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Chemical Structure| 166104-19-4

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Product Details of [ 166104-19-4 ]

CAS No. :166104-19-4
Formula : C13H14N2O4
M.W : 262.26
SMILES Code : [N+](=O)([O-])C2=CC=C1[N](C=CC1=C2)C(=O)OC(C)(C)C
MDL No. :MFCD09953094
InChI Key :GSHXPDVMVVLYLH-UHFFFAOYSA-N
Pubchem ID :11680504

Safety of [ 166104-19-4 ]

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

Computational Chemistry of [ 166104-19-4 ] Show Less

Physicochemical Properties

Num. heavy atoms 19
Num. arom. heavy atoms 9
Fraction Csp3 0.31
Num. rotatable bonds 4
Num. H-bond acceptors 4.0
Num. H-bond donors 0.0
Molar Refractivity 72.96
TPSA ?

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

77.05 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.68
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

3.1
Log Po/w (WLOGP)?

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

3.33
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.

1.61
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

-0.08
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.13

Water Solubility

Log S (ESOL):?

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

-3.51
Solubility 0.0819 mg/ml ; 0.000312 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.

-4.39
Solubility 0.0108 mg/ml ; 0.0000411 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

-2.74
Solubility 0.476 mg/ml ; 0.00182 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

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.

-5.7 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

2.0 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)

2.35

Application In Synthesis of [ 166104-19-4 ]

* 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.

  • Upstream synthesis route of [ 166104-19-4 ]

[ 166104-19-4 ] Synthesis Path-Upstream   1~1

  • 1
  • [ 24424-99-5 ]
  • [ 6146-52-7 ]
  • [ 166104-19-4 ]
YieldReaction ConditionsOperation in experiment
100% at 0℃; for 0.0833333 h; Nitro-lH-indole (325 mg, 2.0 mmol)In dichloromethane (6 mL) was added di-tert-butyl dicarbonateEster (524 mg, 2.4 mmol),Stirred at 0 ° C for 5 minutes,A further catalytic amount of 4-dimethylaminopyridine (3 mg, 0.025 mmol) was added,Stirring is then continued for 30 minutes at room temperature.Quenched by adding water (2 mL)Extract with dichloromethane (15 mL x 3).The combined organic phase was washed with water (20 mL)Saturated brine (15 mL × 2)Dried over anhydrous sodium sulfate,The solvent was distilled off under reduced pressure,Obtained as a gray solid (526 mg, 100percent),Directly used for the next reaction.
99% With dmap In tetrahydrofuran at 0 - 20℃; for 3 h; Di-tert-butyl dicarbonate (8.07 g, 37.0 mmol)was siowly added to a stirred solution of 5-nitroindole (6.00 g, 37.0 mmol) and 4-dimethyianiinopyridine (226 Ing, 185 mmol) in THF (60 niL) at 0 °C. The mixture was then stirred for 3h at 20 °C. The reaction solution was concentrated in vacuo and the residue was dissolved in DCM (150 rnL). The organic layer was washed with water, brine, dried (MgSO4), filtered, and the solvent evaporated in vaeuo to yield the title compound (9.60 g, 99percent).
98% With triethylamine In dichloromethane at 0 - 20℃; Triethylamine (3.1 mL, 22.2 mmol) and 4-dimethylaminopyridine (226 mg, 1.85 mmol) were added to a solution of 5-nitro-1H-indole (3 g, 18.5 mmol) in DCM (30 mL) at 0° C., di-tert-butyl dicarbonate (4.3 g, 19.7 mmol) was then added.
The resulting mixture was warmed to room temperature and it was stirred overnight, it was then quenched by addition of water and extracted with DCM.
The organic extracts were dried over MgSO4, filtered and evaporated under reduced pressure; the crude residue was filtered through a silica pad and the filtrate was evaporated under reduced pressure to give 4.77 g (98percent yield) of 5-nitro-indole-1-carboxylic acid tert-butyl ester.
89% With dmap In dichloromethane at 20℃; for 1 h; 4-DMAP (414.4 mg, 3.4 mmol) and di-tert-butyl dicarbonate (740.3 mg, 3.4 mmol) were added to 5-nitro- l //-indole (500.0 mg, 3.1 mmol) in DCM (5 mL), stirred for 1 h at ambient temperature, 2 M HCL was added followed by extraction with DCM, organic phase was collected and the solvent was removed un- der reduced pressure. Yield 724.0 mg (89percent). HPLC 100percent. LC-MS 263 (M+H)+.
78% With dmap In tetrahydrofuran; ethyl acetate Part F.
5-Nitro-1H-indole (2.5 g, 15 mmol), di-tert-butyl dicarbonate (3.6 g, 17 mmol), and DMAP (190 mg, 1.5 mmol) were dissolved in 150 mL of THF.
The solution was stirred for 12 h at rt under N2 and was then concentrated.
The residue was taken up in EtOAc and the mixture was filtered.
The filtered solid was washed with 100 mL of hexanes and dried to give tert-butyl-5-nitro-1H-indole-1-carboxylate as an off-white solid (3.1 g, 78percent). LRMS (AP+): 304.2 (M+H+ACN)+. 1H NMR (CDCl3) δ8.51 (d, 1H), 8.23-8.29 (m, 2H), 7.75 (d, 1H), 6.73 (d, 1H), 1.71 (s, 9H).
78% With dmap In tetrahydrofuran at 20℃; for 12 h; Inert atmosphere Part F.
5-Nitro-1H-indole (2.5 g, 15 mmol), di-tert-butyl dicarbonate (3.6 g, 17 mmol), and DMAP (190 mg, 1.5 mmol) were dissolved in 150 mL of THF.
The solution was stirred for 12 h at rt under N2 and was then concentrated.
The residue was taken up in EtOAc and the mixture was filtered.
The filtered solid was washed with 100 mL of hexanes and dried to give tert-butyl-5-nitro-1H-indole-1-carboxylate as an off-white solid (3.1 g, 78percent). LRMS (AP+): 304.2 (M+H+ACN)+. 1H NMR (CDCl3) δ 8.51 (d, 1H), 8.23-8.29 (m, 2H), 7.75 (d, 1H), 6.73 (d, 1H), 1.71 (s, 9H).
1 g With dmap; triethylamine In dichloromethane at 20℃; for 16 h; 1(1.0 g, 6.17 mmol), DCM (30 mL). DMAP (cat.), TEA (3 eq), (Boc)20 (1.2 eq) reacted at RT. After 16 h anon-polar product was observed by TLC. The reaction was quenched with ice cold water and extracted with DCM (2X10 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by silica gel column chromatography [using 100-200 mesh, eluting with 10percent EtOAc-hexanej to afford 1 g of 2.

References: [1] Journal of Medicinal Chemistry, 2013, vol. 56, # 15, p. 6273 - 6277.
[2] Patent: CN104311541, 2017, B, . Location in patent: Paragraph 0162; 0163.
[3] Synthesis, 2009, # 21, p. 3617 - 3632.
[4] Patent: WO2016/176460, 2016, A1, . Location in patent: Page/Page column 96.
[5] Patent: US2009/247568, 2009, A1, . Location in patent: Page/Page column 35-36.
[6] Patent: WO2007/147874, 2007, A1, . Location in patent: Page/Page column 158-159.
[7] Synlett, 2008, # 2, p. 294 - 296.
[8] Patent: US2003/191115, 2003, A1, .
[9] Patent: US2017/50964, 2017, A1, . Location in patent: Paragraph 0733.
[10] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 23, p. 6481 - 6488.
[11] Journal of Medicinal Chemistry, 2011, vol. 54, # 4, p. 1106 - 1110.
[12] Patent: WO2016/73652, 2016, A1, . Location in patent: Page/Page column 121.
 

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