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Chemical Structure| 81224-16-0 Chemical Structure| 81224-16-0

Structure of 81224-16-0

Chemical Structure| 81224-16-0

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Product Details of [ 81224-16-0 ]

CAS No. :81224-16-0
Formula : C9H8BrNO
M.W : 226.07
SMILES Code : COC1=CC=C(Br)C2=C1C=CN2
MDL No. :MFCD04037872
InChI Key :WWKHWWGUJPWWDF-UHFFFAOYSA-N
Pubchem ID :3695499

Safety of [ 81224-16-0 ]

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

Computational Chemistry of [ 81224-16-0 ] Show Less

Physicochemical Properties

Num. heavy atoms 12
Num. arom. heavy atoms 9
Fraction Csp3 0.11
Num. rotatable bonds 1
Num. H-bond acceptors 1.0
Num. H-bond donors 1.0
Molar Refractivity 52.49
TPSA ?

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

25.02 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.15
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

2.71
Log Po/w (WLOGP)?

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

2.94
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.

1.95
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

3.17
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.58

Water Solubility

Log S (ESOL):?

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

-3.44
Solubility 0.0825 mg/ml ; 0.000365 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.

-2.89
Solubility 0.292 mg/ml ; 0.00129 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

-4.27
Solubility 0.0121 mg/ml ; 0.0000537 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

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.

-5.75 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)

1.61

Application In Synthesis of [ 81224-16-0 ]

* 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 [ 81224-16-0 ]

[ 81224-16-0 ] Synthesis Path-Downstream   1~35

  • 1
  • [ 79-37-8 ]
  • [ 81224-16-0 ]
  • (7-Bromo-4-methoxy-1H-indol-3-yl)-oxo-acetyl chloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran;Inert atmosphere; To a flame-dried flask containing 10a5 (50.0 mg, 0.233 mmol) in anhyd. THF (600 muL), added oxalyl chloride (97 muL, 1.11 mmol, 5 equiv) and let stir under an atmosphere of N2 until TLC (5:1 hexanes/EtOAc) indicated consumption of starting material (5-12 hr, depending on scale). All volatiles were removed by rotoevaporation and resulting green residue was immediately suspended in anhyd. THF (1 mL), followed by the addition of N-Boc piperazine6 (52 mg, 0.28 mmol, 1.2 equiv) and DIPEA (78 muL, 2 equiv). Resulting mixture was stirred under an atmosphere of N2 at RT for 12 hr. and then at reflux for 30 min (if needed) when TLC (5:1 hexanes/EtOAc) indicated reaction completion. Reaction was allowed to cool to RT, poured into H2O (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were dried over anhyd. MgSO4, filtered, and all solvents were evaporated. Crude 18 was purified by flash chromatography (CombiFlash Automated Chromatographer, 12 g column, dryloaded with 4 g pre-packed dry loading column. Run using 100% Hexanes to 50% EtOAc:Hexanes gradient over 30 column volumes, followed by EtOAc flush) to yield 18 as a light brown powder (78 mg, 75%). 1H NMR (400 MHz, CDCl3) delta 9.44 (s, 1H), 7.94 (d, J=3.1, 1H), 7.28 (d, J=8.5, 1H), 6.56 (d, J=8.5, 1H), 3.90 (s, 3H), 3.71 (m, 2H), 3.60-3.51 (m, 2H), 3.46 (m, 4H), 1.47 (s, 9H). (ES+) m/z (M+H)+ 466; (M+Na)+ 488; Rt=1.34. 5. US PATENT: US200300692456. Faust, A.; Waschkau, B.; Waldeck, J.; Holtke, C.; Breyholtz, H.; Wagner, S.; Kopka, K.; Heindel, W.; Schafer, M.; Bremer, C. Bioconjug. Chem. 2008, 19, 1001-1008.
In tetrahydrofuran; FIGURE 88 shows the synthesis of GP120 binding bifunctional molecule CPD7-GN3.
  • 2
  • [ 81224-15-9 ]
  • [ 81224-16-0 ]
  • 3
  • [ 50-00-0 ]
  • [ 81224-16-0 ]
  • [ 124-40-3 ]
  • [ 81224-17-1 ]
  • 4
  • [ 5344-78-5 ]
  • [ 1826-67-1 ]
  • [ 81224-16-0 ]
YieldReaction ConditionsOperation in experiment
70.1% In tetrahydrofuran; at -40℃; for 1.5h; To a solution of 1-bromo-4-methoxy-2-nitrobenzene (33, 10.0 g, 43.1 mmol) in THF (100 mL)were added vinylmagnesium bromide (110 mL) dropwise at -40 C. The reaction mixture was sealedand stirred at -40 C for 1.5 hour. After warmed up to room temperature, the resulting solution wasquenched with sat. NH4Cl (120 mL) and extracted with ethyl acetate (2 × 150 mL). The combinedorganic layers were washed with brine (50 mL) and H2O (50 mL), dried over anhydrous Na2SO4,filtered and concentrated under reduced pressure. The residue was purified by silica gel column(petroleum ether/ethyl acetate = 2:1, v/v) to give 34 as a yellow solid (6.8 g, yield = 70.1%). LC-MS (ESI): m/z [M/M + 1]+ = 226.04/228.04.
  • 5
  • [ 81224-16-0 ]
  • 7-azido-4-methoxy-1<i>H</i>-indole [ No CAS ]
  • 6
  • [ 81224-16-0 ]
  • [ 77-78-1 ]
  • [ 408355-32-8 ]
  • 8
  • [ 81224-16-0 ]
  • 3-(1H-indol-3-yl)-4-(4-methoxy-1-methyl-1H-indol-7-yl)-pyrrole-2,5-dione [ No CAS ]
  • 10
  • [ 81224-16-0 ]
  • [ 292636-25-0 ]
  • 11
  • [ 81224-16-0 ]
  • 4-amino-<i>N</i>-(3-chloro-4-methoxy-1<i>H</i>-indol-7-yl)-benzenesulfonamide [ No CAS ]
  • 12
  • [ 81224-16-0 ]
  • [ 292636-19-2 ]
  • 13
  • [ 81224-16-0 ]
  • [ 81224-19-3 ]
  • 14
  • [ 81224-16-0 ]
  • [ 81224-18-2 ]
  • 15
  • [ 81224-14-8 ]
  • [ 81224-16-0 ]
  • 16
  • [ 81224-45-5 ]
  • [ 81224-16-0 ]
  • 17
  • [ 25016-01-7 ]
  • [ 81224-16-0 ]
YieldReaction ConditionsOperation in experiment
59.8% (a) 5-Methoxy-7-bromoindole. 2-Bromo-4-methoxy-aniline (5.0 g, 24.7 mmol) was added dropwise to a solution of boron trichloride in methylene chloride (1.0 M, 27 mL, 27 mmol) cooled with ice water. The reaction mixture was warmed to room temperature, stirred for 30 min, and chloroacetonitrile (4.55 mL, 29.7 mmol) and aluminum chloride (4.54 g, 27.2 mmol) added, followed by 1,2-dichloroethane (32 mL). The reaction mixture was heated to 70 C. to distill off methylene chloride, and then refluxed for 24 h. The mixture was cooled to 0-5 C., treated with 2.5 M HCl (44 mL) at 0~5 C. carefully, and then heated to 80 C. for 1 h until all solids dissolved. The aqueous layer was separated and extracted with methylene chloride. The combined organic layers were washed with water and brine, dried (sodium sulfate) and concentrated a yellow solid, that was used without further purification. The crude product was taken into dioxane (19 mL) and water (2.1 mL), and treated with sodium borohydride (0.46 g, 12.2 mmol) in portions. After 30 min at room temperature, all the starting material had been consumed, and the reaction mixture was heated to reflux overnight. The mixture was then cooled to room temperature, treated with 0.1 N hydrochloric acid (195 mL), diluted with ethyl acetate, treated with concentrated hydrochloric acid and trifluoroacetic acid and stirred until all the hydroxy-intermediate was converted to the final product. The reaction mixture was then extracted with ethyl acetate, and the extract was washed with sodium bicarbonate, water and brine, dried (Na2SO4) and concentrated. Column chromatography on silica gel (hexanes/ethyl acetate) gave 4-methoxy-7-bromoindole (1.5 g, 59.8%). 1H NMR (400 MHz, CDCl3) 3.77 (s, 3H), 6.47~6.49 (m, 1H), 6.99 (s, 2H), 7.17(m, 1H), 8.11 (br, 1H); MS (ES, m/z): C9H8BrNO: 228 (M+(79Br)+1), 226.01 (M+(81Br)+1), 224.03 (M+(79Br)-1), 226.04 (M+(81Br)-1).
  • 19
  • [ 59557-92-5 ]
  • [ 107-14-2 ]
  • [ 107-06-2 ]
  • [ 81224-16-0 ]
YieldReaction ConditionsOperation in experiment
24% With hydrogenchloride; sodium borohydrid; boron trichloride;aluminium trichloride; In 1,4-dioxane; dichloromethane; water; (a) 4-Methoxy-7-bromoindole. 2-Bromo-5-methoxy-aniline (4.4 g, 21.8 mmol) was added dropwise to a solution of boron trichloride in methylene chloride (1.0 M, 24 mL, 24 mmol) cooled with ice water. The reaction mixture was warmed to room temperature, stirred for 30 min, and chloroacetonitrile (4.01 mL, 26.2 mmol) and aluminum chloride (4.01 g, 24.0 mmol) were added, followed by 1,2-dichloroethane (28.5 mL). The reaction mixture was heated to 70 C. to distill off methylene chloride, and then heated to reflux for 24 hrs. After cooling to 0-5 C., the mixture was treated with 2.5 M HCl (38.4 mL) carefully, and then heated to 80 C. for 1 h until all solids dissolved. The aqueous layer was separated, extracted with methylene chloride and the combined extracts washed with water and brine, dried (sodium sulfate) and evaporated to a yellow solid, which was used without further purification. The crude product was taken into dioxane (37 mL) and water (4.2 mL), and treated with sodium borohydride (0.91 g, 24.0 mmol) in portions. After stirring at room temperature for 30 min, all the starting material was consumed and the reaction mixture was then heated to reflux for 14 hrs. After cooling to room temperature, the mixture was treated with concentrated HCl, and extracted with ethyl acetate. The organic extract was washed with water and brine; dried (sodium sulfate), and concentrated. Column chromatography on silica gel (hexanes/ethyl acetate) gave 4-methoxyl-7-bromoindole (1.2 g, 24%). 1H NMR (400 MHz, CDCl3) 3.94 (s, 3H), 6.44 (d, J=8.21 Hz, 1H), 6.73 (m, 1H), 7.17 (t, J=2.74 Hz, 1H), 7.22~7.26 (m, 1H), 8.32 (br, 1H); MS (ES, m/z): C9H8BrNO: 227.99 (M+(79Br)+1), 230.0(M+(81Br)+1).
  • 20
  • copper(l) cyanide [ No CAS ]
  • [ 81224-16-0 ]
  • [ 389628-45-9 ]
YieldReaction ConditionsOperation in experiment
65.8% In N,N-dimethyl-formamide; at 140℃; An oven-dried screw cap test tube was charged with a magnetic stir bar, CuCN (152.4 mg, 0.8mmol), then 34 (6.8 g, Y = 70.1%) in DMF (75 mL) was added into the tube. The reaction mixture wasstirred at 140 C overnight. After cooled down to room temperature, the resulting solution wasfiltered through Celite. The filtrate was diluted with ethyl acetate (100 mL) and washed withsaturated NaHCO3 solution (30 mL), water (30 mL) and brine (30 mL). The organic phase was driedover anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purifiedby silica gel column (petroleum ether/ethyl acetate = 1:1, v/v) to give 35 as a yellow solid (3.4 g, yield %). LC-MS (ESI): m/z [M + 1]+ = 173.10.
  • 21
  • [ 81224-16-0 ]
  • [ 1313530-00-5 ]
  • 23
  • [ 81224-16-0 ]
  • [ 1293397-09-7 ]
  • 24
  • [ 81224-16-0 ]
  • [ 1293397-11-1 ]
  • 25
  • [ 81224-16-0 ]
  • [ 1293397-15-5 ]
  • 26
  • [ 81224-16-0 ]
  • C31H37BrN4O8 [ No CAS ]
  • 27
  • [ 81224-16-0 ]
  • C26H29BrN4O6 [ No CAS ]
  • 28
  • [ 81224-16-0 ]
  • C30H32N4O7 [ No CAS ]
  • 29
  • [ 81224-16-0 ]
  • methyl 2-(7-cyano-4-methoxy-1H-indol-3-yl)-2-oxoacetate [ No CAS ]
  • 30
  • [ 81224-16-0 ]
  • 2-(7-cyano-4-methoxy-1H-indol-3-yl)-2-oxoacetic acid [ No CAS ]
  • 31
  • [ 81224-16-0 ]
  • N-(3-benzoyl-3-azabicyclo[3.1.0]hexan-6-yl)-2-(7-cyano-4-methoxy-1H-indol-3-yl)-2-oxoacetamide [ No CAS ]
  • 32
  • [ 81224-16-0 ]
  • N-(3-benzoyl-3-azabicyclo[3.1.0]hexan-6-yl)-2-(7-(N-hydroxycarbamimidoyl)-4-methoxy-1H-indol-3-yl)-2-oxoacetamide [ No CAS ]
  • 33
  • [ 81224-16-0 ]
  • N-(3-benzoyl-3-azabicyclo[3.1.0]hexan-6-yl)-2-(4-methoxy-7-(5-(trichloro-methyl)-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl)-2-oxoacetamide [ No CAS ]
  • 34
  • [ 81224-16-0 ]
  • 2-(7-(5-amino-1,2,4-oxadiazol-3-yl)-4-methoxy-1H-indol-3-yl)-N-(3-benzoyl-3-azabicyclo[3.1.0]hexan-6-yl)-2-oxoacetamide [ No CAS ]
  • 35
  • [ 81224-16-0 ]
  • [ 313335-01-2 ]
 

Historical Records

Technical Information

Categories

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[ 81224-16-0 ]

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Indoles

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