.87 mmol) and 4.4.4'.4'.5.5.5'.5'-octamethyl-2.2'-bi-1 .3,2-dioxaborolane (4.39g, 17 mmol) were dissolved in 1 ,4-dioxane (40ml), stirred at 800C under nitrogen for 2h and allowed to cool. Water (30ml) was added and the mixture was extracted with ethyl acetate (3x 20ml).The combined organic phases were concentrated in vacuo. Purification of the residue by flash chromatography (ethyl acetate in cyclohexane 15%) gave 1 ,1- dimethylethyl 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3,4-dihydro-2(1 H)- isoquinolinecarboxylate as a clear gel (3.25g, 105%). LCMS (Method formate): Retention time 1.51 min, MH+ = 360
89% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In N,N-dimethyl-formamide; at 90℃;Inert atmosphere; A mixture of tert-butyl 5-bromo-3,4-dihydroisoquinoline-2(lH)-carboxylate (0.500 g, 1.60 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (0.488 g, 1.92 mmol) in DMF (8 mL) was subjected to 3 evacuate-fill cycles with nitrogen. Potassium acetate (0.472 g, 4.80 mmol) and PdCi2(dppf) DCM complex (0.117 g, 0.160 mmol) were added, the mixture was subjected to 2 more evacuate-fill cycles with nitrogen, and heated 90 C overnight under a nitrogen atmosphere. The mixture was cooled to room temperature, diluted with EtOAc, washed sequentially with water, 10% aqueous LiCl and saturated brine, dried and concentrated. The residue was subjected to column chromatography on silica gel, eluting with EtOAc-hexanes, to provide tert-butyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(17i)- carboxylate as a white solid (0.514 g, 89% yield). Mass spectrum m/z 360 (M+H)+.
57% With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 80℃; for 2h;Inert atmosphere; 1 ,1-Dimethylethyl 5-bromo-3,4-dihydro-2(1H)-isoquinolinecarboxylate (Preparation 27) (0.281 g, 0.899 mmol), potassium acetate (0.265 g, 2.70 mmol), [1,f- bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (0.066 g, 0.090 mmol) and 4i4i4li4Ii5,5,5',5'-octamethyl-2,2'-bi-1I3,2-dioxaborolane (0.274 g, 1.079 mmol) were dissolved in 1 ,4-dioxane (5 ml) and the resulting mixture was stirred at 800C under nitrogen for 2 hours then cooled to room temperature and diluted with water (15 ml). The aqueous phase was extracted with AcOEt (3 x 10 ml). The combined organic phases were dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (c-Hexane/AcOEt: 15%) gave 1,1- dimethylethyl 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3,4-dihydro-2(1 H)- isoquinolinecarboxylate 158 mg, 57%) as a light yellow oil. LCMS: retention time 1.54 min; no mass ion detected.
15.45 g With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); XPhos; In 1,4-dioxane; at 120℃; for 48h;Inert atmosphere; Intermediate E: tert-Butyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,4- dihydroisoquinoline-2(lH)-carboxylate A solution of tert-butyl 5-bromo-3,4-dihydroisoquinoline-2(lH)-carboxylate (20.00 g, 64.1 mmol), bis(pinacolato)diboron (Boron Molecular, Research Triangle, NC, 24.40 g, 96 mmol), potassium phosphate (40.8 g, 192 mmol), Pd2(dba)3 (Sigma- Aldrich, St. Louis, MO, 0.750 g, 3.20 mmol) and X-Phos (Strem Chemicals Inc., Newburyport, MA, 7.63 g, 16.02 mmol) in 100 mL dioxane was placed under argon and was heated to 120 C for 48 hours. LC/MS showed mostly product, so the reaction mixture was allowed to cool to room temperature, diluted with diethyl ether, and filtered through a plug of diatomaceous earth eluting with diethyl ether. The filtrate was concentrated and the resulting residue was purified by silica gel chromatography (0 to 15% EA in heaxanes) to provide tert-butyl 5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(lH)-carboxylate (15.45 g, 43.0 mmol) as a light yellow oil.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 80℃; for 3h;Inert atmosphere; To a solution of tert-butyl 5-bromo-3,4- dihydroisoquinoline-2(lH)-carboxylate (4.0 g, 12.8 mmol) in dioxane (60 mL) was added bis(pinacolato)diboron (6.5 g, 25.6 mmol), KOAc (3.76 g, 38.4 mmol) and Pd(dppf)Cl2 (936 mg, 1.15 mmol), and the mixture was stirred at 80C for 3 hours under Ar atmosphere. After cooling down to room temperature, the mixture was filtered through Celite. The filtrate was diluted with water (30 mL), extracted with EtOAc (30 mLx3). The combined organic layers was washed with brine (20 mL), dried over Na2S04 filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether/ EtOAc = 9/1) to afford tert-butyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,4-dihydro- isoquinoline-2(lH)-F

  • 2
  • [ 24424-99-5 ]
  • [ 923591-51-9 ]
  • [ 215184-78-4 ]
 

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