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Structure of 158626-15-4
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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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 |
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: | Ⅱ |
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 |
36.68 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.66 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.16 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.7 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.62 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.31 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.49 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.17 |
Solubility | 1.33 mg/ml ; 0.00675 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.53 |
Solubility | 5.88 mg/ml ; 0.0298 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.37 |
Solubility | 0.0837 mg/ml ; 0.000425 mol/l |
Class? Solubility class: Log S scale |
Soluble |
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) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
Yes |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.68 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
1.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.91 |
* 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.
Yield | Reaction Conditions | Operation 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). |
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