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Chemical Structure| 183208-35-7 Chemical Structure| 183208-35-7

Structure of 5-Bromo-7-azaindole
CAS No.: 183208-35-7

Chemical Structure| 183208-35-7

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Product Details of [ 183208-35-7 ]

CAS No. :183208-35-7
Formula : C7H5BrN2
M.W : 197.03
SMILES Code : BrC1=CN=C(NC=C2)C2=C1
MDL No. :MFCD06659677
InChI Key :LPTVWZSQAIDCEB-UHFFFAOYSA-N
Pubchem ID :10307932

Safety of [ 183208-35-7 ]

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

Computational Chemistry of [ 183208-35-7 ] Show Less

Physicochemical Properties

Num. heavy atoms 10
Num. arom. heavy atoms 9
Fraction Csp3 0.0
Num. rotatable bonds 0
Num. H-bond acceptors 1.0
Num. H-bond donors 1.0
Molar Refractivity 43.79
TPSA ?

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

28.68 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.68
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

2.0
Log Po/w (WLOGP)?

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

2.33
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.

1.75
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

2.75
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.1

Water Solubility

Log S (ESOL):?

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

-2.99
Solubility 0.203 mg/ml ; 0.00103 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.

-2.23
Solubility 1.16 mg/ml ; 0.0059 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

-3.77
Solubility 0.0337 mg/ml ; 0.000171 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

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.

-6.08 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<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)

1.47

Application In Synthesis of [ 183208-35-7 ]

* 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 [ 183208-35-7 ]
  • Downstream synthetic route of [ 183208-35-7 ]

[ 183208-35-7 ] Synthesis Path-Upstream   1~3

  • 1
  • [ 75-36-5 ]
  • [ 183208-35-7 ]
  • [ 866545-96-2 ]
YieldReaction ConditionsOperation in experiment
93% at 20℃; for 6 h; Step 1:
Synthesis of 1-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-ethanone.
To a stirring solution of aluminum chloride (6.77 g, 50.75 mmol) suspended in anhydrous CH2Cl2 (100 mL) under N2 was added 5-bromo-1H-pyrrolo[2,3-b]pyridine (2.00 g, 10.15 mmol).
The reaction solution was stirred for 1 hour at ambient temperature whereupon acetyl chloride (3.61 mL, 50.75 mmol) was added dropwise and the resulting solution was stirred for 5 more hours.
The reaction was cooled to 0° C. in an ice bath and quenched carefully by addition of MeOH until the solution became clear.
The reaction was concentrated under vacuum.
H2O was added and 1 N NaOH was added dropwise until the pH=4.
The product was extracted into ethyl acetate and the organic layer was washed with a saturated solution of sodium potassium tartrate to remove any remaining aluminum salts.
The organic layer was dried over Na2SO4 and concentrated under vacuum.
The material was redissolved in ethyl acetate and filtered through a bed of silica gel.
The filtrate was concentrated to afford the title compound as an orange solid (2.25 g, 93percent yield).
1H NMR (500 MHz, d6-DMSO) δ 12.70 (br s, 1H), 8.56 (d, J=2.5 Hz, 1H), 8.55 (s, 1H), 8.40 (d, J=2.5 Hz, 1H), 2.46 (s, 3H). MS: m/z 238.9/240.9 (M+H+).
93%
Stage #1: With aluminum (III) chloride In dichloromethane at 20℃; for 1 h;
Stage #2: for 5 h;
To a stirring solution of aluminum chloride (6.77 g, 50.75 mmol) suspended in anhydrous CH2Cl2 (100 mL) under N2 was added 5-bromo-1H -pyrrolo[2,3-δ]pyridine (2.00 g, 10.15 mmol). The reaction solution was stirred for 1 hour at ambient temperature whereupon acetyl chloride (3.61 mL, 50.75 mmol) was added dropwise and the resulting solution was stirred for 5 more hours. The reaction was cooled to 0 °C in an ice bath and quenched carefully by addition of MeOH until the solution became clear. The reaction was concentrated under vacuum. H2O was added and 1 N NaOH was added dropwise until the pH = 4. The product was extracted into ethyl acetate and the organic layer was washed with a saturated solution of sodium potassium tartrate to remove any remaining aluminum salts. The organic layer was dried over Na2SO* and concentrated under vacuum. The material was redissolved in ethyl acetate and filtered through a bed of silica gel. The filtrate was concentrated to afford the title compound as an orange <n="79"/>solid (2.25 g, 93percent yield). 1H NMR (500 MHz, ^-DMSO) δ 12.70 (br s, 1H), 8.56 (d, J = 2.5 Hz, 1H),8.55 (s, 1H), 8.40 (d, J = 2.5 Hz, 1H), 2.46 (s, 3H). MS: m/z 238.9/240.9 (M + H+).
87%
Stage #1: With aluminum (III) chloride In dichloromethane at 20℃; for 1 h;
Stage #2: at 20℃;
5-Bromo-1H-pyrrolo[2,3-b]pyridine (5 g, 25.2 mmol) was added to aluminum chloride (16.8 g, 126.2 mmol) in dichloromethane (200 ml) under nitrogen. The mixture was allowed to stir at room temperature for 1 hour. Acetyl chloride (9 ml, 126.2 mmol) in dichloromethane was added drop wise and the reaction was allowed to proceed at room temperature overnight. Next day the reaction was cooled to 0° C. and quenched with methanol (500 ml) until the reaction turned clear. The reaction was concentrated under vacuum and resuspended in water (300 ml). The pH was adjusted to 4 with 7N sodium hydroxide solution and then extracted with ethyl acetate (300 ml.x.3). The combined organic layers were extracted with saturated sodium potassium tartrate and brine and dried with Na2SO4. Silica chromatography of the crude using a gradient of ethyl acetate and hexane afforded 1-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-yl)-ethanone (5.2 g, 87percent yield). 1H NMR (500 MHz, DMSO-d6) δ 2.48 (s, 3H), 8.41 (s, 1H), 8.57 (s, 1H), 8.58 (s, 1H). MS: m/z 241.0 (M+H+).
References: [1] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 24, p. 7212 - 7215.
[2] Patent: US2006/30583, 2006, A1, . Location in patent: Page/Page column 61-62.
[3] Patent: WO2008/124849, 2008, A2, . Location in patent: Page/Page column 77-78.
[4] Patent: US2008/261921, 2008, A1, . Location in patent: Page/Page column 141-142.
[5] Patent: US2011/82138, 2011, A1, . Location in patent: Page/Page column 65.
[6] Patent: WO2014/111496, 2014, A1, . Location in patent: Page/Page column 100; 101.
[7] Patent: WO2016/142310, 2016, A1, . Location in patent: Page/Page column 65-66.
  • 2
  • [ 183208-35-7 ]
  • [ 951626-91-8 ]
YieldReaction ConditionsOperation in experiment
85% With N-chloro-succinimide; dibenzoyl peroxide In N,N-dimethyl-formamide at 20℃; for 18 h; 0.50 g (2.54 mmol) of 5-bromo-lH-pyrrolo[2,3-b]pyridine was dissolved in 10 n L of Ν,Ν-dimethylformamide to which 0.37 g (2.79 mmol) of N-cMorosuccinimide and 0.38 g (2.79 mmol) of dibenzoyl peroxide were added, followed by stirring at room temperature for 18 hours. After extracting with ethyl acetate/distilled water, the organic layer was concentrated under reduced pressure. The residue was separated by column chromatography to give 0.50 g (85.0percent yield) of 5-bromo-3-chloro-lH-pyrrolo[2,3-b] pyridine. 1H NMR (DMSO) δ: 12.24 (br s, 1H), 8.35 (s, 1H), 8.14 (s, 1H), 8.03 (d, 1H), 7.81 (m, 1H), 7.77 (s, 1H), 7.64 (t, 1H)
85% With N-chloro-succinimide In tetrahydrofuran at 20℃; for 24 h; 5 -Bromo-3 -chloro- 1H-pyrrolo[2,3 -bipyridine. To a solution of 5 -bromo- 1H-pyrrolo [2,3 -bjpyridine (5.0 g, 25.4 mmol, 1.0 eq) in THF (100 mL) was added N-chlorosuccinimide (4.0 g,30.4 mmol, 1.2 eq) and the mixture was stirred at room temperature for 24 h. Water (100 mL)was added to the reaction mixture, followed by extraction with EA (3 x 80 mL). The combinedorganic layer was dried over Mg2SO4, filtered and the filtrate was concentrated in vacuo to givea cmde residue, which was purified by silica gel column chromatography (EtOAc/Hexane, 1/5)to afford 5-bromo-3-chloro-1H-pyrrolo[2,3-bjpyridine (5.0 g, 85percent). ‘H NMR (300 MHz,DMSO-d6): 5 12.26 (br, 1H), 8.37 (s, 1H), 8.16 (s, 1H), 7.79 (s, 1H). ESI-MS (m/z): 232.9 (M-t-H).
References: [1] Journal of Organic Chemistry, 2018, vol. 83, # 2, p. 930 - 938.
[2] Patent: WO2016/129933, 2016, A2, . Location in patent: Page/Page column 48.
[3] Patent: WO2019/10295, 2019, A1, . Location in patent: Page/Page column 155; 156.
  • 3
  • [ 183208-35-7 ]
  • [ 1220696-34-3 ]
References: [1] Patent: US2017/8889, 2017, A1, .
 

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