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Structure of 219928-13-9

Chemical Structure| 219928-13-9

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Product Details of [ 219928-13-9 ]

CAS No. :219928-13-9
Formula : C10H12BrN
M.W : 226.11
SMILES Code : BrC1=CC(N2CCCC2)=CC=C1
MDL No. :MFCD04112531
InChI Key :SKCNYQBWULWGAP-UHFFFAOYSA-N
Pubchem ID :7016459

Safety of [ 219928-13-9 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302+H312+H332-H315-H319-H335
Precautionary Statements:P261-P280-P305+P351+P338

Computational Chemistry of [ 219928-13-9 ] Show Less

Physicochemical Properties

Num. heavy atoms 12
Num. arom. heavy atoms 6
Fraction Csp3 0.4
Num. rotatable bonds 1
Num. H-bond acceptors 0.0
Num. H-bond donors 0.0
Molar Refractivity 58.78
TPSA ?

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

3.24 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.58
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

4.25
Log Po/w (WLOGP)?

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

2.67
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.

3.07
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

3.02
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

3.12

Water Solubility

Log S (ESOL):?

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

-4.22
Solubility 0.0135 mg/ml ; 0.0000598 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.

-4.03
Solubility 0.0211 mg/ml ; 0.0000934 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Moderately 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

-3.7
Solubility 0.0449 mg/ml ; 0.000199 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

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.

-4.66 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<2.0
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)

1.56

Application In Synthesis of [ 219928-13-9 ]

* 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 [ 219928-13-9 ]

[ 219928-13-9 ] Synthesis Path-Upstream   1~4

  • 1
  • [ 123-75-1 ]
  • [ 108-36-1 ]
  • [ 219928-13-9 ]
YieldReaction ConditionsOperation in experiment
99% With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In toluene at 80℃; for 4.5 h; Sealed tube Commercial 1,3-dibromobenzene 1 (200.0mg, 0.85mmol), 12 pyrrolidine (60.5mg, 0.85mmol) and 157.0mg of a reagent constituted by 13 tris(dibenzylideneacetone)dipalladium(0), 14 BINAP and 15 t-BuONa (mol ratio: 0.05:0.15:2) were suspended in 16 toluene (2.5mL) and allowed to react in a sealed tube, at 80°C for 4.5h, under magnetic stirring. After cooling to room temperature, the mixture was filtered under reduced pressure and the resulting solution evaporated in vacuo. The residue was dissolved in CHCl3 and washed with a 10percent aqueous solution of 60 NaOH. The organic phase was dried over anhydrous Na2SO4, filtered, evaporated in vacuo, and purified by flash column chromatography on silica gel (petroleum ether), obtaining the intermediate 2 as a transparent oil (190.5mg, 0.84mmol). Yield: 99percent. 1H NMR (CDCl3, 400MHz) δ (ppm): 7.05 (t, 1H, J=8.0Hz), 6.76–6.74 (m, 1H), 6.68 (m, 1H), 6.46 (m, 1H), 3.27–3.24 (m, 4H), 2.05–1.99 (m, 4H).
54% With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In toluene for 4 h; Reflux 1,3-Dibromobenzene (1.0 g, 4.24 mmol), pyrrolidine (0.43 mL, 5.0 mmol), sodium tert-butoxide (1.14 g, 11.87mmol) and BINAP (0.2 g, 0.32 mmol) were dissolved in 17 mL of toluene. Pd2(dba)3 (0.097 g, 0.1 mmol) was addedthereto, and the mixture was stirred 4 hours under reflux. Solids were filtered through Celite and purified by columnchromatography to obtain the title compound (0.52 g, 54percent).1H-NMR (CDCl3) δ 7.05 (1H, t), 6.75 (1H, d), 6.67 (1H, m), 6.45 (1H, m), 3.26 (4H, m), 2.00 (4H, m)
45% With caesium carbonate In toluene at 120℃; Synthesis of 1-(3-bromophenyl)pyrrolidine
Into a 500 mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 1,3-dibromobenzene (20 g, 84.78 mmol, 1.00 equiv) in toluene (300 mL).
To this was added pyrrolidine (6.03 g, 84.80 mmol, 1.00 equiv).
Addition of Pd(OAc)2 (190 mg, 0.85 mmol, 0.01 equiv) was next.
This was followed by the addition of BINAP (760 mg, 2.53 mmol, 0.03 equiv).
To the mixture was added Cs2CO3 (69.1 g, 211.96 mmol, 2.50 equiv).
The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at 120° C. in a bath of oil.
The reaction progress was monitored by TLC (EtOAc/PE=1:5).
A filtration was performed.
The filtrate was concentrated by evaporation under vacuum using a rotary evaporator.
The residue was purified by eluding through a column with a PE solvent system.
This resulted in 8.51 g (45percent) of 1-(3-bromophenyl)pyrrolidine as a light yellow liquid.
LC-MS (ES, m/z): [M+H]+ calcd for C10H13BrN 226, found 226
45% With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 120℃; Synthesis of 1-3-bromophenyl)pyrrolidine
Into a 500 mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 1,3-dibromobenzene (20 g, 84.78 mmol, 1.00 equiv) in toluene (300 mL).
To this was added pyrrolidine (6.03 g, 84.80 mmol, 1.00 equiv).
Addition of Pd(OAc)2 (190 mg, 0.85 mmol, 0.01 equiv) was next.
This was followed by the addition of BINAP (760 mg, 2.53 mmol, 0.03 equiv).
To the mixture was added Cs2CO3 (69.1 g, 211.96 mmol, 2.50 equiv).
The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at 120° C. in a bath of oil.
The reaction progress was monitored by TLC (EtOAc/PE=1:5).
A filtration was performed.
The filtrate was concentrated by evaporation under vacuum using a rotary evaporator.
The residue was purified by eluding through a column with a PE solvent system.
This resulted in 8.51 g (45percent) of 1-(3-bromophenyl)pyrrolidine as a light yellow liquid.
LC-MS (ES, m/z): [M+H]+ calcd for C10H13BrN 226, found 226

References: [1] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 24, p. 6427 - 6434.
[2] Tetrahedron, 2008, vol. 64, # 13, p. 2938 - 2950.
[3] Patent: EP3239143, 2017, A2, . Location in patent: Paragraph 0165.
[4] Patent: US2008/318941, 2008, A1, . Location in patent: Page/Page column 44.
[5] Patent: US2008/200471, 2008, A1, . Location in patent: Page/Page column 66.
  • 2
  • [ 123-75-1 ]
  • [ 1073-06-9 ]
  • [ 219928-13-9 ]
YieldReaction ConditionsOperation in experiment
70% With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 7 h; To a solution of 1-bromo-3-fluorobenzene (250 mg, 1.429 mmol) in DMF (Volume: 5 mL) was added pyrrolidine (122 mg, 1.714 mmol) followed by K2C03 (395 mg, 2.86 mmol) and heated to 100 °C for 7 h. The reaction was diluted with 50 mL DCM and 50 mL water. The organic layer was separated, washed with water (2x20 mL), dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluting with 10-50percent ethyl acetate:hexanes to afford the desired product 62 (226 mg, 1.000 mmol, 70percent yield). 1H NMR (500 MHz, CD3OD) : 7.02 (t, J= 8.0 Hz, 1H), 6.68 (dd, J= 8.0 Hz, J= 1.0 Hz, 1H), 6.65 (t, J= 2.0 Hz, 1H), 6.48 (dd, J= 8.5 Hz, J= 2.5 Hz, 1H), 3.23 (t, J= 6.5 Hz, 4H), 2.01 (quintet, J=3.5 Hz, 4H)
References: [1] Patent: WO2015/27160, 2015, A2, . Location in patent: Paragraph 0247.
  • 3
  • [ 110-52-1 ]
  • [ 591-19-5 ]
  • [ 219928-13-9 ]
References: [1] Journal of the American Chemical Society, 2015, vol. 137, # 27, p. 8700 - 8703.
[2] Synthetic Communications, 2012, vol. 42, # 17, p. 2512 - 2525.
[3] Chemical Communications, 2018, vol. 54, # 50, p. 6939 - 6942.
[4] Chemistry - A European Journal, 2018, vol. 24, # 52, p. 13778 - 13782.
  • 4
  • [ 696-59-3 ]
  • [ 591-19-5 ]
  • [ 107302-22-7 ]
  • [ 219928-13-9 ]
References: [1] Synthesis, 1999, # 1, p. 74 - 79.
[2] Synthesis, 1999, # 1, p. 74 - 79.
 

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