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Chemical Structure| 158626-15-4 Chemical Structure| 158626-15-4

Structure of 158626-15-4

Chemical Structure| 158626-15-4

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Product Details of [ 158626-15-4 ]

CAS No. :158626-15-4
Formula : C7H5BrN2
M.W : 197.03
SMILES Code : BrCC1=CC=C(C=N1)C#N
MDL No. :MFCD11227190
InChI Key :QWCGOMIAXFNYIV-UHFFFAOYSA-N
Pubchem ID :21927776

Safety of [ 158626-15-4 ]

GHS Pictogram:
Signal Word:Danger
Hazard Statements:H302-H314
Precautionary Statements:P501-P260-P270-P264-P280-P303+P361+P353-P301+P330+P331-P363-P301+P312+P330-P304+P340+P310-P305+P351+P338+P310-P405
Class:8
UN#:3261
Packing Group:

Computational Chemistry of [ 158626-15-4 ] Show Less

Physicochemical Properties

Num. heavy atoms 10
Num. arom. heavy atoms 6
Fraction Csp3 0.14
Num. rotatable bonds 1
Num. H-bond acceptors 2.0
Num. H-bond donors 0.0
Molar Refractivity 41.79
TPSA ?

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

36.68 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.66
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

1.16
Log Po/w (WLOGP)?

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

1.7
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.

0.62
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

2.31
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.49

Water Solubility

Log S (ESOL):?

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

-2.17
Solubility 1.33 mg/ml ; 0.00675 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.

-1.53
Solubility 5.88 mg/ml ; 0.0298 mol/l
Class?

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

Very 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

-3.37
Solubility 0.0837 mg/ml ; 0.000425 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.

-6.68 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

1.0 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)

1.91

Application In Synthesis of [ 158626-15-4 ]

* 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 [ 158626-15-4 ]

[ 158626-15-4 ] Synthesis Path-Upstream   1~1

  • 1
  • [ 3222-48-8 ]
  • [ 158626-15-4 ]
YieldReaction ConditionsOperation in experiment
60% With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In 1,2-dichloro-ethane at 80℃; for 3.5 - 6 h; Preparation 22; 3-Aminomethyl-6-(tert-butylthio)methyl-pyridine; 6-Bromomethyl-pyridine-S-carbonitrile; Dissolve 6-methyl-nicotinonitrile (2 g, 17 mmol) and NBS (3.01 g, 17 mmol) in anhydrous DCE (56 mL) under nitrogen. Add AIBN (277 mg, 1.7 mmol) and heat the mixture at 80°C for 1.5-2 h. Add another batch of AIBN (277 EPO <DP n="77"/>mg, 1.7 mmol) and heat the mixture at 80°C for a further 1-2 h. Then add a third batch of AIBN (277 mg, 1.7 mmol) and heat the mixture at 8O0C for a further 1-2 h. Cool the reaction to room temperature and concentrate in vacuo. Dissolve the residue in DCM, add silica gel and concentrate in vacuo. Purify by chromatography on silica gel (12O g, pre-packed cartridge) eluting with cyclohexane/EtOAc (98:2 to 7:3 gradient over 55 min, 40 mL/min) to isolate the desired intermediate (2 g, 60percent) as a white solid that turns red on standing at room temperature. MS (ES+) m/z: 199 (M+2)+.
52.9% With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane at 85℃; for 20 h; A slurry of 6-methylnicotinonitrile (500 mg, 4.23 mmol), iV-brornosucciniinide (791mg, 4.44 mmol) and AIBN (208 mg, 1.270 mmol) in CC14 (5 mL) was heated at 85°C for 20hours. The mixture was concentrated in vacuo and the residue was purified by flash columnchromatography on silica gel (40 g Si02) eluting with a gradient of 0-40percent EtOAc in hexanesto give the title compound as a light red oil (441 mg, 52.9percent). ‘H NMR (400 MHz, CDC13) ö ppm 4.58 (s, 2 H), 7.60 (dd, J=8.1, 0.8 Hz, 1 H), 7.99 (dd, J=8.1, 2.0 Hz, 1 H), 8.82 - 8.88(m, 1 H); ESI-MS m/z [M+Hj 197, 199.
40% With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 86℃; for 17 h; Step 1: 5-Cyano-2-methylpyridine (1. 025 g, 8.68 mmol) was dissolved in carbon tetrachloride (50 ml). N-bromosuccinimide (1.7 g, 9.54 mmol) and benzoyl peroxide (75percent,140 mg, 0.43 mmol) were added, and the mixture was heated to reflux in a heat block at 86°C. After 17 h, the reaction was filtered, rinsed with DCM and evaporated. The residue was purified by silica gel chromatography (ethyl acetate/hexanes gradient) to give 6- (bromomethyl)pyridine-3-carbonitrile as a brownish oil (0.69 g , 40percent).
37% With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane at 85℃; for 5 h; [0351] Into a 250-mL round-bottom flask, was placed a solution of 6-methylpyridine-3- carbonitrile (8 g, 67.72 mmol, 1.00 equiv) in CC14 (125 mL). N-Bromosuccinimide (13.4 g, 75.29 mmol, 1.10 equiv), and AIBN (480 mg, 2.92 mmol, 0.04 equiv) were added to the reaction solution. The resulting solution was stirred for 5 h at 85°C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 :5) as eluent to yield 5 g (37percent) of 6-(bromomethyl)pyridine-3- carbonitrile as a beige solid.
37% With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane at 85℃; for 5 h; Into a 250-mE round-bottom flask, was placed a solution of 6-methylpyridine-3-carbonitrile (8 g, 67.72 mmol, 1.00 equiv) in CC14 (125 mE). N-l3romosuccinimide (13.4 g, 75.29 mmol, 1.10 equiv), and AII3N (480 mg, 2.92 mmol, 0.04 equiv) were added to the reaction solution. The resulting solution was stirred for 5 h at 85° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5) as eluent to yieldS g (37percent) of 6-(bromomethyl) pyridine-3-carbonitrile as a beige solid.
36% With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In 1,2-dichloro-ethane at 20 - 80℃; for 14 h; 6-(Bromomethyl)nicotinonitrile (I-4)To a stirred solution of 6-methylnicotinonitrile (1.0 g, 8.47 mmol) in 1,2-dichloroethane (30 mL) was added N-bromosuccinimide (NBS; 1.52 g, 8.54 mmol) and followed by 2,2'-azobis(isobutyronitrile) (AIBN; 0.14 g, 0.85 mmol) at RT. The reaction mixture was then heated to 80° C. and stirred for 14 h. After complete consumption of the starting material (by TLC), the reaction mixture was cooled to RT, and the volatiles were removed under reduced pressure to obtain the crude material. Purification by silica gel column chromatography eluting with 10percent EtOAc/Hexane) afforded compound I-4 (0.6 g, 3.05 mmol, 36percent) as a colorless liquid. 1H NMR (500 MHz, CDCl3): δ 7.67-7.62 (m, 2H), 7.21 (dd, J=9.0, 2.0 Hz, 1H), 4.44 (s, 2H).
34.1% With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane at 85℃; for 2 h; Inert atmosphere Compound SM (2.5 g, 21.2 mmol) was dissolved in CCl4 (40 mL) and NBS (3.77 g, 21.2 mmol) and AIBN (347.5 mg, 2.12 mmol) were added with stirring. Under nitrogen, the reaction was carried out at 85 ° C for 2 hours. TLC showed that there was no reaction finished. AIBN (347.5 mg, 2.12 mmol) was added and the reaction was continued at 85 ° C for 2 hours. Cool to room temperature, add H20 (100 mL) and extract with DCM (25 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated and purified (SiO2, PE: EA = 30: 1) to give the title compound (1.42 g, 34.1percent).
40% With N-Bromosuccinimide; azobisisobutyronitrile; nitrogen In tetrachloromethane; ethyl acetate Example 50
Preparation of 6-Bromomethylnicotinonitrile (11-2)
To a solution of 6-Methylnicotinonitrile (11-1) (Lancaster) (15 g, 127 mmol) in carbon tetrachloride (300 ml) was added N-bromosuccinimide (27.12 g, 152.4 mmol).
The resulting solution was degassed and purged with nitrogen and AIBN (2,21-azobisisobutyronitrile) (2.08 g, 12.6 mmol) was added.
After 7 hours at 85° C., another batch of AIBN (1.04 g) was added and stirring was continued for another hour.
After removal of the solvent the crude product was subjected to flash column chromatography in ethylacetate/hexanes to yield 10 g pure material (40percent).
40% With N-Bromosuccinimide; azobisisobutyronitrile; nitrogen In tetrachloromethane; ethyl acetate Example 50
Preparation of 6-Bromomethylnicotinonitrile (11-2)
To a solution of 6-Methylnicotinonitrile (11-1) (Lancaster) (15 g, 127 mmol) in carbon tetrachloride (300 ml) was added N-bromosuccinimide (27.12 g, 152.4 mmol).
The resulting solution was degassed and purged with nitrogen and AIBN (2,2'-azobisisobutyronitrile) (2.08 g, 12.6 mmol) was added.
After 7 hours at 85° C., another batch of AIBN (1.04 g) was added and stirring was continued for another hour.
After removal of the solvent the crude product was subjected to flash column chromatography in ethylacetate/hexanes to yield 10 g pure material (40percent).

References: [1] Patent: WO2007/28083, 2007, A2, . Location in patent: Page/Page column 74-75.
[2] Patent: WO2019/60850, 2019, A1, . Location in patent: Paragraph 0186; 0187.
[3] Inorganic Chemistry, 2014, vol. 53, # 15, p. 7824 - 7836.
[4] Patent: WO2016/201052, 2016, A1, . Location in patent: Page/Page column 265.
[5] Patent: WO2013/102145, 2013, A1, . Location in patent: Paragraph 0351.
[6] Patent: US2015/344483, 2015, A1, . Location in patent: Paragraph 0649; 0650.
[7] Patent: US2012/329788, 2012, A1, . Location in patent: Page/Page column 27.
[8] Patent: CN106831840, 2017, A, . Location in patent: Paragraph 0089; 0090; 0091.
[9] Patent: US2003/186969, 2003, A1, .
[10] Patent: US2002/37857, 2002, A1, .
[11] Patent: US6586405, 2003, B2, .
[12] Journal of Medicinal Chemistry, 2011, vol. 54, # 23, p. 8013 - 8029.
[13] Patent: WO2004/14902, 2004, A2, . Location in patent: Page 65.
 

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