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CAS No. : | 156001-51-3 | MDL No. : | MFCD08061920 |
Formula : | C8H6BrN | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | WNVUTFDOGUGEIS-UHFFFAOYSA-N |
M.W : | 196.04 | Pubchem ID : | 12994004 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.12 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 43.82 |
TPSA : | 23.79 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.58 cm/s |
Log Po/w (iLOGP) : | 2.16 |
Log Po/w (XLOGP3) : | 2.7 |
Log Po/w (WLOGP) : | 2.63 |
Log Po/w (MLOGP) : | 2.52 |
Log Po/w (SILICOS-IT) : | 2.94 |
Consensus Log Po/w : | 2.59 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.2 |
Solubility : | 0.124 mg/ml ; 0.00063 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.85 |
Solubility : | 0.275 mg/ml ; 0.0014 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.73 |
Solubility : | 0.0368 mg/ml ; 0.000188 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.86 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302 | Packing Group: | N/A |
GHS Pictogram: |
* 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 |
---|---|---|
74% | Stage #1: With magnesium In diethyl ether at 20℃; for 2 h; Stage #2: for 4 h; Reflux |
To a suspension of magnesium (1.44 g) in dry Et2O (50 mL) methyl iodide (8.4 g) in dry Et2O (10 mL) was added and the reaction mixture stirred for 2 h at rt. Subsequent addition of 5-bromo-2-methyl-benzonitrile (4 g) was followed by 4 h at reflux before the mixture was quenched with saturated aqueous ammonium chloride solution at 0° C. EtOAc was added. After phase separation the organic layer was dried over sodium sulfate and the solvent removed under reduced pressure. The residual was taken up in ice and concentrated sulfuric acid and stirred for 68 h at rt. The mixture was extracted with EtOAc and the phases separated. The organic layer was washed with water, dried and concentrated under reduced pressure. The crude material was purified by chromatography with Cy/EtOAc 9:1 to furnish the desired product (74percent yield). LC-MS (Method 1): Rt=3.52 min. |
74% | Stage #1: With magnesium In diethyl ether at 20℃; for 2 h; Stage #2: for 4 h; Reflux |
Intermediate 1a): To a suspension of magnesium (1.44 g) in dry Et20 (50 mL) methyl iodide (8.4 g) in dry Et20 (10 mL) was added and the reaction mixture stirred for 2 h at rt. Subsequent addition of 5-bromo-2-methyl-benzonitrile (4 g) was followed by 4 h at reflux before the mixture was quenched with saturated aqueous ammonium chloride solution at 0 °C. EtOAc was added. After phase separation the organic layer was dried over sodium sulfate and the solvent removed under reduced pressure. The residual was taken up in ice and concentrated sulfuric acid and stirred for 68 h at rt. The mixture was extracted with EtOAc and the phases separated. The organic layer was washed with water, dried and concentrated under reduced pressure. The crude material was purified by chromatography with Cy / EtOAc 9:1 to furnish the desired product (74percent yield). LC-MS (Method 1): R, = 3.52 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | Stage #1: With hydrogen bromide In water at 50℃; for 0.333333 h; Stage #2: With sodium nitrite In water at 0 - 5℃; for 0.166667 h; Stage #3: With hydrogen bromide; copper(I) bromide In water for 2 h; Reflux |
Example 22 5-Bromo-2-methylbenzonitrile Water (13.5 mL), HBr (74percent, 14.4 mL) and 5-amino-2-methylbenzonitrile (2.0 g, 15.1 mmol) dissolved in water (24 mL) was added to a flask and heated to 50° C. for 20 min. Then the mixture was cooled to 0~5° C., and a solution of NaNO2 (1.2 g, 17.4 mmol) in water was added. The reaction mixture was stirred for 10 min at 0~5° C., then was warmed to 40° C. A solution of CuBr (6.5 g, 45.1 mmol) in water (36 mL) and HBr (7.2 mL) was added to the mixture, and refluxed for 2 h. The mixture was extracted with AcOEt, and the organic layer was washed by saturated NaHCO3 solution and brine, and dried over Na2SO4. The crude product was purified by flask chromatograph (PE:EA=50:1), obtaining 2.3 g of 5-bromo-2-methylbenzonitrile as a white solid (yield: 77percent). 1H NMR (400 MHz, CDCl3) δ 7.72 (s, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.19 (d, J=8.0 Hz, 1H), 2.51 (s, 3H). |
77% | Stage #1: With hydrogen bromide In water at 50℃; for 0.333333 h; Stage #2: With sodium nitrite In water at 0 - 5℃; Stage #3: With hydrogen bromide; copper(I) bromide In water at 40℃; Reflux |
Example 22 5-Bromo-2-methylbenzonitrile Water (13.5 mL), HBr (74percent, 14.4 mL) and 5-amino-2-methylbenzonitrile (2.0 g, 15.1 mmol) dissolved in water (24 mL) was added to a flask and heated to 50° C. for 20 min. Then the mixture was cooled to 0~5° C., and a solution of NaNO2 (1.2 g, 17.4 mmol) in water was added. The reaction mixture was stirred for 10 min at 0~5° C., then was warmed to 40° C. A solution of CuBr (6.5 g, 45.1 mmol) in water (36 mL) and HBr (7.2 mL) was added to the mixture, and refluxed for 2 h. The mixture was extracted with AcOEt, and the organic layer was washed by saturated NaHCO3 solution and brine, and dried over Na2SO4. The crude product was purified by flask chomatograph (PE:EA=50:1), obtaining 2.3 g of 5-bromo-2-methylbenzonitrile as a white solid (yield: 77percent). 1H NMR (400 MHz, CDCl3) δ 7.72 (s, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.19 (d, J=8.0 Hz, 1H), 2.51 (s, 3H). |
77% | Stage #1: With hydrogen bromide In water for 0.333333 h; Stage #2: With sodium nitrite In water at 0 - 5℃; for 0.166667 h; Stage #3: With hydrogen bromide; copper(I) bromide In water at 40℃; for 2 h; |
Example 25 5-Bromo-2-methylbenzonitrile Keep the solution of 5-amino-2-methylbenzonitrile (2.0 g, 15.1 mmol) dissolved in water (24 mL) and HBr (74percent, 14.4 mL) stirring for 20 min, then the mixture was cooled to 0~5° C., and the solution of NaNO2 (1.2 g, 17.4 mmol) in water (13.5 mL) was added. The reaction mixture was stirred for 10 min at 0~5° C., then was warmed to 40° C. A solution of CuBr (6.5 g, 45.1 mmol) in water (36 mL) and HBr (7.2 mL) was added to the mixture, and it was stirred for 2 h. The mixture was extracted with AcOEt, and the organic layer was washed with saturated NaHCO3 solution, brine, and dried over Na2SO4. The crude product was purified by flask chromatograph (PE:EA=50:1), obtaining 2.3 g of 5-bromo-2-methylbenzonitrile as a white solid (Yield: 77percent). 1H NMR (400 MHz, CDCl3): δ 7.72 (s, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.19 (d, J=8.0 Hz, 1H), 2.51 (s, 3H). |
77% | With sulfuric acid; hydrogen bromide; copper(I) bromide; sodium nitrite In water; acetic acid at 16 - 40℃; for 0.75 h; | Step 3: 5-Bromo-2-methylbenzonitrile: Conc. sulfuric acid (60 mL) is added to sodium nitrite (5.75 g, 83.4 mmol). The temperature rises to 70°C and solution is effected. After cooling to 20-40°C, the above solution is added dropwise to a mechanically stirred solution of 5-amino- 2-methylbenzonitrile (10.0 g, 75.8 mmol) in acetic acid (150 mL). The temperature is maintained at 20-40°C throughout the addition. The reaction mixture is cooled to 16-20°C and a solution of cuprous bromide (24 g, 167 mmol) in conc. hydrobromic acid (150 mL) is added keeping the temperature between 16-20°C. After 45 min, the reaction mixture is poured onto ice (500 g) and the solids are collected by filtration then dissolved in dichloromethane (600 mL), washed with brine, dried, filtered and concentrated to give 5-bromo-2-methylbenzonitrile (see also, Dressler, J. et al. EP 0 594 019) (11.5 g, 77percent) as a brown solid. 1H NMR (CDC13, 8 ppm) : 7.72 (lH, s), 7.60 (1H, dd), 7.20 (1H, dd), 2.50 (3H, s). |
77% | Stage #1: With hydrogen bromide In water at 50℃; for 0.333333 h; Stage #2: With sodium nitrite In water at 0 - 5℃; for 0.166667 h; Stage #3: With copper(I) bromide In water at 40℃; for 2 h; Reflux |
Example 22 5-Bromo-2-methylbenzonitrileWater (13.5 mL), HBr (74percent, 14.4 mL) and 5-amino-2-methylbenzonitrile (2.0 g, 15.1 mmol) dissolved in water (24 mL) was added to a flask and heated to 50° C for for 20 min. Then the mixture was cooled to 0-5 0C, and a solution OfNaNO2 (1.2 g, 17.4 mmol) in water was added. The reaction mixture was stirred for 10 min at 0-5 °C, then was warmed to 40 °C. A solution of CuBr (6.5 g, 45.1 mmol) in water (36 mL) and HBr (7.2 mL) was added to the mixture, and refluxed for 2 h. The mixture was extracted with AcOEt, and the organic layer was washed by saturated NaHCψ3 solution and brine, and dried over Na2SOφ The crude product was purified by flask chomatograph (PE:EA=50: 1), obtaining 2.3 g of 5-bromo-2-methylbenzonitrile as a white solid (yield: 77percent). 1H NMR (400 MHz, CDCl3) δ 7.72 (s, 1 H), 7.59 (d, J=8.0 Hz, 1 H), 7.19 (d, J=8.0 Hz, 1 H), 2.51 (s, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 80℃; for 8 h; Inert atmosphere | [0465] A mixture of 5-bromo-2-methylbenzonitrile (10.0 g, 51.01 mmol), N135 (9.99 g, 56.11 mmol) and benzoylperoxide (0.62 g, 2.6 mmol) in CC14 (100 mE) was stirred at 80° C. for 8 h under N2 atmosphere. The mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by column chromatography on silica gel (0.—Spercent EtOAc in petroleum ether) to afford the title compound (9.8 g, yield 70percent) as a light yellow oil. ‘H NMR (400 MHz, CDC13) ö 7.80 (d, J=2.0 Hz, 1H), 7.72 (dd, J=8.4, 2.0 Hz, 1H), 7.43 (d, J=8.4 Hz, 1H), 4.58 (s, 2H). |
43% | at 60℃; for 16 h; Inert atmosphere | 5-bromo-2-(bromomethyl)benzonitrile To a solution of 5-bromo-2-methylbenzonitrile (10.0 g, 51.0 mmol) in chloroform (150 mL) was added benzoperoxide (1.3 g, 5.07 mmol) and NBS (9.0 g, 50.0 mmol) at room temperature. The resulting solution was stirred for 16 h at 60° C., cooled to room temperature, and treated with water (100 mL). The resulting solution was extracted with ethyl acetate (300 mL*3). The organic phases were combined, washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with ethyl acetate in hexane (0percent to 5percent gradient) to yield 5-bromo-2-(bromomethyl)benzonitrile as purple solid (6.0 g, 43percent). |
38% | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane for 1.25 h; Heating / reflux | Step 4: 5-Bromo-2-bromomethvlbenzonitrile: A mixture of 5-bromo-2-methylbenzonitrile (5.0 g, 25.5 mmol), N-bromosuccinimide (4.54 g, 25.5 mmol), 2',2'-azobis (2- methylpropionitrile) (0.05 g) and carbon tetrachloride (25 mL) is heated at reflux for 75 min. After cooling to room temperature, the solids are removed by filtration. The filtrate is concentrated and the residue purified by chromatography eluting with cyclohexane-20percent ethyl acetate. Product containing fractions are combined and concentrated to afford 5-bromo-2- bromomethylbenzonitrile (2.69 g, 38percent). LC/MS: MS showed no parent molecular ion peak; RT 3.52 min. |