Structure of 22445-42-7
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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. : | 22445-42-7 |
Formula : | C9H9N |
M.W : | 131.17 |
SMILES Code : | C1=C(C=C(C=C1C)C)C#N |
MDL No. : | MFCD00060670 |
InChI Key : | YFKRLZLGVDDKAL-UHFFFAOYSA-N |
Pubchem ID : | 89718 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338 |
Num. heavy atoms | 10 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.22 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 1.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 41.09 |
TPSA ? Topological Polar Surface Area: Calculated from |
23.79 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.09 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.42 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.18 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.1 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.74 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.3 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.62 |
Solubility | 0.313 mg/ml ; 0.00239 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.56 |
Solubility | 0.36 mg/ml ; 0.00274 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.22 |
Solubility | 0.0789 mg/ml ; 0.000601 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 |
-5.38 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 |
2.0 |
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 |
0.0 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) |
1.24 |
* 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 |
---|---|---|
81% | With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 3h;Heating / reflux; UV-irradiation; | 3-(bromomethyl)-5-methylbenzonitrile; To a stirred solution of carbon tetrachloride (270 mL), was added <strong>[22445-42-7]3,5-dimethylbenzonitrile</strong> (37 g, 0.282M), N-bromo succinimide (NBS) (50 g, 0.282 M), and benzoyl peroxide (3.4 g, 14 mmol). The mixture was then refluxed for 3 hr. under a light of 500 W tungsten lamp. After cooling to room temperature, the mixture was filtered, evaporated, and the residue was purified by silica gel column chromatography (eluent, ether:hexane (1:10)) to give 48 g (81%) of 3-(bromomethyl)-5-methylbenzonitrile as a white solid. m.p. 80-81 C. 1H NMR (200 MHz, CDCl3) delta 2.39(3H, s), 4.43 (2H, s), 7.39 (1H, s), 7.43 (1H, s), 7.48 (1H, s). |
48% | With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 3h;Heating / reflux; UV-irradiation; | To a solution of 3,5- dimethylbenzonitrile (25 g, 190 mmol) in carbon tetrachloride (190 mL) was added N-bromosuccinimide (33.9 g, 190 mmol) and benzoyl peroxide (2.28 g, 9.4 mmol). The reaction mixture was refluxed under a UV lamp for 3 h, cooled to room temperature and filtered. The filtrate was concentrated and purified by silica gel chromatography (10% ethyl ether/ hexanes) to give an impure product. The product was crystallized from refluxing ethyl ether (100 mL) and hexanes (400 mL) to give a white solid (19.11 g, 48%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With thionyl chloride;N,N-dimethyl-formamide; In benzene; for 2h;Heating / reflux; | 3,5-dimethylbenzonitrile; 3,5-dimethylbenzamide (50 g, 0.3356M) was suspended in benzene (400 mL). Thionyl chloride (49 mL, 0.671M) and DMF (2 mL) were added and the mixture was refluxed for 2 hr. After cooling to room temperature, the mixture was poured into a crushed ice. After 1 hr., the solution was neutralized by the addition of 6N sodium hydroxide solution. The product was then extracted with ether, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a yellow solid. The crude product was then purified by silica gel column chromatography (eluent, EA:hexane (1:4)) to afford 42 g (95%) of 3,5-dimethylbenzonitrile as a yellow solid. m.p. 51-52 C. 1H NMR (300 MHz, CDCl3) delta 2.34(6H, s), 7.21 (1H, s), 7.26 (2H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In 1,2-dichloro-ethane; at 80℃; for 9h;Inert atmosphere; | 3,5-Bis(bromomethyl)benzonitrile To a solution of <strong>[22445-42-7]3,5-dimethylbenzonitrile</strong> (1.00 g, 7.62 mmol, 1 euiv.) in 1 ,2-dichloroethane (76 ml_), were added A/-bromosuccinimide (2.98 g, 16.8 mmol, 2.2 equiv.) and azobisisobutyronitrile (0.250 g, 1.52 mmol, 0.2 equiv.). The reaction mixture was stirred under an argon atmosphere for 9 h at 80 C. H20 was added to the medium which was extracted three times with CH2CI2. The combined organic layers were washed with brine, dried over Na2S04 and concentrated under reduced pressure. The residue was purified by flash chromatography (25 g BioTage HP Sil cartridge, 2% to 15% EtOAc/Hexane gradient, 20 CV) to yield 3,5-bis(bromomethyl)benzonitrile (0.618 g, 28%) as white crystals. Similar data as described in literature. NMR (CDCI3, 500 MHz) delta 7.64 (s, 1 H), 7.61 (d, 2H, J= 1.2 Hz), 4.45 (s, 4H); HPLC purity: 99%, tR = 2.9 min (Method 1 ). Similar data as described in literature (Easson, M. W.; Fronczek, F. R.; Jensen, T.; Vicente, M. G. H. Bioorg. Med. Chem. 2008, 16, 3191 -3208). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: A solution (50 mL) containing the nitrile (5 mmol), and dichloro(p-cymene)ruthenium(II) dimer (0.05mmol) in 2-propanol (solution was sonicated until the catalyst was solubilized 10-50 min) was pumpedat 4 mL/min through the reactor coil heated at 200 C. The Phoenix backpressure regulator was set tomanual at 30%, which correlated to approximately 100 bar. A 10 mL fraction of the solution obtainedfrom the system in steady state was used to prepare the hydrochloric salt by method A or B dependingon substrate. Yields are reported as isolated hydrochloride salts, unless otherwise stated. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86 - 90%Chromat. | An oven dried screw cap test tube was charged with [NACN] (59 mg, [1.] 20 mmol), dried KI (33 mg, 0.199 mmol, 20 mol%) and Cul (20 mg, 0.105 mmol, 10 mol%), evacuated and backfilled with argon three times. [L-BROMO-3,] 5-dimethylbenzene [(135 PL,] 0.994 mmol), [NN'-DIMETHYLETHYLENEDIAMINE (110 GL,] 1.033 mmol) and anhydrous toluene (650 [RL)] were added under argon. The tube was sealed and the reaction mixture was stirred magnetically at [110 C] for 24 h. The resulting yellow suspension was cooled to room temperature, 2 mL of ethyl acetate, 150 [PL] of n-dodecane as internal standard, 1 [ML] of ammonium hydroxide (30%) and 1 mL of water were added. The mixture was stirred at 25 [C] for 10 min then the organic layer was washed with 1 mL of water and dried over [MGS04.] The GC analysis showed a conversion of 90% with a 86% yield of the title product, calculated vs internal standard.; An oven dried 100 mL three necked round bottom flask was charged, under positive pressure of argon, with [NACN] (2.04 g, 41.6 mmol) Cul (660 mg, 3.47 mmol, 10 mol%), KI (1.14 g, 6.87 mmol, 20 mol%), and anhydrous toluene (25 mL). [N, N'-] Dimethylethylenediamine (3.7 mL, 35 mmol) and 5-bromo-m-xylene (4.7 mL, 35 mmol) were added dropwise under mechanical stirring. The reaction mixture was stirred at 110 [C] for 24 h. The resulting suspension was allowed to reach room temperature, diluted with 30% aq ammonia (20 mL) and extracted with toluene [(2X10] mL). The combined organic phases were dried over [MGS04,] concentrated, and the residue was purified by distillation under reduced pressure (bp 100 [C] [&COMMAT; 10 ] Torr) to provide the desired product as a white crystalline solid (4.08 g, 90% yield). Mp [42-43 C] (lit. 42. [9 C,] See Birch, S. F.; Dean, R. A.; Fidler, F. A.; Lowry, R. A. [J.] [AM.] [CHEM. SOC.] 1949, [71,] [1362). IN] NMR (400 MHz, [CDC13] ; lit. See Nomura, Y.; Takeuchi, Y. [TETRAHEDROII] 1969, [25,] 3825): [8] 7.27 (s, 2H), 7.23 (s, 1H), 2.36 (s, 6H) ; 13C NMR (100 MHz, CDC13) : 139.4, 135.0, 130.1, 119.7, 112.4, 21.5 ; IR (neat, cm-1) : 2230,1605, 1378,907, 854,682. Anal. Calcd. for [C9H9N] : C, 82.41 ; H, 6.92 ; N, 10.68. Found: C, 82.11 ; H, 6.88, N, 10.52. | |
88%Chromat. | An oven dried screw cap test tube was charged with [NACN] (140 mg, 2.857 mmol) dried KI (79 mg, 0.476 mmol, 20 mol%) and Cul (45 mg, 0. [236] mmol, 10 mol%), evacuated and backfilled with argon three times. Anhydrous toluene (1550 [P1), N, N'-] dimethylethylenediamine (255 [UL,] 2.395 mmol), [1-BROMO-3,] 5-dimethyl-benzene [(255] [UL,] 1.877 mmol), and benzyl alcohol (155 [P1,] 1.498 mmol) were added under argon. The tube was sealed and the reaction mixture was stirred magnetically at [110C] for 12 h. The resulting yellow color suspension was cooled to room temperature, 2 mL of ethyl acetate, 250 [UL] of n-dodecane as internal standard, 1 mL of ammonium hydroxide 30% and 1 mL of water were added. The mixture was stirred at [25C] for 10 min then the organic layer was washed with 1 mL of water and dried over [MGS04.] The GC analysis showed a conversion of 91% with a yield of the title product, calculated vs internal standard, of 88%. | |
An oven dried three necked 50 mL round bottom flask was charged with [NACN] (1.127 g, 23 mmol), dried KI (630 mg, 3. [8] mmol, 20 mol%), evacuated and backfilled with argon three times. Anhydrous toluene (10 [ML),] [L-BROMO-3,] 5-dimethylbenzene (2.6 mL, 19 mmol), were added under argon. In a separate oven dried flask, CuI (360 mg, 1.9 mmol, 10 mol%) was mixed under stirring with N, N'-dimethylethylenediamine (2 mL, 19 mmol). The resulting dark-green mixture was diluted with anhydrous toluene (2 mL) and added, under vigorous stirring at [25C,] to the mixture containing aryl bromide. The obtained reaction mixture was magnetically stirred under reflux in an argon atmosphere, at [110 C] for 36 h. The resulting yellow suspension was cooled to room temperature. 50 iL of the mixture were diluted with 0.5 mL of ethyl acetate and treated with 0.5 mL of ammonium hydroxide (30%) and water. The resulting organic layer was washed with 1 mL of water and dried over MgS04. The GC analysis showed essentially complete consumption of the starting material, and formation of the title compound (confirmed by GC-MS). |
An oven dried screw cap test tube was charged with [NACN] (73 mg, [1.] 489 mmol), dried KI (42 mg, 0.253 mmol, 20 mol%) and Cul (24 mg, 0.126 mmol, 10 mol%), evacuated and backfilled with argon three times. [L-BROMO-3,] 5-dimethylbenzene (170 [PL,] 1.251 mmol), [N, N'-DIMETHYLETHYLENEDIAMINE (135, UL,] 1.271 mmol) and anhydrous benzotrifluoride [(825] muL) were added under argon. The tube was sealed and the reaction mixture was stirred magnetically at [102 C FOR] 24 h. The resulting yellow suspension was cooled to room temperature, 2 mL of ethyl acetate, 1 mL of ammonium hydroxide (30%) and 1 mL of water were added. The mixture was stirred at [25 C] for 10 min, then the organic layer was washed with 1 mL of water and dried over [MGS04.] The GC analysis showed complete consumption of the starting material, and formation of the title compound (confirmed by GC-MS). | ||
An oven dried screw cap test tube was charged with [NACN] [(88] mg, 1.796 mmol), dried NaI (44 mg, 0.294 mmol, 20 mol%) and Cul (28 mg, 0.147 mmol, 10 mol%), evacuated and backfilled with argon three times. [L-BROMO-3,] 5-dimethylbenzene [(200, UL,] 1.472 mmol), [N, N'-DIMETHYLETHYLENEDIAMINE (160, UL,] 1.503 mmol) and anhydrous toluene (1 [ML)] were added under argon. The tube was sealed and the reaction mixture was stirred magnetically at [110 C] for 24 h. The resulting yellow suspension was cooled to room temperature, 2 mL of ethyl acetate, 1 mL of ammonium hydroxide (30%) and 1 mL of water were added. The mixture was stirred at [25 C] for 10 min then the organic layer was washed with 1 mL of water and dried over [MGS04.] The GC analysis showed essentially complete consumption of the starting material, and formation of the title compound (confined by GC- MS). |