Structure of 14143-26-1
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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. : | 14143-26-1 |
Formula : | C8H7NO |
M.W : | 133.15 |
SMILES Code : | N#CC1=CC=C(O)C=C1C |
MDL No. : | MFCD16997502 |
InChI Key : | PNQUZYVEQUGPPO-UHFFFAOYSA-N |
Pubchem ID : | 308741 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335-H412 |
Precautionary Statements: | P261-P273-P305+P351+P338 |
Num. heavy atoms | 10 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.12 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 38.15 |
TPSA ? Topological Polar Surface Area: Calculated from |
44.02 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.44 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.98 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.57 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.12 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.78 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.38 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.73 |
Solubility | 2.5 mg/ml ; 0.0188 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.49 |
Solubility | 4.28 mg/ml ; 0.0322 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.26 |
Solubility | 0.73 mg/ml ; 0.00548 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) |
Yes |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.42 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 |
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) |
1.2 |
* 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 |
---|---|---|
96% | With boron dimethyl-trifluoro sulphide; In dichloromethane; at 0 - 20℃; for 16h; | To a dry flask of dichloromethane (34 mL) was added <strong>[21883-13-6]4-methoxy-2-methylbenzonitrile</strong> (14, 1.5 g, 10.2 mmol). Boron trifluoride-dimethyl sulfide complex(10.7 mL, 102 mmol) was then added slowly to the reaction mixture over 5 minutes. The reaction was allowed to stir 16 hours at room temperature. The reaction was quenched by the addition of water, and was allowed to stir for 15 minutes until fuming stopped. The reaction was diluted with EtOAc (~100 mL) and partitioned via separatory funnel. The aqueous layer was extracted 2 more times with EtOAc, then the combined organic extract was washed with water 2x and brine. The organic layer was isolated, dried over MgSO4, vacuum filtered and concentrated in vacuo to a light pink solid (1.305 g, 96% yield over 2 steps). This phenol intermediate was combined with dry DMF (1.7mL) in a flask at room temperature. Imidazole (1.67 g, 24.5 mmol) and TBS-Cl (1.77 g, 11.8 mmol) were added,and the reaction was allowed to stir for 16h. The reaction mixture was thenpoured into diethyl ether and washed 3x with water and 1x with brine. The organic layer was isolated, dried over MgSO4, vacuum filtered, and concentrated in vacuo to a transparent red oil. After further solvent removal via vacuum pump, the resulting oil (2.41g, 96% yield over 2 steps) was carried on without further purification. |
68% | Boron trichloride in dichloromethane (61.2 ml_, 1 M) was added slowly todichloromethane (93 ml.) and cooled to -78 degrees Celsius. To this was added a solution of <strong>[21883-13-6]4-methoxy-2-methylbenzonitrile</strong> (3.00 g, 20.4 mmol) andtetrabutylammonium iodide (7.17 g, 61.2 mmol) in dichloromethane (20 ml_). The reaction mixture was allowed to stir at -78 degrees Celsius for 5 minutes. The reaction mixture was then gradually warmed to room temperature and stirred for 2 hours. An ice slurry was slowly added to quench the reaction. The reaction was allowed to stir for 30 minutes and the layers were separated. The aqueous layer was extracted with dichloromethane (2x) and the combined organic extracts were passed through a phase separated cartridge and concentrated in vacuo. The crude mixture was purified by flash chromatography eluting with 0% to 60% ethyl acetate in pentane to give the target compound as a yellow solid (1.85 g, 68 %). 1 H NMR deuteromethanol delta ppm 7.40 (d, 1 H), 6.80 (s, 1 H), 6.70 (d, 1 H), 2.40 (s, 3H); GCMS (CI method) ES+= 133 [M] AP+ = 133 [M]. | |
36.4% | Boron trichloride (1M in dichloromethane, 747 ml, 747 mmol) was added dropwise, at -78 C., to a suspension of commercially available <strong>[21883-13-6]4-methoxy-2-methyl-benzonitrile</strong> (44 g, 298 mmol) and tetrabutylammonium iodide (121 g, 327 mmol) in dichloromethane (750 ml), under nitrogen, over 40 minutes. Once the addition was complete, the yellow solution was warmed to room temperature and stirred for 16 hours at room temperature. The reaction mixture was then quenched by dropwise addition of water maintaining the internal at temperature below 10 C. The mixture was then filtered through Arbocel, and the layers were separated. The aqueous layers were extracted with dichloromethane (250 ml). The organic layers were combined, washed with a sodium thiosulphate solution, dried over magnesium sulphate, filtered and concentrated under reduced pressure to give a thick yellow oil. Trituration of the oil in dichloromethane, followed by filtration, provided a first crop of the title compound (10.85 g, 27:4%) as a white solid. The filtrate was evaporated and purified by flash chromatography on silica gel, eluting with pentane:ethyl acetate (70:30, by volume) to provide more of the title compound as a white solid (14.44 g, 36.4%). 1H-NMR (400 MHz, CDCl3): delta=2.46 (s, 3H), 6.68 (d, 1H), 6.72 (s, 1H), 7.45 (d, 1H); LRMS: APCl-: m/z 132 [M-H]-. |
36% | Preparation 42 4-Hydroxy-2-methyl benzonitrile Boron trichloride (1M in dichloromethane, 747 ml, 747 mmol) was added dropwise, at -78 C., to a suspension of commercially available <strong>[21883-13-6]4-methoxy-2-methyl-benzonitrile</strong> (44 g, 298 mmol) and tetrabutylammonium iodide (121 g, 327 mmol) in dichloromethane (750 ml), under nitrogen, over 40 minutes. Once the addition was complete, the yellow solution was warmed to room temperature and stirred for 16 hours at room temperature. The reaction mixture was then quenched by dropwise addition of water maintaining the internal temperature below 10 C. The mixture was filtered through Arbocel and the layers were separated. The aqueous layers were extracted again with dichloromethane (250 ml). The organic layers were combined, washed with a sodium thiosulphate solution (150 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure to give thick yellow oil. Trituration of the oil in dichloromethane, followed by filtration, provided a first crop of the title compound (10.8 g, 27%) as a white solid. The filtrate was evaporated and purified by flash chromatography on silica gel, eluding with pentane:ethyl acetate (70:30, by volume) to provide more of the title compound as a white solid (14.4 g, 36%). 1H-NMR (400 MHz, CDCl3): delta=2.46 (s, 3H), 6.68 (d, 1H), 6.72 (s, 1H), 7.45 (d, 1H); LRMS: APCl-: m/z 132 [M-H]-. | |
4-Hydroxy-2-methyl-benzonitrile A solution of <strong>[21883-13-6]4-methoxy-2-methylbenzonitrile</strong> (5.0 g, 33.97 mmol) in DCM (150 mL) is cooled down to 0 C. before adding dropwise a 1M BBr3 in DCM solution (136 mL, 136 mmol). The reaction mixture is allowed to reach rt and stirring is then continued at 45 C. for 5 days. Ice water (500 mL) is then added and the reaction mixture is stirred for 1 h before sat. aq. NaHCO3 (250 mL) is added. The mixture is extracted with DCM (200 mL then 4*100 mL) and the combined org. extracts are dried over MgSO4, filtered and evaporated to give the title compound as a brown solid (4.7 g); LC-MS: tR=0.76 min. 1H NMR (D6-DMSO): delta 2.38 (s, 3H), 6.73 (dd, J=8.5, 2.0 Hz, 1H), 6.79 (d, J=2.0 Hz, 1H), 7.55 (d, J=8.5 Hz, 1H), 10.49 (s, 1H). | ||
A solution of <strong>[21883-13-6]4-methoxy-2-methylbenzonitrile</strong> (5.0 g, 33.97 mmol) in DCM (150 mL) is cooled down to 0 C. before adding dropwise a 1M BBr3 in DCM solution (136 mL, 136 mmol). The reaction mixture is allowed to reach rt and stirring is then continued at 45 C. for 5 days. Ice water (500 mL) is then added and the reaction mixture is stirred for 1 h before sat. aq. NaHCO3 (250 mL) is added. The mixture is extracted with DCM (200 mL then 4×100 mL) and the combined organic extracts are dried over MgSO4, filtered and evaporated to give the title compound as a brown solid (4.7 g); LC-MS: tR=0.76 min. 1H NMR (D6-DMSO): delta 2.38 (s, 3H), 6.73 (dd, J=8.5, 2.0 Hz, 1H), 6.79 (d, J=2.0 Hz, 1H), 7.55 (d, J=8.5 Hz, 1H), 10.49 (s, 1H). | ||
Description for D33 4-Hydroxy-2-methylbenzonitrile (D33)To a solution of 2-methyl-4-(methyloxy)benzo?iotat?le (7 g) in anhydrous DCM (100 mL) was added drapwise BBr3 (51 5 g) at -78 C The resulting mixture was allowed to warm to RT and stirred for 24 hours LCMS indicated the reaction was completed Water was added dropwise slowly to quech the reaction. The mixture was extracted with EA (3x100 mL) and the combined organic layer was washed with brine dried over sodium sulfate, and concentrated to give 5 4 g of 4-hydroxy-2-methylbenzo nitrile (D33) as a white solid. deltaH (DMSO-Cf6, 400MHz). 2.45(3H, s), 6.67(1H1 d), 6 69(1H1 d), 7 51(1H, d), 1043(1H1 s). MS (ES) C8H7NO requires 133, found 134 1 (M+ H+) | ||
With decylthiol; potassium tert-butylate; In N,N-dimethyl-formamide; at 110℃; for 3h; | Decanethiol (261 mg, 1.5 mmol) and t-BuOK (168 mg, 1.5 mmol) were added to a solution of <strong>[21883-13-6]4-methoxy-2-methylbenzonitrile</strong> (147 mg, 1 mmol) in DMF (5 mL). The reaction mixture was stirred at 110 C for 3 h. The mixture was then diluted with water (30 mL) and extracted with EtOAc (10 mL x 3). The extracts were washed with brine (10 mL x 3), dried over Na2SO4, and concentrated under reduced pressure. The resulting residue was purified by silica gel column with (petroleum ether:EtOAc = 10:1) to provide 4-hydroxy-2-methylbenzonitrile (70 mg, yield: 52.6%). LC-MS (011): 134.70 [M+H]+; Rt: 1.44 min, Purity: 80% (254 nm). | |
A solution of <strong>[21883-13-6]4-methoxy-2-methylbenzonitrile</strong> (5.O g, 33.97 mmol) in DCM (15O mL) is cooled down to 00C before adding dropwise a 1IW solution of BBr3 in DCM (136 mL, 136 mmol). The reaction mixture is allowed to reach rt and stirring is then continued at 45C for 5 days. Ice water (500 mL) is then added and the reaction mixture is stirred for 1 h before sat. aq. NaHCO3 (250 mL) is added. The mixture is extracted wit DCM (200 mL then 4 x 100 mL) and the combined org. extracts are dried over MgSO4, filtered and evaporated to give the title compound as a brown solid (4.7 g). LC-MS: tR = 0.76 min. 1H NMR (D6-DMSO): delta 2.38 (s, 3H), 6.73 (dd, J = 8.5, 2.0 Hz, 1 H), 6.79 (d, J = 2.0 Hz, 1 H), 7.55 (d, J = 8.5 Hz, 1 H), 10.49 (s, 1 H). |
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